Douglas College Human Anatomy and Physiology II

01_01ab_Gross_and_Microscopic_Anatomy-1

barkerj1 — Sat, 15 Apr 2017 23:56:00 +0000

01_06_Extreme_Heat

barkerj1 — Sat, 15 Apr 2017 23:56:01 +0000

01_07_Harsh_Conditions

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105_Negative_Feedback_Loops

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H2Ocon

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106_Pregnancy-Positive_Feedback

barkerj1 — Sat, 15 Apr 2017 23:56:05 +0000

201_Elements_of_the_Human_Body-01

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202_Two_Models_of_Atomic_Structure

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203_Periodic_Table-02

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ptable

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204_Isotopes_of_Hydrogen-01

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205_Multi-image_Panel_of_PET_Scan-01

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206_Electron_Shells-01

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electenergy

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207_Ionic_Bonding-01

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208_Covalent_Bonding-01

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209_Polar_Covalent_Bonds_in_a_Water_Molecule

barkerj1 — Sat, 15 Apr 2017 23:56:26 +0000

210_Hydrogen_Bonds_Between_Water_Molecules-01

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213_Dehydration_Synthesis_and_Hydrolysis-01

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214_Dissociation_of_Sodium_Chloride_in_Water-01

barkerj1 — Sat, 15 Apr 2017 23:56:29 +0000

215_Acids_and_Bases-01

barkerj1 — Sat, 15 Apr 2017 23:56:32 +0000

216_pH_Scale-01

barkerj1 — Sat, 15 Apr 2017 23:56:33 +0000

217_Five_Important_Monosaccharides-01

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218_Three_Important_Disaccharides-01

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disaccharide

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219_Three_Important_Polysaccharides-01

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220_Triglycerides-01

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221_Fatty_Acids_Shapes-01

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222_Other_Important_Lipids-01

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223_Structure_of_an_Amino_Acid-01

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224_Peptide_Bond-01

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225_Peptide_Bond-01

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227_Steps_in_an_Enzymatic_Reaction-01

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228_Nucleotides-01

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229_Nucleotides-01

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230_Structure_of_Adenosine_Triphosphate_ATP-01

barkerj1 — Sat, 15 Apr 2017 23:56:54 +0000

0330_Homologous_Pair_of_Chromosomes-1

barkerj1 — Sat, 15 Apr 2017 23:56:54 +0000

0331_Stages_of-_Mitosis_and_Cytokinesis-e1459277007217-1

barkerj1 — Sat, 15 Apr 2017 23:56:55 +0000

0332_Cell_Cycle_With_Cyclins_and_Checkpoints-1

barkerj1 — Sat, 15 Apr 2017 23:56:56 +0000

mitosis-1

barkerj1 — Sat, 15 Apr 2017 23:56:56 +0000

402_Types_of_Cell_Junctions_new

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403_Epithelial_Tissue

barkerj1 — Sat, 15 Apr 2017 23:57:04 +0000

404_Goblet_Cell_new

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404b_Goblet_Cell_new

barkerj1 — Sat, 15 Apr 2017 23:57:09 +0000

goblet_new

barkerj1 — Sat, 15 Apr 2017 23:57:11 +0000

423_Table_04_02_Summary_of_Epithelial_Tissue_CellsN

barkerj1 — Sat, 15 Apr 2017 23:57:13 +0000

etissues

barkerj1 — Sat, 15 Apr 2017 23:57:14 +0000

406_Types_of_Glands

barkerj1 — Sat, 15 Apr 2017 23:57:15 +0000

405_Modes_of_Secretion_by_Glands_updated

barkerj1 — Sat, 15 Apr 2017 23:57:17 +0000

407_Sebaceous_Glands

barkerj1 — Sat, 15 Apr 2017 23:57:19 +0000

1223_Graded_Potentials-02-1

barkerj1 — Sat, 15 Apr 2017 23:57:20 +0000

1224_Post_Synaptic_Potential_Summation-1

barkerj1 — Sat, 15 Apr 2017 23:57:20 +0000

summation-1

barkerj1 — Sat, 15 Apr 2017 23:57:21 +0000

1225_Chemical_Synapse-1

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1226_Receptor_Types-1

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neurotrans-1

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1215_Cell_Membrane_Channels-1

barkerj1 — Sat, 15 Apr 2017 23:57:26 +0000

1216_Ligand-gated_Channels-1

barkerj1 — Sat, 15 Apr 2017 23:57:27 +0000

1217_Mechanically-gated_Channels-02-1

barkerj1 — Sat, 15 Apr 2017 23:57:30 +0000

1218_Voltage-gated_Channels-1

barkerj1 — Sat, 15 Apr 2017 23:57:31 +0000

1219_Leakage_Channels-1

barkerj1 — Sat, 15 Apr 2017 23:57:32 +0000

1220_Resting_Membrane_Potential-1

barkerj1 — Sat, 15 Apr 2017 23:57:33 +0000

1221_Action_Potential-1

barkerj1 — Sat, 15 Apr 2017 23:57:34 +0000

dynamic1-1

barkerj1 — Sat, 15 Apr 2017 23:57:34 +0000

1222_Action_Potential_Labels-1

barkerj1 — Sat, 15 Apr 2017 23:57:36 +0000

neurolab-1

barkerj1 — Sat, 15 Apr 2017 23:57:36 +0000

1201_Overview_of_Nervous_System-1

barkerj1 — Sat, 15 Apr 2017 23:57:38 +0000

1202_White_and_Gray_Matter-1

barkerj1 — Sat, 15 Apr 2017 23:57:39 +0000

1203_Concept_of_NucleusN-1

barkerj1 — Sat, 15 Apr 2017 23:57:40 +0000

1204_Optic_Nerve_vs_Optic_Tract-1

barkerj1 — Sat, 15 Apr 2017 23:57:41 +0000

nobel-1-1

barkerj1 — Sat, 15 Apr 2017 23:57:42 +0000

1205_Somatic_Autonomic_Enteric_StructuresN-1

barkerj1 — Sat, 15 Apr 2017 23:57:43 +0000

troublewstairs-1

barkerj1 — Sat, 15 Apr 2017 23:57:44 +0000

1206_FMRI-1

barkerj1 — Sat, 15 Apr 2017 23:57:45 +0000

1206_The_Neuron-1-1

barkerj1 — Sat, 15 Apr 2017 23:57:46 +0000

nervetissue3-1-1

barkerj1 — Sat, 15 Apr 2017 23:57:47 +0000

1207_Neuron_Shape_Classification-1-1

barkerj1 — Sat, 15 Apr 2017 23:57:48 +0000

1208_Other_Types_of_Neurons-1-1

barkerj1 — Sat, 15 Apr 2017 23:57:49 +0000

1209_Glial_Cells_of_the_CNS-02-1-1

barkerj1 — Sat, 15 Apr 2017 23:57:50 +0000

1210_Glial_Cells_of_the_PNS-1-1

barkerj1 — Sat, 15 Apr 2017 23:57:51 +0000

nervefiber-1-1

barkerj1 — Sat, 15 Apr 2017 23:57:51 +0000

1211_Myelinated_Neuron-1

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1212_Sensory_Neuron_Test_Water-1

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1213_Sensory_Input_Test_Water-1

barkerj1 — Sat, 15 Apr 2017 23:57:55 +0000

1214_Motor_Response_Test_Water-1

barkerj1 — Sat, 15 Apr 2017 23:57:56 +0000

1200_Robotic_Arms-1

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1305_CerebrumN-1

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1306_Lobes_of_Cerebral_CortexN-1

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1307_Brodmann_Areas-1

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1308_Frontal_Section_Basal_Nuclei-1

barkerj1 — Sat, 15 Apr 2017 23:58:01 +0000

1309_Basal_Nuclei_Connections-1

barkerj1 — Sat, 15 Apr 2017 23:58:02 +0000

basalnuclei1-1

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basalnuclei2-1

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1310_Diencephalon-1

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1311_Brain_Stem-1

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1312_CerebellumN-1

barkerj1 — Sat, 15 Apr 2017 23:58:09 +0000

1313_Spinal_Cord_Cross_Section-1

barkerj1 — Sat, 15 Apr 2017 23:58:10 +0000

graymatter-1

barkerj1 — Sat, 15 Apr 2017 23:58:12 +0000

parkinsons-1

barkerj1 — Sat, 15 Apr 2017 23:58:13 +0000

hugebrain-1

barkerj1 — Sat, 15 Apr 2017 23:58:14 +0000

1314_Circle_of_WillisN-1

barkerj1 — Sat, 15 Apr 2017 23:58:16 +0000

bloodflow1-1

barkerj1 — Sat, 15 Apr 2017 23:58:16 +0000

1315_Brain_Sinuses-1

barkerj1 — Sat, 15 Apr 2017 23:58:18 +0000

1316_Meningeal_LayersN-1

barkerj1 — Sat, 15 Apr 2017 23:58:19 +0000

lumbarpuncture-1

barkerj1 — Sat, 15 Apr 2017 23:58:20 +0000

1317_CFS_Circulation-1

barkerj1 — Sat, 15 Apr 2017 23:58:21 +0000

CSFflow-1

barkerj1 — Sat, 15 Apr 2017 23:58:22 +0000

1318b_Dorsal_Root_Ganglion

barkerj1 — Sat, 15 Apr 2017 23:58:24 +0000

1318b_DRG

barkerj1 — Sat, 15 Apr 2017 23:58:25 +0000

spinalroot

barkerj1 — Sat, 15 Apr 2017 23:58:27 +0000

1319_Nerve_Structure

barkerj1 — Sat, 15 Apr 2017 23:58:28 +0000

1319B_Nerve_Mag

barkerj1 — Sat, 15 Apr 2017 23:58:30 +0000

nervetrunk

barkerj1 — Sat, 15 Apr 2017 23:58:31 +0000

1320_The_Cranial_Nerves

barkerj1 — Sat, 15 Apr 2017 23:58:32 +0000

NYTmeningitis

barkerj1 — Sat, 15 Apr 2017 23:58:33 +0000

1321_Spinal_Nerve_Plexuses

barkerj1 — Sat, 15 Apr 2017 23:58:34 +0000

1401_Receptor_Types-1

barkerj1 — Sat, 15 Apr 2017 23:58:35 +0000

1402_The_Tongue-1

barkerj1 — Sat, 15 Apr 2017 23:58:37 +0000

DanielleReed-1

barkerj1 — Sat, 15 Apr 2017 23:58:39 +0000

1403_Olfaction-1

barkerj1 — Sat, 15 Apr 2017 23:58:41 +0000

1404_The_Structures_of_the_Ear-1

barkerj1 — Sat, 15 Apr 2017 23:58:43 +0000

1405_Sound_Waves_and_the_Ear-1

barkerj1 — Sat, 15 Apr 2017 23:58:45 +0000

1406_Cochlea-1

barkerj1 — Sat, 15 Apr 2017 23:58:47 +0000

1407_The_Hair_Cell-1

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1427_Cochlea_Micrograph-1

barkerj1 — Sat, 15 Apr 2017 23:58:50 +0000

cochleaMG-1

barkerj1 — Sat, 15 Apr 2017 23:58:51 +0000

1408_Frequency_Coding_in_The_Cochlea-1

barkerj1 — Sat, 15 Apr 2017 23:58:52 +0000

ear1-1

barkerj1 — Sat, 15 Apr 2017 23:58:54 +0000

ear2-1

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1409_Maculae_and_Equilibrium-1

barkerj1 — Sat, 15 Apr 2017 23:58:56 +0000

1410_Equilibrium_and_Semicircular_Canals-1

barkerj1 — Sat, 15 Apr 2017 23:58:58 +0000

1411_Eye_in_The_Orbit-1

barkerj1 — Sat, 15 Apr 2017 23:58:59 +0000

1412_Extraocular_Muscles-1

barkerj1 — Sat, 15 Apr 2017 23:59:01 +0000

1413_Structure_of_the_Eye-1

barkerj1 — Sat, 15 Apr 2017 23:59:02 +0000

1414_Rods_and_Cones-1

barkerj1 — Sat, 15 Apr 2017 23:59:04 +0000

1415_Retinal_Isomers-1

barkerj1 — Sat, 15 Apr 2017 23:59:06 +0000

1416_Color_Sensitivity-1

barkerj1 — Sat, 15 Apr 2017 23:59:08 +0000

occipital-1

barkerj1 — Sat, 15 Apr 2017 23:59:08 +0000

1417_Ascending_Pathways_of_Spinal_Cord

barkerj1 — Sat, 15 Apr 2017 23:59:10 +0000

1418_Auditory_Brainstem_Mechanisms

barkerj1 — Sat, 15 Apr 2017 23:59:13 +0000

1419_Vestibulo-Ocular_Reflex

barkerj1 — Sat, 15 Apr 2017 23:59:15 +0000

1420_Optical_Fields

barkerj1 — Sat, 15 Apr 2017 23:59:17 +0000

1421_Sensory_Homunculus

barkerj1 — Sat, 15 Apr 2017 23:59:18 +0000

1422_Topographical_Image_on_Retina

barkerj1 — Sat, 15 Apr 2017 23:59:20 +0000

l_3-D1

barkerj1 — Sat, 15 Apr 2017 23:59:21 +0000

1423_Retinal_Disparity

barkerj1 — Sat, 15 Apr 2017 23:59:23 +0000

1424_Visual_Streams

barkerj1 — Sat, 15 Apr 2017 23:59:25 +0000

faces

barkerj1 — Sat, 15 Apr 2017 23:59:26 +0000

1425_Phineas_Gage

barkerj1 — Sat, 15 Apr 2017 23:59:28 +0000

Phineas_gage_-_1868_skull_diagram

barkerj1 — Sat, 15 Apr 2017 23:59:29 +0000

1426_Corticospinal_Pathway

barkerj1 — Sat, 15 Apr 2017 23:59:29 +0000

motorpathway

barkerj1 — Sat, 15 Apr 2017 23:59:31 +0000

NYTmotor

barkerj1 — Sat, 15 Apr 2017 23:59:32 +0000

reflexarc

barkerj1 — Sat, 15 Apr 2017 23:59:33 +0000

newreflex

barkerj1 — Sat, 15 Apr 2017 23:59:35 +0000

fightflight-1

barkerj1 — Sat, 15 Apr 2017 23:59:37 +0000

1501_Connections_of_the_Sympathetic_Nervous_System-1

barkerj1 — Sat, 15 Apr 2017 23:59:38 +0000

1502_Symphatetic_Connections_and_the_Ganglia-1

barkerj1 — Sat, 15 Apr 2017 23:59:40 +0000

1503_Connections_of_the_Parasympathetic_Nervous_System-1

barkerj1 — Sat, 15 Apr 2017 23:59:43 +0000

1504_Autonomic_Varicosities-1

barkerj1 — Sat, 15 Apr 2017 23:59:45 +0000

nervsystem-1

barkerj1 — Sat, 15 Apr 2017 23:59:46 +0000

1505_Comparison_of_Somatic_and_Visceral_Reflexes

barkerj1 — Sat, 15 Apr 2017 23:59:48 +0000

1506_Referred_Pain_Chart

barkerj1 — Sat, 15 Apr 2017 23:59:50 +0000

1507_Short_and_Long_Reflexes

barkerj1 — Sat, 15 Apr 2017 23:59:52 +0000

strokespell

barkerj1 — Sat, 15 Apr 2017 23:59:54 +0000

1508_Autonomic_Control_of_Pupil_Size

barkerj1 — Sat, 15 Apr 2017 23:59:56 +0000

pupillary

barkerj1 — Sat, 15 Apr 2017 23:59:57 +0000

1509_Pupillary_Reflex_Pathways

barkerj1 — Sat, 15 Apr 2017 23:59:59 +0000

1510_Fiber_Tracts_of_the_Central_Autonomic_System

barkerj1 — Sun, 16 Apr 2017 00:00:01 +0000

1511_The_Limbic_Lobe

barkerj1 — Sun, 16 Apr 2017 00:00:03 +0000

emotions

barkerj1 — Sun, 16 Apr 2017 00:00:05 +0000

hormonebind-1

barkerj1 — Sun, 16 Apr 2017 00:00:06 +0000

1801_The_Endocrine_System

barkerj1 — Sun, 16 Apr 2017 00:00:08 +0000

1802_Examples_of_Amine_Peptide_Protein_and_Steroid_Hormone_Structure-1

barkerj1 — Sun, 16 Apr 2017 00:00:09 +0000

1803_Binding_of_Lipid-Soluble_Hormones-1

barkerj1 — Sun, 16 Apr 2017 00:00:11 +0000

1804_Binding_of_Water-Soluble_Hormones-1

barkerj1 — Sun, 16 Apr 2017 00:00:12 +0000

1805_Negative_Feedback_Loop-1

barkerj1 — Sun, 16 Apr 2017 00:00:14 +0000

1806_The_Hypothalamus-Pituitary_Complex-1

barkerj1 — Sun, 16 Apr 2017 00:00:15 +0000

1807_The_Posterior_Pituitary_Complex-1

barkerj1 — Sun, 16 Apr 2017 00:00:17 +0000

1808_The_Anterior_Pituitary_Complex-1

barkerj1 — Sun, 16 Apr 2017 00:00:18 +0000

1809_Hormonal_Regulation_of_Growth-1

barkerj1 — Sun, 16 Apr 2017 00:00:20 +0000

1810_Major_Pituitary_Hormones-1

barkerj1 — Sun, 16 Apr 2017 00:00:22 +0000

roleofhypo-1

barkerj1 — Sun, 16 Apr 2017 00:00:23 +0000

1811_The_Thyroid_Gland-1

barkerj1 — Sun, 16 Apr 2017 00:00:25 +0000

1813_A_Classic_Negative_Feedback_Loop-1

barkerj1 — Sun, 16 Apr 2017 00:00:26 +0000

1823_Goiter-1

barkerj1 — Sun, 16 Apr 2017 00:00:29 +0000

1814_The_Parathyroid_Glands-1

barkerj1 — Sun, 16 Apr 2017 00:00:30 +0000

parathyroid-1

barkerj1 — Sun, 16 Apr 2017 00:00:31 +0000

1817_The_Role_of_Parathyroid_Hormone_in_Maintaining_Blood_Calcium_Homeostasis-1

barkerj1 — Sun, 16 Apr 2017 00:00:33 +0000

1818_The_Adrenal_Glands-1

barkerj1 — Sun, 16 Apr 2017 00:00:34 +0000

adrenal-1

barkerj1 — Sun, 16 Apr 2017 00:00:35 +0000

adrenalglands-1

barkerj1 — Sun, 16 Apr 2017 00:00:36 +0000

melatonin-1

barkerj1 — Sun, 16 Apr 2017 00:00:38 +0000

1820_The_Pancreas-1

barkerj1 — Sun, 16 Apr 2017 00:00:40 +0000

pancreaticislet-1

barkerj1 — Sun, 16 Apr 2017 00:00:40 +0000

1822_The_Homostatic_Regulation_of_Blood_Glucose_Levels-1

barkerj1 — Sun, 16 Apr 2017 00:00:42 +0000

pancreas1-1

barkerj1 — Sun, 16 Apr 2017 00:00:44 +0000

insulin-1

barkerj1 — Sun, 16 Apr 2017 00:00:45 +0000

2318_Partial_and_Total_Pressure_of_a_Gas

barkerj1 — Sun, 16 Apr 2017 00:00:47 +0000

2319_Fig_23.19

barkerj1 — Sun, 16 Apr 2017 00:00:48 +0000

2320_Fig_23.20_NEW_KGX

barkerj1 — Sun, 16 Apr 2017 00:00:50 +0000

2332_Hyperbaric_Chamber

barkerj1 — Sun, 16 Apr 2017 00:00:54 +0000

2322_Fig_23.22-a

barkerj1 — Sun, 16 Apr 2017 00:00:56 +0000

2323_Oxygen-hemoglobin_Dissociation-a

barkerj1 — Sun, 16 Apr 2017 00:00:57 +0000

2323_Oxygen-hemoglobin_Dissociation-b

barkerj1 — Sun, 16 Apr 2017 00:00:59 +0000

2323_Oxygen-hemoglobin_Dissociation-c

barkerj1 — Sun, 16 Apr 2017 00:01:00 +0000

2324_Oxygen-hemoglobin_Dissociation_Fetus_Adult

barkerj1 — Sun, 16 Apr 2017 00:01:01 +0000

2325_Carbon_Dioxide_Transport

barkerj1 — Sun, 16 Apr 2017 00:01:03 +0000

oxyblood

barkerj1 — Sun, 16 Apr 2017 00:01:04 +0000

2328_Development_of_Lower_Respiratory_SystemN

barkerj1 — Sun, 16 Apr 2017 00:01:06 +0000

2139_Fetal_Circulation

barkerj1 — Sun, 16 Apr 2017 00:01:08 +0000

2400_Women_Eating_Apples-1

barkerj1 — Sun, 16 Apr 2017 00:01:11 +0000

2401_Components_of_the_Digestive_System-1

barkerj1 — Sun, 16 Apr 2017 00:01:12 +0000

2402_Layers_of_the_Gastrointestinal_Tract-1

barkerj1 — Sun, 16 Apr 2017 00:01:14 +0000

2403_The_PeritoneumN-1

barkerj1 — Sun, 16 Apr 2017 00:01:15 +0000

fooddigestion-1

barkerj1 — Sun, 16 Apr 2017 00:01:15 +0000

fooddigestion2-1

barkerj1 — Sun, 16 Apr 2017 00:01:17 +0000

2404_PeristalsisN-1

barkerj1 — Sun, 16 Apr 2017 00:01:18 +0000

2405_Digestive_Process-1

barkerj1 — Sun, 16 Apr 2017 00:01:19 +0000

2406_Structures_of_the_Mouth-1

barkerj1 — Sun, 16 Apr 2017 00:01:20 +0000

2407_Tongue-1

barkerj1 — Sun, 16 Apr 2017 00:01:21 +0000

2408_Salivary_Glands-1

barkerj1 — Sun, 16 Apr 2017 00:01:22 +0000

2410_Permanent_and_Deciduous_TeethN-1

barkerj1 — Sun, 16 Apr 2017 00:01:23 +0000

2409_Tooth-1

barkerj1 — Sun, 16 Apr 2017 00:01:23 +0000

2411_Pharynx-1

barkerj1 — Sun, 16 Apr 2017 00:01:24 +0000

2412_The_Esophagus-1

barkerj1 — Sun, 16 Apr 2017 00:01:25 +0000

2413_DeglutitionN-1

barkerj1 — Sun, 16 Apr 2017 00:01:26 +0000

swallowing-1

barkerj1 — Sun, 16 Apr 2017 00:01:26 +0000

2414_Stomach-1

barkerj1 — Sun, 16 Apr 2017 00:01:28 +0000

2415_Histology_of_StomachN-1

barkerj1 — Sun, 16 Apr 2017 00:01:29 +0000

stomach1-1

barkerj1 — Sun, 16 Apr 2017 00:01:30 +0000

2416_Three_Phases_Gastric_Secretion-1

barkerj1 — Sun, 16 Apr 2017 00:01:32 +0000

2417_Small_IntestineN-1

barkerj1 — Sun, 16 Apr 2017 00:01:33 +0000

2418_Histology_Small_IntestinesN-1

barkerj1 — Sun, 16 Apr 2017 00:01:34 +0000

sintestine-1

barkerj1 — Sun, 16 Apr 2017 00:01:35 +0000

2419_Segmentation-1

barkerj1 — Sun, 16 Apr 2017 00:01:36 +0000

2420_Large_Intestine-1

barkerj1 — Sun, 16 Apr 2017 00:01:37 +0000

2421_Histology_of_the_Large_IntestineN-1

barkerj1 — Sun, 16 Apr 2017 00:01:38 +0000

2433_Teniae_Coli_Haustra_Epiploic_Appendage-1

barkerj1 — Sun, 16 Apr 2017 00:01:39 +0000

foodgroups-1

barkerj1 — Sun, 16 Apr 2017 00:01:40 +0000

2422_Accessory_Organs-1

barkerj1 — Sun, 16 Apr 2017 00:01:41 +0000

2423_Microscopic_Anatomy_of_Liver-1

barkerj1 — Sun, 16 Apr 2017 00:01:42 +0000

liver-1

barkerj1 — Sun, 16 Apr 2017 00:01:43 +0000

2424_Exocrine_and_Endocrine_Pancreas-1

barkerj1 — Sun, 16 Apr 2017 00:01:44 +0000

2425_Gallbladder-1

barkerj1 — Sun, 16 Apr 2017 00:01:45 +0000

2426_Mechanical_and_Chemical_DigestionN-1

barkerj1 — Sun, 16 Apr 2017 00:01:46 +0000

2427_Carbon_Digestion-1

barkerj1 — Sun, 16 Apr 2017 00:01:47 +0000

2429_Digestion_of_Proteins_Physiology-1

barkerj1 — Sun, 16 Apr 2017 00:01:48 +0000

2428_Digestion_of_Proteins-1

barkerj1 — Sun, 16 Apr 2017 00:01:48 +0000

2430_Digestive_Secretions_Absorption_of_WaterN-1

barkerj1 — Sun, 16 Apr 2017 00:01:49 +0000

2431_Lipid_Absorption-1

barkerj1 — Sun, 16 Apr 2017 00:01:50 +0000

2501_The_Structure_of_ATP_Molecules-1

barkerj1 — Sun, 16 Apr 2017 00:01:51 +0000

2502_Catabolic_Reactions-1

barkerj1 — Sun, 16 Apr 2017 00:01:53 +0000

2503_Cellular_Respiration-1

barkerj1 — Sun, 16 Apr 2017 00:01:54 +0000

2504_Glycosis_Overview-1

barkerj1 — Sun, 16 Apr 2017 00:01:56 +0000

glycolysis1-1

barkerj1 — Sun, 16 Apr 2017 00:01:58 +0000

2505_Aerobic_Versus_Anaerobic_Respiration-1

barkerj1 — Sun, 16 Apr 2017 00:02:00 +0000

2507_The_Krebs_Cycle-1

barkerj1 — Sun, 16 Apr 2017 00:02:03 +0000

krebscycle-1

barkerj1 — Sun, 16 Apr 2017 00:02:05 +0000

2508_The_Electron_Transport_Chain-1

barkerj1 — Sun, 16 Apr 2017 00:02:07 +0000

ETchain-1

barkerj1 — Sun, 16 Apr 2017 00:02:08 +0000

2509_Carbohydrate_Metabolism-1

barkerj1 — Sun, 16 Apr 2017 00:02:10 +0000

2510_Gluconeogenesis-1

barkerj1 — Sun, 16 Apr 2017 00:02:13 +0000

2511_A_Triglyceride_Molecule_a_Is_Broken_Down_Into_Monoglycerides_b-1

barkerj1 — Sun, 16 Apr 2017 00:02:15 +0000

2512_Chylomicrons_Contain_Triglycerides_Cholesterol_Molecules_and_Other_Lipids-1

barkerj1 — Sun, 16 Apr 2017 00:02:17 +0000

2513_The_Breakdown_of_Fatty_Acids-1

barkerj1 — Sun, 16 Apr 2017 00:02:19 +0000

2514_Ketogenesis-1

barkerj1 — Sun, 16 Apr 2017 00:02:22 +0000

2515_Ketone_Oxidation-1

barkerj1 — Sun, 16 Apr 2017 00:02:23 +0000

2516_Lipid_Metabolism-1

barkerj1 — Sun, 16 Apr 2017 00:02:25 +0000

2517_Protein-Digesting_EnzymesN-1

barkerj1 — Sun, 16 Apr 2017 00:02:27 +0000

2518_Urea_Cycle-1

barkerj1 — Sun, 16 Apr 2017 00:02:29 +0000

2519_Energy_From_Amino_Acids-1

barkerj1 — Sun, 16 Apr 2017 00:02:32 +0000

2520_Catabolic_and_Anabolic-Pathways-815x1024-1

barkerj1 — Sun, 16 Apr 2017 00:02:34 +0000

2521_The_Absorptive_Stage-1

barkerj1 — Sun, 16 Apr 2017 00:02:36 +0000

2522_The_Postabsorptive_Stage-1

barkerj1 — Sun, 16 Apr 2017 00:02:39 +0000

2524_MyPlate-1

barkerj1 — Sun, 16 Apr 2017 00:02:41 +0000

2601_Urine_Color_Chart-1

barkerj1 — Sun, 16 Apr 2017 00:02:42 +0000

Female_and_Male_Urethra-1

barkerj1 — Sun, 16 Apr 2017 00:02:43 +0000

2605_The_Bladder-1

barkerj1 — Sun, 16 Apr 2017 00:02:45 +0000

bladderMG-1

barkerj1 — Sun, 16 Apr 2017 00:02:46 +0000

2604_Nerves_Innervating_the_Urinary_SystemN-1

barkerj1 — Sun, 16 Apr 2017 00:02:48 +0000

2607_Ureter-1

barkerj1 — Sun, 16 Apr 2017 00:02:50 +0000

TED-1

barkerj1 — Sun, 16 Apr 2017 00:02:51 +0000

2608_Kidney_Position_in_Abdomen-1

barkerj1 — Sun, 16 Apr 2017 00:02:53 +0000

2610_The_Kidney-1

barkerj1 — Sun, 16 Apr 2017 00:02:55 +0000

2612_Blood_Flow_in_the_Kidneys-1

barkerj1 — Sun, 16 Apr 2017 00:02:56 +0000

2611_Blood_Flow_in_the_Nephron-1

barkerj1 — Sun, 16 Apr 2017 00:02:58 +0000

bloodflow5-1

barkerj1 — Sun, 16 Apr 2017 00:03:00 +0000

2613_Podocytes-1

barkerj1 — Sun, 16 Apr 2017 00:03:02 +0000

2614_Fenestrated_Capillary-1

barkerj1 — Sun, 16 Apr 2017 00:03:03 +0000

Juxtaglomerular_Apparatus_and_Glomerulus-1

barkerj1 — Sun, 16 Apr 2017 00:03:04 +0000

2626_Renin_Aldosterone_Angiotensin-1

barkerj1 — Sun, 16 Apr 2017 00:03:06 +0000

2625_Aquaporin_-Water_Channel-1024x515-1

barkerj1 — Sun, 16 Apr 2017 00:03:08 +0000

2617_Net_Filtration_PressureN-1

barkerj1 — Sun, 16 Apr 2017 00:03:08 +0000

2618_Nephron_Secretion_Reabsorption-1

barkerj1 — Sun, 16 Apr 2017 00:03:10 +0000

2619_Substances_Reabsorbed_And_Secreted_By_The_PCT-1

barkerj1 — Sun, 16 Apr 2017 00:03:12 +0000

2620_Reabsorption_of_Bicarbonate_from_the_PCT-1

barkerj1 — Sun, 16 Apr 2017 00:03:14 +0000

2621_Loop_of_Henle_Countercurrent_Multiplier_System-1

barkerj1 — Sun, 16 Apr 2017 00:03:15 +0000

multiplier-1

barkerj1 — Sun, 16 Apr 2017 00:03:17 +0000

2701_Water_Content_in_the_Body-01-1

barkerj1 — Sun, 16 Apr 2017 00:03:18 +0000

2702_Fluid_Compartments_ICF_ECF-1

barkerj1 — Sun, 16 Apr 2017 00:03:20 +0000

2703_Distribution_of_Water_in_the_Human_Body_in_Terms_of_ICF_and_ECF_Pie_Chart-1

barkerj1 — Sun, 16 Apr 2017 00:03:21 +0000

2704_Concentration_of_Elements_in_Body_Fluids-1

barkerj1 — Sun, 16 Apr 2017 00:03:21 +0000

bodyfluids-1

barkerj1 — Sun, 16 Apr 2017 00:03:22 +0000

2705_Sodium_Potassium_Pump-1

barkerj1 — Sun, 16 Apr 2017 00:03:23 +0000

2108_Capillary_Exchange-1

barkerj1 — Sun, 16 Apr 2017 00:03:24 +0000

dynamicfluid-1

barkerj1 — Sun, 16 Apr 2017 00:03:25 +0000

2706_Facilitated_Diffusion-1

barkerj1 — Sun, 16 Apr 2017 00:03:26 +0000

2707_Edema_of_Right_Hand_Due_to_Allergic_Reaction-1

barkerj1 — Sun, 16 Apr 2017 00:03:27 +0000

2708_Flowchart_of_Thirst_Response-01-1

barkerj1 — Sun, 16 Apr 2017 00:03:28 +0000

2709_ADH-1

barkerj1 — Sun, 16 Apr 2017 00:03:30 +0000

2710_Aquaporins-01-1

barkerj1 — Sun, 16 Apr 2017 00:03:31 +0000

saltwater-1

barkerj1 — Sun, 16 Apr 2017 00:03:32 +0000

2711_Aldosterone_Feedback_Loop-01-1

barkerj1 — Sun, 16 Apr 2017 00:03:33 +0000

2712_Renin_Angiotensin_System-01-1

barkerj1 — Sun, 16 Apr 2017 00:03:35 +0000

2713_pH_Scale-01-1

barkerj1 — Sun, 16 Apr 2017 00:03:37 +0000

2714_Respiratory_Regulation_of_Blood-1

barkerj1 — Sun, 16 Apr 2017 00:03:38 +0000

2715_Conservation_of_Bicarbonate_in_Kidney-01-1

barkerj1 — Sun, 16 Apr 2017 00:03:39 +0000

2716_Symptoms_of_Acidosis_Alkalosis-1

barkerj1 — Sun, 16 Apr 2017 00:03:40 +0000

altitude-1

barkerj1 — Sun, 16 Apr 2017 00:03:41 +0000

Figure_28_01_01-1

barkerj1 — Sun, 16 Apr 2017 00:03:42 +0000

Figure_28_01_02-1

barkerj1 — Sun, 16 Apr 2017 00:03:43 +0000

Figure_28_01_03-1

barkerj1 — Sun, 16 Apr 2017 00:03:44 +0000

Figure_28_01_04-1

barkerj1 — Sun, 16 Apr 2017 00:03:45 +0000

Figure_28_01_05-1

barkerj1 — Sun, 16 Apr 2017 00:03:45 +0000

vasectomy-1

barkerj1 — Sun, 16 Apr 2017 00:03:46 +0000

spermpath-1

barkerj1 — Sun, 16 Apr 2017 00:03:47 +0000

Figure_28_01_06-1

barkerj1 — Sun, 16 Apr 2017 00:03:49 +0000

Figure_28_01_07-1

barkerj1 — Sun, 16 Apr 2017 00:03:50 +0000

Figure_28_02_01-1

barkerj1 — Sun, 16 Apr 2017 00:03:51 +0000

Figure_28_02_02-1

barkerj1 — Sun, 16 Apr 2017 00:03:51 +0000

Figure_28_02_03-1

barkerj1 — Sun, 16 Apr 2017 00:03:52 +0000

Figure_28_02_04-1

barkerj1 — Sun, 16 Apr 2017 00:03:53 +0000

Figure_28_02_05-1

barkerj1 — Sun, 16 Apr 2017 00:03:53 +0000

ovulation-1

barkerj1 — Sun, 16 Apr 2017 00:03:54 +0000

Figure_28_02_06-1

barkerj1 — Sun, 16 Apr 2017 00:03:56 +0000

oocyte-1

barkerj1 — Sun, 16 Apr 2017 00:03:56 +0000

Figure_28_02_07-1

barkerj1 — Sun, 16 Apr 2017 00:03:58 +0000

Figure_28_02_08-1

barkerj1 — Sun, 16 Apr 2017 00:03:59 +0000

Figure_28_02_09-1

barkerj1 — Sun, 16 Apr 2017 00:03:59 +0000

2901_Sperm_Fertilization

barkerj1 — Sun, 16 Apr 2017 00:04:01 +0000

2902_IVF-02

barkerj1 — Sun, 16 Apr 2017 00:04:03 +0000

fertilization

barkerj1 — Sun, 16 Apr 2017 00:04:04 +0000

2903_Preembryonic_Cleavages-02

barkerj1 — Sun, 16 Apr 2017 00:04:06 +0000

conceptus

barkerj1 — Sun, 16 Apr 2017 00:04:07 +0000

2904_Preembryonic_Development-02

barkerj1 — Sun, 16 Apr 2017 00:04:09 +0000

2905_Implantation

barkerj1 — Sun, 16 Apr 2017 00:04:12 +0000

2906_Placenta_Previa-02

barkerj1 — Sun, 16 Apr 2017 00:04:14 +0000

2907_Embroyonic_Disc_Amniotic_Cavity_Yolk_Sac-02

barkerj1 — Sun, 16 Apr 2017 00:04:15 +0000

2908_Germ_Layers-02

barkerj1 — Sun, 16 Apr 2017 00:04:17 +0000

2909_Embryo_Week_3-02

barkerj1 — Sun, 16 Apr 2017 00:04:19 +0000

2910_The_Placenta-02

barkerj1 — Sun, 16 Apr 2017 00:04:21 +0000

2911_Photo_of_Placenta-02

barkerj1 — Sun, 16 Apr 2017 00:04:22 +0000

2912_Neurulation-02

barkerj1 — Sun, 16 Apr 2017 00:04:24 +0000

2913_Embryonic_Folding

barkerj1 — Sun, 16 Apr 2017 00:04:27 +0000

2914_Photo_of_Embryo-02

barkerj1 — Sun, 16 Apr 2017 00:04:29 +0000

embryogenesis

barkerj1 — Sun, 16 Apr 2017 00:04:30 +0000

2915_Sexual_Differentation-02

barkerj1 — Sun, 16 Apr 2017 00:04:32 +0000

2916_Fetal_Circulatory_System-02

barkerj1 — Sun, 16 Apr 2017 00:04:34 +0000

pregstages

barkerj1 — Sun, 16 Apr 2017 00:04:36 +0000

2901_Sperm_Fertilization-1

barkerj1 — Sun, 16 Apr 2017 00:04:38 +0000

2902_IVF-02-1

barkerj1 — Sun, 16 Apr 2017 00:04:40 +0000

fertilization-1

barkerj1 — Sun, 16 Apr 2017 00:04:42 +0000

2903_Preembryonic_Cleavages-02-2

barkerj1 — Sun, 16 Apr 2017 00:04:43 +0000

conceptus-2

barkerj1 — Sun, 16 Apr 2017 00:04:45 +0000

2904_Preembryonic_Development-02-2

barkerj1 — Sun, 16 Apr 2017 00:04:49 +0000

2905_Implantation-2

barkerj1 — Sun, 16 Apr 2017 00:04:51 +0000

2906_Placenta_Previa-02-2

barkerj1 — Sun, 16 Apr 2017 00:04:53 +0000

2907_Embroyonic_Disc_Amniotic_Cavity_Yolk_Sac-02-2

barkerj1 — Sun, 16 Apr 2017 00:04:55 +0000

2908_Germ_Layers-02-2

barkerj1 — Sun, 16 Apr 2017 00:04:57 +0000

2909_Embryo_Week_3-02-2

barkerj1 — Sun, 16 Apr 2017 00:04:59 +0000

2910_The_Placenta-02-2

barkerj1 — Sun, 16 Apr 2017 00:05:00 +0000

2911_Photo_of_Placenta-02-2

barkerj1 — Sun, 16 Apr 2017 00:05:02 +0000

2912_Neurulation-02-1

barkerj1 — Sun, 16 Apr 2017 00:05:04 +0000

2913_Embryonic_Folding-1

barkerj1 — Sun, 16 Apr 2017 00:05:07 +0000

2914_Photo_of_Embryo-02-1

barkerj1 — Sun, 16 Apr 2017 00:05:09 +0000

embryogenesis-1

barkerj1 — Sun, 16 Apr 2017 00:05:10 +0000

2915_Sexual_Differentation-02-1

barkerj1 — Sun, 16 Apr 2017 00:05:12 +0000

2916_Fetal_Circulatory_System-02-1

barkerj1 — Sun, 16 Apr 2017 00:05:14 +0000

pregstages-1

barkerj1 — Sun, 16 Apr 2017 00:05:16 +0000

2917_Size_of_Uterus_Throughout_Pregnancy-02

barkerj1 — Sun, 16 Apr 2017 00:05:18 +0000

2918_Photo_of_Linea_Nigra

barkerj1 — Sun, 16 Apr 2017 00:05:20 +0000

2919_Hormones_Initiating_Labor-02

barkerj1 — Sun, 16 Apr 2017 00:05:21 +0000

2920_Stages_of_Childbirth-02

barkerj1 — Sun, 16 Apr 2017 00:05:23 +0000

2921_Neonatal_Circulatory_System

barkerj1 — Sun, 16 Apr 2017 00:05:26 +0000

2922_Let_Down_Reflex-new

barkerj1 — Sun, 16 Apr 2017 00:05:28 +0000

2923_Male_Chromosomes-1

barkerj1 — Sun, 16 Apr 2017 00:05:31 +0000

2924_Mendelian_Pea_Plant_Cross-1

barkerj1 — Sun, 16 Apr 2017 00:05:32 +0000

2925_Autosomal_Dominant_Inheritance-1

barkerj1 — Sun, 16 Apr 2017 00:05:33 +0000

2926_Autosomal_Recessive_Inheritance-new-1

barkerj1 — Sun, 16 Apr 2017 00:05:34 +0000

2927_X-linked_Dominant_Inheritance-new-1

barkerj1 — Sun, 16 Apr 2017 00:05:36 +0000

Print

barkerj1 — Sun, 16 Apr 2017 00:05:38 +0000

gencounselor1-1

barkerj1 — Sun, 16 Apr 2017 00:05:39 +0000

gencounselor2-1

barkerj1 — Sun, 16 Apr 2017 00:05:40 +0000

Preface

barkerj1 — Sun, 16 Apr 2017 00:06:19 +0000

Preface2

barkerj1 — Sun, 16 Apr 2017 00:06:20 +0000

01_01ab_Gross_and_Microscopic_Anatomy-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:03 +0000

01_06_Extreme_Heat-4

barkerj1 — Wed, 30 Aug 2017 18:54:03 +0000

01_07_Harsh_Conditions-4

barkerj1 — Wed, 30 Aug 2017 18:54:03 +0000

105_Negative_Feedback_Loops-4

barkerj1 — Wed, 30 Aug 2017 18:54:03 +0000

1.5-1-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:04 +0000

106_Pregnancy-Positive_Feedback-4

barkerj1 — Wed, 30 Aug 2017 18:54:04 +0000

201_Elements_of_the_Human_Body-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:04 +0000

202_Two_Models_of_Atomic_Structure-4

barkerj1 — Wed, 30 Aug 2017 18:54:05 +0000

203_Periodic_Table-02-4

barkerj1 — Wed, 30 Aug 2017 18:54:06 +0000

ptable-4

barkerj1 — Wed, 30 Aug 2017 18:54:08 +0000

204_Isotopes_of_Hydrogen-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:08 +0000

205_Multi-image_Panel_of_PET_Scan-01

barkerj1 — Wed, 30 Aug 2017 18:54:10 +0000

206_Electron_Shells-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:12 +0000

2.2-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:13 +0000

207_Ionic_Bonding-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:13 +0000

208_Covalent_Bonding-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:14 +0000

209_Polar_Covalent_Bonds_in_a_Water_Molecule-4

barkerj1 — Wed, 30 Aug 2017 18:54:15 +0000

210_Hydrogen_Bonds_Between_Water_Molecules-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:16 +0000

213_Dehydration_Synthesis_and_Hydrolysis-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:16 +0000

2.4-amoeba-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:17 +0000

2.4-water-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:17 +0000

214_Dissociation_of_Sodium_Chloride_in_Water-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:17 +0000

215_Acids_and_Bases-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:18 +0000

216_pH_Scale-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:19 +0000

217_Five_Important_Monosaccharides-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:20 +0000

218_Three_Important_Disaccharides-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:21 +0000

219_Three_Important_Polysaccharides-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:22 +0000

220_Triglycerides-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:22 +0000

221_Fatty_Acids_Shapes-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:23 +0000

222_Other_Important_Lipids-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:23 +0000

223_Structure_of_an_Amino_Acid-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:25 +0000

224_Peptide_Bond-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:25 +0000

225_Peptide_Bond-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:25 +0000

227_Steps_in_an_Enzymatic_Reaction-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:27 +0000

228_Nucleotides-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:27 +0000

229_Nucleotides-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:28 +0000

230_Structure_of_Adenosine_Triphosphate_ATP-01-4

barkerj1 — Wed, 30 Aug 2017 18:54:29 +0000

2.5-amoeba-biomolecules-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:29 +0000

0330_Homologous_Pair_of_Chromosomes-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:29 +0000

0331_Stages_of-_Mitosis_and_Cytokinesis-e1459277007217-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:30 +0000

0332_Cell_Cycle_With_Cyclins_and_Checkpoints-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:30 +0000

3.5-1-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:30 +0000

3.5-amoeba-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:30 +0000

3.5-amoeba-meiosis-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:30 +0000

402_Types_of_Cell_Junctions_new-4

barkerj1 — Wed, 30 Aug 2017 18:54:31 +0000

403_Epithelial_Tissue-4

barkerj1 — Wed, 30 Aug 2017 18:54:36 +0000

404_Goblet_Cell_new-4

barkerj1 — Wed, 30 Aug 2017 18:54:36 +0000

404b_Goblet_Cell_new-4

barkerj1 — Wed, 30 Aug 2017 18:54:39 +0000

423_Table_04_02_Summary_of_Epithelial_Tissue_CellsN-4

barkerj1 — Wed, 30 Aug 2017 18:54:40 +0000

4.2-1-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:41 +0000

406_Types_of_Glands-4

barkerj1 — Wed, 30 Aug 2017 18:54:41 +0000

405_Modes_of_Secretion_by_Glands_updated-4

barkerj1 — Wed, 30 Aug 2017 18:54:42 +0000

407_Sebaceous_Glands-4

barkerj1 — Wed, 30 Aug 2017 18:54:43 +0000

1200_Robotic_Arms-1

barkerj1 — Wed, 30 Aug 2017 18:54:43 +0000

1201_Overview_of_Nervous_System-1

barkerj1 — Wed, 30 Aug 2017 18:54:44 +0000

1202_White_and_Gray_Matter-1

barkerj1 — Wed, 30 Aug 2017 18:54:44 +0000

1203_Concept_of_NucleusN-1

barkerj1 — Wed, 30 Aug 2017 18:54:44 +0000

1204_Optic_Nerve_vs_Optic_Tract-1

barkerj1 — Wed, 30 Aug 2017 18:54:45 +0000

1205_Somatic_Autonomic_Enteric_StructuresN-1

barkerj1 — Wed, 30 Aug 2017 18:54:45 +0000

troublewstairs-1

barkerj1 — Wed, 30 Aug 2017 18:54:45 +0000

12.1-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:46 +0000

1206_The_Neuron-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:46 +0000

1207_Neuron_Shape_Classification-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:47 +0000

1208_Other_Types_of_Neurons-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:47 +0000

1209_Glial_Cells_of_the_CNS-02-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:47 +0000

1210_Glial_Cells_of_the_PNS-1-1

barkerj1 — Wed, 30 Aug 2017 18:54:47 +0000

1211_Myelinated_Neuron-1

barkerj1 — Wed, 30 Aug 2017 18:54:47 +0000

1212_Sensory_Neuron_Test_Water-1

barkerj1 — Wed, 30 Aug 2017 18:54:48 +0000

1213_Sensory_Input_Test_Water-1

barkerj1 — Wed, 30 Aug 2017 18:54:48 +0000

1214_Motor_Response_Test_Water-1

barkerj1 — Wed, 30 Aug 2017 18:54:49 +0000

1215_Cell_Membrane_Channels-1

barkerj1 — Wed, 30 Aug 2017 18:54:49 +0000

1216_Ligand-gated_Channels-1

barkerj1 — Wed, 30 Aug 2017 18:54:49 +0000

1217_Mechanically-gated_Channels-02-1

barkerj1 — Wed, 30 Aug 2017 18:54:50 +0000

1218_Voltage-gated_Channels-1

barkerj1 — Wed, 30 Aug 2017 18:54:50 +0000

1219_Leakage_Channels-1

barkerj1 — Wed, 30 Aug 2017 18:54:50 +0000

1220_Resting_Membrane_Potential-1

barkerj1 — Wed, 30 Aug 2017 18:54:51 +0000

1221_Action_Potential-1

barkerj1 — Wed, 30 Aug 2017 18:54:51 +0000

12.4-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:51 +0000

1222_Action_Potential_Labels-1

barkerj1 — Wed, 30 Aug 2017 18:54:51 +0000

1223_Graded_Potentials-02-1

barkerj1 — Wed, 30 Aug 2017 18:54:52 +0000

1224_Post_Synaptic_Potential_Summation-1

barkerj1 — Wed, 30 Aug 2017 18:54:52 +0000

1225_Chemical_Synapse-1

barkerj1 — Wed, 30 Aug 2017 18:54:52 +0000

1226_Receptor_Types-1

barkerj1 — Wed, 30 Aug 2017 18:54:52 +0000

1305_CerebrumN-1

barkerj1 — Wed, 30 Aug 2017 18:54:53 +0000

1306_Lobes_of_Cerebral_CortexN-1

barkerj1 — Wed, 30 Aug 2017 18:54:53 +0000

1307_Brodmann_Areas-1

barkerj1 — Wed, 30 Aug 2017 18:54:54 +0000

1308_Frontal_Section_Basal_Nuclei-1

barkerj1 — Wed, 30 Aug 2017 18:54:55 +0000

1309_Basal_Nuclei_Connections-1

barkerj1 — Wed, 30 Aug 2017 18:54:55 +0000

1310_Diencephalon-1

barkerj1 — Wed, 30 Aug 2017 18:54:55 +0000

1311_Brain_Stem-1

barkerj1 — Wed, 30 Aug 2017 18:54:55 +0000

1312_CerebellumN-1

barkerj1 — Wed, 30 Aug 2017 18:54:55 +0000

1313_Spinal_Cord_Cross_Section-1

barkerj1 — Wed, 30 Aug 2017 18:54:56 +0000

13.2-150x150

barkerj1 — Wed, 30 Aug 2017 18:54:57 +0000

1314_Circle_of_WillisN-1

barkerj1 — Wed, 30 Aug 2017 18:54:57 +0000

1315_Brain_Sinuses-1

barkerj1 — Wed, 30 Aug 2017 18:54:57 +0000

1316_Meningeal_LayersN-1

barkerj1 — Wed, 30 Aug 2017 18:54:58 +0000

1317_CFS_Circulation-1

barkerj1 — Wed, 30 Aug 2017 18:54:58 +0000

1318b_Dorsal_Root_Ganglion

barkerj1 — Wed, 30 Aug 2017 18:54:59 +0000

1318b_DRG

barkerj1 — Wed, 30 Aug 2017 18:54:59 +0000

1319_Nerve_Structure

barkerj1 — Wed, 30 Aug 2017 18:55:00 +0000

1319B_Nerve_Mag

barkerj1 — Wed, 30 Aug 2017 18:55:01 +0000

1320_The_Cranial_Nerves

barkerj1 — Wed, 30 Aug 2017 18:55:01 +0000

1321_Spinal_Nerve_Plexuses

barkerj1 — Wed, 30 Aug 2017 18:55:01 +0000

1401_Receptor_Types-1

barkerj1 — Wed, 30 Aug 2017 18:55:02 +0000

1402_The_Tongue-1

barkerj1 — Wed, 30 Aug 2017 18:55:03 +0000

1403_Olfaction-1

barkerj1 — Wed, 30 Aug 2017 18:55:04 +0000

14.1-hearing-and-balance-150x150

barkerj1 — Wed, 30 Aug 2017 18:55:05 +0000

1404_The_Structures_of_the_Ear-1

barkerj1 — Wed, 30 Aug 2017 18:55:05 +0000

1405_Sound_Waves_and_the_Ear-1

barkerj1 — Wed, 30 Aug 2017 18:55:07 +0000

1406_Cochlea-1

barkerj1 — Wed, 30 Aug 2017 18:55:09 +0000

1407_The_Hair_Cell-1

barkerj1 — Wed, 30 Aug 2017 18:55:10 +0000

1427_Cochlea_Micrograph-1

barkerj1 — Wed, 30 Aug 2017 18:55:10 +0000

1408_Frequency_Coding_in_The_Cochlea-1

barkerj1 — Wed, 30 Aug 2017 18:55:11 +0000

1409_Maculae_and_Equilibrium-1

barkerj1 — Wed, 30 Aug 2017 18:55:12 +0000

1410_Equilibrium_and_Semicircular_Canals-1

barkerj1 — Wed, 30 Aug 2017 18:55:12 +0000

1411_Eye_in_The_Orbit-1

barkerj1 — Wed, 30 Aug 2017 18:55:13 +0000

1412_Extraocular_Muscles-1

barkerj1 — Wed, 30 Aug 2017 18:55:14 +0000

1413_Structure_of_the_Eye-1

barkerj1 — Wed, 30 Aug 2017 18:55:14 +0000

1414_Rods_and_Cones-1

barkerj1 — Wed, 30 Aug 2017 18:55:15 +0000

1415_Retinal_Isomers-1

barkerj1 — Wed, 30 Aug 2017 18:55:16 +0000

1416_Color_Sensitivity-1

barkerj1 — Wed, 30 Aug 2017 18:55:17 +0000

14.1-vision-150x150

barkerj1 — Wed, 30 Aug 2017 18:55:18 +0000

1417_Ascending_Pathways_of_Spinal_Cord

barkerj1 — Wed, 30 Aug 2017 18:55:18 +0000

1418_Auditory_Brainstem_Mechanisms

barkerj1 — Wed, 30 Aug 2017 18:55:20 +0000

1419_Vestibulo-Ocular_Reflex

barkerj1 — Wed, 30 Aug 2017 18:55:21 +0000

1420_Optical_Fields

barkerj1 — Wed, 30 Aug 2017 18:55:22 +0000

1421_Sensory_Homunculus

barkerj1 — Wed, 30 Aug 2017 18:55:23 +0000

1422_Topographical_Image_on_Retina

barkerj1 — Wed, 30 Aug 2017 18:55:24 +0000

l_3-D1

barkerj1 — Wed, 30 Aug 2017 18:55:25 +0000

1423_Retinal_Disparity

barkerj1 — Wed, 30 Aug 2017 18:55:26 +0000

1424_Visual_Streams

barkerj1 — Wed, 30 Aug 2017 18:55:26 +0000

1425_Phineas_Gage

barkerj1 — Wed, 30 Aug 2017 18:55:27 +0000

Phineas_gage_-_1868_skull_diagram

barkerj1 — Wed, 30 Aug 2017 18:55:28 +0000

1426_Corticospinal_Pathway

barkerj1 — Wed, 30 Aug 2017 18:55:28 +0000

NYTmotor

barkerj1 — Wed, 30 Aug 2017 18:55:29 +0000

14.3-150x150

barkerj1 — Wed, 30 Aug 2017 18:55:30 +0000

1501_Connections_of_the_Sympathetic_Nervous_System-1

barkerj1 — Wed, 30 Aug 2017 18:55:30 +0000

1502_Symphatetic_Connections_and_the_Ganglia-1

barkerj1 — Wed, 30 Aug 2017 18:55:31 +0000

1503_Connections_of_the_Parasympathetic_Nervous_System-1

barkerj1 — Wed, 30 Aug 2017 18:55:32 +0000

1504_Autonomic_Varicosities-1

barkerj1 — Wed, 30 Aug 2017 18:55:34 +0000

15.1-150x150

barkerj1 — Wed, 30 Aug 2017 18:55:34 +0000

1505_Comparison_of_Somatic_and_Visceral_Reflexes

barkerj1 — Wed, 30 Aug 2017 18:55:35 +0000

1506_Referred_Pain_Chart

barkerj1 — Wed, 30 Aug 2017 18:55:36 +0000

1507_Short_and_Long_Reflexes

barkerj1 — Wed, 30 Aug 2017 18:55:37 +0000

strokespell

barkerj1 — Wed, 30 Aug 2017 18:55:39 +0000

1508_Autonomic_Control_of_Pupil_Size

barkerj1 — Wed, 30 Aug 2017 18:55:40 +0000

1509_Pupillary_Reflex_Pathways

barkerj1 — Wed, 30 Aug 2017 18:55:41 +0000

1510_Fiber_Tracts_of_the_Central_Autonomic_System

barkerj1 — Wed, 30 Aug 2017 18:55:42 +0000

1511_The_Limbic_Lobe

barkerj1 — Wed, 30 Aug 2017 18:55:43 +0000

hormonebind-1

barkerj1 — Wed, 30 Aug 2017 18:55:43 +0000

1801_The_Endocrine_System

barkerj1 — Wed, 30 Aug 2017 18:55:44 +0000

17.1-150x150

barkerj1 — Wed, 30 Aug 2017 18:55:45 +0000

1802_Examples_of_Amine_Peptide_Protein_and_Steroid_Hormone_Structure-1

barkerj1 — Wed, 30 Aug 2017 18:55:45 +0000

1803_Binding_of_Lipid-Soluble_Hormones-1

barkerj1 — Wed, 30 Aug 2017 18:55:46 +0000

1804_Binding_of_Water-Soluble_Hormones-1

barkerj1 — Wed, 30 Aug 2017 18:55:46 +0000

1805_Negative_Feedback_Loop-1

barkerj1 — Wed, 30 Aug 2017 18:55:46 +0000

1806_The_Hypothalamus-Pituitary_Complex-1

barkerj1 — Wed, 30 Aug 2017 18:55:47 +0000

1807_The_Posterior_Pituitary_Complex-1

barkerj1 — Wed, 30 Aug 2017 18:55:47 +0000

1808_The_Anterior_Pituitary_Complex-1

barkerj1 — Wed, 30 Aug 2017 18:55:48 +0000

1809_Hormonal_Regulation_of_Growth-1

barkerj1 — Wed, 30 Aug 2017 18:55:48 +0000

1810_Major_Pituitary_Hormones-1

barkerj1 — Wed, 30 Aug 2017 18:55:49 +0000

1811_The_Thyroid_Gland-1

barkerj1 — Wed, 30 Aug 2017 18:55:50 +0000

1813_A_Classic_Negative_Feedback_Loop-1

barkerj1 — Wed, 30 Aug 2017 18:55:51 +0000

1823_Goiter-1

barkerj1 — Wed, 30 Aug 2017 18:55:51 +0000

1814_The_Parathyroid_Glands-1

barkerj1 — Wed, 30 Aug 2017 18:55:52 +0000

1817_The_Role_of_Parathyroid_Hormone_in_Maintaining_Blood_Calcium_Homeostasis-1

barkerj1 — Wed, 30 Aug 2017 18:55:52 +0000

1818_The_Adrenal_Glands-1

barkerj1 — Wed, 30 Aug 2017 18:55:53 +0000

1820_The_Pancreas-1

barkerj1 — Wed, 30 Aug 2017 18:55:53 +0000

1822_The_Homostatic_Regulation_of_Blood_Glucose_Levels-1

barkerj1 — Wed, 30 Aug 2017 18:55:53 +0000

2139_Fetal_Circulation

barkerj1 — Wed, 30 Aug 2017 18:55:54 +0000

2318_Partial_and_Total_Pressure_of_a_Gas

barkerj1 — Wed, 30 Aug 2017 18:55:56 +0000

2319_Fig_23.19-1

barkerj1 — Wed, 30 Aug 2017 18:55:56 +0000

2320_Fig_23.20_NEW_KGX-1

barkerj1 — Wed, 30 Aug 2017 18:55:57 +0000

2322_Fig_23.22-a-1

barkerj1 — Wed, 30 Aug 2017 18:55:57 +0000

2323_Oxygen-hemoglobin_Dissociation-a-1

barkerj1 — Wed, 30 Aug 2017 18:55:58 +0000

2323_Oxygen-hemoglobin_Dissociation-b-1

barkerj1 — Wed, 30 Aug 2017 18:55:59 +0000

2323_Oxygen-hemoglobin_Dissociation-c-1

barkerj1 — Wed, 30 Aug 2017 18:56:00 +0000

2324_Oxygen-hemoglobin_Dissociation_Fetus_Adult-1

barkerj1 — Wed, 30 Aug 2017 18:56:01 +0000

2325_Carbon_Dioxide_Transport-1

barkerj1 — Wed, 30 Aug 2017 18:56:02 +0000

oxyblood

barkerj1 — Wed, 30 Aug 2017 18:56:02 +0000

22.5-1-150x150

barkerj1 — Wed, 30 Aug 2017 18:56:03 +0000

2328_Development_of_Lower_Respiratory_SystemN

barkerj1 — Wed, 30 Aug 2017 18:56:04 +0000

2400_Women_Eating_Apples-1

barkerj1 — Wed, 30 Aug 2017 18:56:05 +0000

2401_Components_of_the_Digestive_System-1

barkerj1 — Wed, 30 Aug 2017 18:56:05 +0000

2402_Layers_of_the_Gastrointestinal_Tract-1

barkerj1 — Wed, 30 Aug 2017 18:56:05 +0000

2403_The_PeritoneumN-1

barkerj1 — Wed, 30 Aug 2017 18:56:06 +0000

23.1-150x150

barkerj1 — Wed, 30 Aug 2017 18:56:06 +0000

fooddigestion2-1

barkerj1 — Wed, 30 Aug 2017 18:56:06 +0000

2404_PeristalsisN-1

barkerj1 — Wed, 30 Aug 2017 18:56:07 +0000

2405_Digestive_Process-1

barkerj1 — Wed, 30 Aug 2017 18:56:07 +0000

23.2-150x150

barkerj1 — Wed, 30 Aug 2017 18:56:08 +0000

2406_Structures_of_the_Mouth-1

barkerj1 — Wed, 30 Aug 2017 18:56:08 +0000

2407_Tongue-1

barkerj1 — Wed, 30 Aug 2017 18:56:08 +0000

2408_Salivary_Glands-1

barkerj1 — Wed, 30 Aug 2017 18:56:09 +0000

2410_Permanent_and_Deciduous_TeethN-1

barkerj1 — Wed, 30 Aug 2017 18:56:09 +0000

2409_Tooth-1

barkerj1 — Wed, 30 Aug 2017 18:56:09 +0000

2411_Pharynx-1

barkerj1 — Wed, 30 Aug 2017 18:56:09 +0000

2412_The_Esophagus-1

barkerj1 — Wed, 30 Aug 2017 18:56:10 +0000

2413_DeglutitionN-1

barkerj1 — Wed, 30 Aug 2017 18:56:10 +0000

swallowing-1

barkerj1 — Wed, 30 Aug 2017 18:56:10 +0000

2414_Stomach-1

barkerj1 — Wed, 30 Aug 2017 18:56:11 +0000

2415_Histology_of_StomachN-1

barkerj1 — Wed, 30 Aug 2017 18:56:11 +0000

stomach1-1

barkerj1 — Wed, 30 Aug 2017 18:56:12 +0000

2416_Three_Phases_Gastric_Secretion-1

barkerj1 — Wed, 30 Aug 2017 18:56:13 +0000

2417_Small_IntestineN-1

barkerj1 — Wed, 30 Aug 2017 18:56:13 +0000

2418_Histology_Small_IntestinesN-1

barkerj1 — Wed, 30 Aug 2017 18:56:14 +0000

sintestine-1

barkerj1 — Wed, 30 Aug 2017 18:56:14 +0000

2419_Segmentation-1

barkerj1 — Wed, 30 Aug 2017 18:56:15 +0000

2420_Large_Intestine-1

barkerj1 — Wed, 30 Aug 2017 18:56:15 +0000

2421_Histology_of_the_Large_IntestineN-1

barkerj1 — Wed, 30 Aug 2017 18:56:15 +0000

2433_Teniae_Coli_Haustra_Epiploic_Appendage-1

barkerj1 — Wed, 30 Aug 2017 18:56:16 +0000

foodgroups-1

barkerj1 — Wed, 30 Aug 2017 18:56:16 +0000

23.5-150x150

barkerj1 — Wed, 30 Aug 2017 18:56:17 +0000

2422_Accessory_Organs-1

barkerj1 — Wed, 30 Aug 2017 18:56:17 +0000

2423_Microscopic_Anatomy_of_Liver-1

barkerj1 — Wed, 30 Aug 2017 18:56:17 +0000

2424_Exocrine_and_Endocrine_Pancreas-1

barkerj1 — Wed, 30 Aug 2017 18:56:18 +0000

2425_Gallbladder-1

barkerj1 — Wed, 30 Aug 2017 18:56:18 +0000

2426_Mechanical_and_Chemical_DigestionN-1

barkerj1 — Wed, 30 Aug 2017 18:56:18 +0000

2427_Carbon_Digestion-1

barkerj1 — Wed, 30 Aug 2017 18:56:18 +0000

2429_Digestion_of_Proteins_Physiology-1

barkerj1 — Wed, 30 Aug 2017 18:56:19 +0000

2428_Digestion_of_Proteins-1

barkerj1 — Wed, 30 Aug 2017 18:56:19 +0000

2430_Digestive_Secretions_Absorption_of_WaterN-1

barkerj1 — Wed, 30 Aug 2017 18:56:19 +0000

2431_Lipid_Absorption-1

barkerj1 — Wed, 30 Aug 2017 18:56:19 +0000

2501_The_Structure_of_ATP_Molecules-1

barkerj1 — Wed, 30 Aug 2017 18:56:19 +0000

2502_Catabolic_Reactions-1

barkerj1 — Wed, 30 Aug 2017 18:56:20 +0000

24.1-150x150

barkerj1 — Wed, 30 Aug 2017 18:56:21 +0000

2503_Cellular_Respiration-1

barkerj1 — Wed, 30 Aug 2017 18:56:21 +0000

2504_Glycosis_Overview-1

barkerj1 — Wed, 30 Aug 2017 18:56:22 +0000

glycolysis1-1

barkerj1 — Wed, 30 Aug 2017 18:56:23 +0000

2505_Aerobic_Versus_Anaerobic_Respiration-1

barkerj1 — Wed, 30 Aug 2017 18:56:24 +0000

2507_The_Krebs_Cycle-1

barkerj1 — Wed, 30 Aug 2017 18:56:26 +0000

2508_The_Electron_Transport_Chain-1

barkerj1 — Wed, 30 Aug 2017 18:56:28 +0000

2509_Carbohydrate_Metabolism-1

barkerj1 — Wed, 30 Aug 2017 18:56:29 +0000

2510_Gluconeogenesis-1

barkerj1 — Wed, 30 Aug 2017 18:56:30 +0000

2511_A_Triglyceride_Molecule_a_Is_Broken_Down_Into_Monoglycerides_b-1

barkerj1 — Wed, 30 Aug 2017 18:56:32 +0000

2512_Chylomicrons_Contain_Triglycerides_Cholesterol_Molecules_and_Other_Lipids-1

barkerj1 — Wed, 30 Aug 2017 18:56:33 +0000

2513_The_Breakdown_of_Fatty_Acids-1

barkerj1 — Wed, 30 Aug 2017 18:56:34 +0000

2514_Ketogenesis-1

barkerj1 — Wed, 30 Aug 2017 18:56:36 +0000

2515_Ketone_Oxidation-1

barkerj1 — Wed, 30 Aug 2017 18:56:36 +0000

2516_Lipid_Metabolism-1

barkerj1 — Wed, 30 Aug 2017 18:56:37 +0000

2517_Protein-Digesting_EnzymesN-1

barkerj1 — Wed, 30 Aug 2017 18:56:39 +0000

2518_Urea_Cycle-1

barkerj1 — Wed, 30 Aug 2017 18:56:40 +0000

2519_Energy_From_Amino_Acids-1

barkerj1 — Wed, 30 Aug 2017 18:56:42 +0000

2520_Catabolic_and_Anabolic-Pathways-815x1024-1

barkerj1 — Wed, 30 Aug 2017 18:56:43 +0000

2521_The_Absorptive_Stage-1

barkerj1 — Wed, 30 Aug 2017 18:56:44 +0000

2522_The_Postabsorptive_Stage-1

barkerj1 — Wed, 30 Aug 2017 18:56:46 +0000

2524_MyPlate-1

barkerj1 — Wed, 30 Aug 2017 18:56:47 +0000

2601_Urine_Color_Chart-1

barkerj1 — Wed, 30 Aug 2017 18:56:48 +0000

25.1-150x150

barkerj1 — Wed, 30 Aug 2017 18:56:48 +0000

Female_and_Male_Urethra-1

barkerj1 — Wed, 30 Aug 2017 18:56:49 +0000

2605_The_Bladder-1

barkerj1 — Wed, 30 Aug 2017 18:56:49 +0000

2604_Nerves_Innervating_the_Urinary_SystemN-1

barkerj1 — Wed, 30 Aug 2017 18:56:50 +0000

2607_Ureter-1

barkerj1 — Wed, 30 Aug 2017 18:56:51 +0000

TED-1

barkerj1 — Wed, 30 Aug 2017 18:56:52 +0000

2608_Kidney_Position_in_Abdomen-1

barkerj1 — Wed, 30 Aug 2017 18:56:53 +0000

2610_The_Kidney-1

barkerj1 — Wed, 30 Aug 2017 18:56:53 +0000

2612_Blood_Flow_in_the_Kidneys-1

barkerj1 — Wed, 30 Aug 2017 18:56:55 +0000

2611_Blood_Flow_in_the_Nephron-1

barkerj1 — Wed, 30 Aug 2017 18:56:56 +0000

2613_Podocytes-1

barkerj1 — Wed, 30 Aug 2017 18:56:57 +0000

2614_Fenestrated_Capillary-1

barkerj1 — Wed, 30 Aug 2017 18:56:57 +0000

Juxtaglomerular_Apparatus_and_Glomerulus-1

barkerj1 — Wed, 30 Aug 2017 18:56:58 +0000

2626_Renin_Aldosterone_Angiotensin-1

barkerj1 — Wed, 30 Aug 2017 18:56:58 +0000

2625_Aquaporin_-Water_Channel-1024x515-1

barkerj1 — Wed, 30 Aug 2017 18:56:59 +0000

2617_Net_Filtration_PressureN-1

barkerj1 — Wed, 30 Aug 2017 18:57:00 +0000

25.5-150x150

barkerj1 — Wed, 30 Aug 2017 18:57:00 +0000

2618_Nephron_Secretion_Reabsorption-1

barkerj1 — Wed, 30 Aug 2017 18:57:01 +0000

2619_Substances_Reabsorbed_And_Secreted_By_The_PCT-1

barkerj1 — Wed, 30 Aug 2017 18:57:02 +0000

2620_Reabsorption_of_Bicarbonate_from_the_PCT-1

barkerj1 — Wed, 30 Aug 2017 18:57:03 +0000

2621_Loop_of_Henle_Countercurrent_Multiplier_System-1

barkerj1 — Wed, 30 Aug 2017 18:57:04 +0000

2701_Water_Content_in_the_Body-01-1

barkerj1 — Wed, 30 Aug 2017 18:57:05 +0000

2702_Fluid_Compartments_ICF_ECF-1

barkerj1 — Wed, 30 Aug 2017 18:57:06 +0000

2703_Distribution_of_Water_in_the_Human_Body_in_Terms_of_ICF_and_ECF_Pie_Chart-1

barkerj1 — Wed, 30 Aug 2017 18:57:06 +0000

2704_Concentration_of_Elements_in_Body_Fluids-1

barkerj1 — Wed, 30 Aug 2017 18:57:06 +0000

bodyfluids-1

barkerj1 — Wed, 30 Aug 2017 18:57:06 +0000

2705_Sodium_Potassium_Pump-1

barkerj1 — Wed, 30 Aug 2017 18:57:07 +0000

2108_Capillary_Exchange-1

barkerj1 — Wed, 30 Aug 2017 18:57:08 +0000

dynamicfluid-1

barkerj1 — Wed, 30 Aug 2017 18:57:08 +0000

2706_Facilitated_Diffusion-1

barkerj1 — Wed, 30 Aug 2017 18:57:09 +0000

2708_Flowchart_of_Thirst_Response-01-1

barkerj1 — Wed, 30 Aug 2017 18:57:09 +0000

2709_ADH-1

barkerj1 — Wed, 30 Aug 2017 18:57:10 +0000

2710_Aquaporins-01-1

barkerj1 — Wed, 30 Aug 2017 18:57:10 +0000

saltwater-1

barkerj1 — Wed, 30 Aug 2017 18:57:11 +0000

2711_Aldosterone_Feedback_Loop-01-1

barkerj1 — Wed, 30 Aug 2017 18:57:12 +0000

2712_Renin_Angiotensin_System-01-1

barkerj1 — Wed, 30 Aug 2017 18:57:13 +0000

2713_pH_Scale-01-1

barkerj1 — Wed, 30 Aug 2017 18:57:13 +0000

2714_Respiratory_Regulation_of_Blood-1

barkerj1 — Wed, 30 Aug 2017 18:57:14 +0000

2715_Conservation_of_Bicarbonate_in_Kidney-01-1

barkerj1 — Wed, 30 Aug 2017 18:57:14 +0000

2716_Symptoms_of_Acidosis_Alkalosis-1

barkerj1 — Wed, 30 Aug 2017 18:57:15 +0000

27.1-150x150

barkerj1 — Wed, 30 Aug 2017 18:57:15 +0000

Figure_28_01_01-1

barkerj1 — Wed, 30 Aug 2017 18:57:15 +0000

Figure_28_01_02-1

barkerj1 — Wed, 30 Aug 2017 18:57:16 +0000

Figure_28_01_03-1

barkerj1 — Wed, 30 Aug 2017 18:57:16 +0000

Figure_28_01_04-1

barkerj1 — Wed, 30 Aug 2017 18:57:16 +0000

Figure_28_01_05-1

barkerj1 — Wed, 30 Aug 2017 18:57:16 +0000

vasectomy-1

barkerj1 — Wed, 30 Aug 2017 18:57:16 +0000

spermpath-1

barkerj1 — Wed, 30 Aug 2017 18:57:17 +0000

Figure_28_01_06-1

barkerj1 — Wed, 30 Aug 2017 18:57:18 +0000

Figure_28_01_07-1

barkerj1 — Wed, 30 Aug 2017 18:57:19 +0000

27.2-150x150

barkerj1 — Wed, 30 Aug 2017 18:57:19 +0000

Figure_28_02_01-1

barkerj1 — Wed, 30 Aug 2017 18:57:19 +0000

Figure_28_02_02-1

barkerj1 — Wed, 30 Aug 2017 18:57:19 +0000

Figure_28_02_03-1

barkerj1 — Wed, 30 Aug 2017 18:57:19 +0000

Figure_28_02_04-1

barkerj1 — Wed, 30 Aug 2017 18:57:20 +0000

Figure_28_02_05-1

barkerj1 — Wed, 30 Aug 2017 18:57:20 +0000

Figure_28_02_06-1

barkerj1 — Wed, 30 Aug 2017 18:57:20 +0000

Figure_28_02_07-1

barkerj1 — Wed, 30 Aug 2017 18:57:21 +0000

Figure_28_02_08-1

barkerj1 — Wed, 30 Aug 2017 18:57:21 +0000

Figure_28_02_09-1

barkerj1 — Wed, 30 Aug 2017 18:57:21 +0000

2901_Sperm_Fertilization-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:21 +0000

2902_IVF-02-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:22 +0000

fertilization-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:24 +0000

28.1-150x150

barkerj1 — Wed, 30 Aug 2017 18:57:24 +0000

2903_Preembryonic_Cleavages-02-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:25 +0000

conceptus-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:25 +0000

2904_Preembryonic_Development-02-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:26 +0000

2905_Implantation-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:27 +0000

2906_Placenta_Previa-02-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:29 +0000

2907_Embroyonic_Disc_Amniotic_Cavity_Yolk_Sac-02-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:29 +0000

2908_Germ_Layers-02-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:30 +0000

2909_Embryo_Week_3-02-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:31 +0000

2910_The_Placenta-02-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:32 +0000

2911_Photo_of_Placenta-02-2-1

barkerj1 — Wed, 30 Aug 2017 18:57:33 +0000

2912_Neurulation-02-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:34 +0000

2913_Embryonic_Folding-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:35 +0000

2914_Photo_of_Embryo-02-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:36 +0000

28.2-150x150

barkerj1 — Wed, 30 Aug 2017 18:57:37 +0000

2915_Sexual_Differentation-02-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:37 +0000

2916_Fetal_Circulatory_System-02-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:38 +0000

pregstages-1-1

barkerj1 — Wed, 30 Aug 2017 18:57:39 +0000

2917_Size_of_Uterus_Throughout_Pregnancy-02

barkerj1 — Wed, 30 Aug 2017 18:57:40 +0000

2918_Photo_of_Linea_Nigra

barkerj1 — Wed, 30 Aug 2017 18:57:41 +0000

2919_Hormones_Initiating_Labor-02

barkerj1 — Wed, 30 Aug 2017 18:57:42 +0000

2920_Stages_of_Childbirth-02

barkerj1 — Wed, 30 Aug 2017 18:57:42 +0000

2921_Neonatal_Circulatory_System

barkerj1 — Wed, 30 Aug 2017 18:57:44 +0000

2922_Let_Down_Reflex-new

barkerj1 — Wed, 30 Aug 2017 18:57:45 +0000

2923_Male_Chromosomes-1

barkerj1 — Wed, 30 Aug 2017 18:57:47 +0000

2924_Mendelian_Pea_Plant_Cross-1

barkerj1 — Wed, 30 Aug 2017 18:57:48 +0000

2925_Autosomal_Dominant_Inheritance-1

barkerj1 — Wed, 30 Aug 2017 18:57:49 +0000

2926_Autosomal_Recessive_Inheritance-new-1

barkerj1 — Wed, 30 Aug 2017 18:57:49 +0000

2927_X-linked_Dominant_Inheritance-new-1

barkerj1 — Wed, 30 Aug 2017 18:57:51 +0000

Print

barkerj1 — Wed, 30 Aug 2017 18:57:52 +0000

gencounselor1-1

barkerj1 — Wed, 30 Aug 2017 18:57:52 +0000

gencounselor2-1

barkerj1 — Wed, 30 Aug 2017 18:57:53 +0000

Health Canada Eat Well plate eat-well-bien-manger-eng

barkerj1 — Sat, 28 Apr 2018 00:15:36 +0000

1.1 Overview of Anatomy and Physiology

barkerj1 — Wed, 06 Sep 2017 01:16:21 +0000

Learning Objectives

Review 1103/1109 material

Human anatomy is the scientific study of the body’s structures. Some of these structures are very small and can only be observed and analyzed with the assistance of a microscope. Other larger structures can readily be seen, manipulated, measured, and weighed. The word “anatomy” comes from a Greek root that means “to cut apart.” Human anatomy was first studied by observing the exterior of the body and observing the wounds of soldiers and other injuries. Later, physicians were allowed to dissect bodies of the dead to augment their knowledge. When a body is dissected, its structures are cut apart in order to observe their physical attributes and their relationships to one another. Dissection is still used in medical schools, anatomy courses, and in pathology labs. In order to observe structures in living people, however, a number of imaging techniques have been developed. These techniques allow clinicians to visualize structures inside the living body such as a cancerous tumor or a fractured bone.

Like most scientific disciplines, anatomy has areas of specialization. Gross anatomy is the study of the larger structures of the body, those visible without the aid of magnification (Figure 1a). Macro- means “large,” thus, gross anatomy is also referred to as macroscopic anatomy. In contrast, micro- means “small,” and microscopic anatomy is the study of structures that can be observed only with the use of a microscope or other magnification devices (Figure 1b). Microscopic anatomy includes cytology, the study of cells and histology, the study of tissues. As the technology of microscopes has advanced, anatomists have been able to observe smaller and smaller structures of the body, from slices of large structures like the heart, to the three-dimensional structures of large molecules in the body.

[caption id="" align="aligncenter" width="480"] Figure 1. Gross and Microscopic Anatomy. (a) Gross anatomy considers large structures such as the brain. (b) Microscopic anatomy can deal with the same structures, though at a different scale. This is a micrograph of nerve cells from the brain. LM × 1600. (credit a: “WriterHound”/Wikimedia Commons; credit b: Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Anatomists take two general approaches to the study of the body’s structures: regional and systemic. Regional anatomy is the study of the interrelationships of all of the structures in a specific body region, such as the abdomen. Studying regional anatomy helps us appreciate the interrelationships of body structures, such as how muscles, nerves, blood vessels, and other structures work together to serve a particular body region. In contrast, systemic anatomy is the study of the structures that make up a discrete body system—that is, a group of structures that work together to perform a unique body function. For example, a systemic anatomical study of the muscular system would consider all of the skeletal muscles of the body.

Whereas anatomy is about structure, physiology is about function. Human physiology is the scientific study of the chemistry and physics of the structures of the body and the ways in which they work together to support the functions of life. Much of the study of physiology centers on the body’s tendency toward homeostasis. Homeostasis is the state of steady internal conditions maintained by living things. The study of physiology certainly includes observation, both with the naked eye and with microscopes, as well as manipulations and measurements. However, current advances in physiology usually depend on carefully designed laboratory experiments that reveal the functions of the many structures and chemical compounds that make up the human body.

Like anatomists, physiologists typically specialize in a particular branch of physiology. For example, neurophysiology is the study of the brain, spinal cord, and nerves and how these work together to perform functions as complex and diverse as vision, movement, and thinking. Physiologists may work from the organ level (exploring, for example, what different parts of the brain do) to the molecular level (such as exploring how an electrochemical signal travels along nerves).

Form is closely related to function in all living things. For example, the thin flap of your eyelid can snap down to clear away dust particles and almost instantaneously slide back up to allow you to see again. At the microscopic level, the arrangement and function of the nerves and muscles that serve the eyelid allow for its quick action and retreat. At a smaller level of analysis, the function of these nerves and muscles likewise relies on the interactions of specific molecules and ions. Even the three-dimensional structure of certain molecules is essential to their function.

Your study of anatomy and physiology will make more sense if you continually relate the form of the structures you are studying to their function. In fact, it can be somewhat frustrating to attempt to study anatomy without an understanding of the physiology that a body structure supports. Imagine, for example, trying to appreciate the unique arrangement of the bones of the human hand if you had no conception of the function of the hand. Fortunately, your understanding of how the human hand manipulates tools—from pens to cell phones—helps you appreciate the unique alignment of the thumb in opposition to the four fingers, making your hand a structure that allows you to pinch and grasp objects and type text messages.

1.4 Requirements for Human Life

barkerj1 — Wed, 06 Sep 2017 01:17:19 +0000

Learning Objectives

By the end of this section, you will be able to:

Review 1103/1109 material

Humans have been adapting to life on Earth for at least the past 200,000 years. Earth and its atmosphere have provided us with air to breathe, water to drink, and food to eat, but these are not the only requirements for survival. Although you may rarely think about it, you also cannot live outside of a certain range of temperature and pressure that the surface of our planet and its atmosphere provides. The next sections explore these four requirements of life.

Oxygen

Atmospheric air is only about 20 percent oxygen, but that oxygen is a key component of the chemical reactions that keep the body alive, including the reactions that produce ATP. Brain cells are especially sensitive to lack of oxygen because of their requirement for a high-and-steady production of ATP. Brain damage is likely within five minutes without oxygen, and death is likely within ten minutes.

Nutrients

A nutrient is a substance in foods and beverages that is essential to human survival. The three basic classes of nutrients are water, the energy-yielding and body-building nutrients, and the micronutrients (vitamins and minerals).

The most critical nutrient is water. Depending on the environmental temperature and our state of health, we may be able to survive for only a few days without water. The body’s functional chemicals are dissolved and transported in water, and the chemical reactions of life take place in water. Moreover, water is the largest component of cells, blood, and the fluid between cells, and water makes up about 70 percent of an adult’s body mass. Water also helps regulate our internal temperature and cushions, protects, and lubricates joints and many other body structures.

The energy-yielding nutrients are primarily carbohydrates and lipids, while proteins mainly supply the amino acids that are the building blocks of the body itself. You ingest these in plant and animal foods and beverages, and the digestive system breaks them down into molecules small enough to be absorbed. The breakdown products of carbohydrates and lipids can then be used in the metabolic processes that convert them to ATP. Although you might feel as if you are starving after missing a single meal, you can survive without consuming the energy-yielding nutrients for at least several weeks.

Water and the energy-yielding nutrients are also referred to as macronutrients because the body needs them in large amounts. In contrast, micronutrients are vitamins and minerals. These elements and compounds participate in many essential chemical reactions and processes, such as nerve impulses, and some, such as calcium, also contribute to the body’s structure. Your body can store some of the micronutrients in its tissues, and draw on those reserves if you fail to consume them in your diet for a few days or weeks. Some others micronutrients, such as vitamin C and most of the B vitamins, are water-soluble and cannot be stored, so you need to consume them every day or two.

Narrow Range of Temperature

You have probably seen news stories about athletes who died of heat stroke, or hikers who died of exposure to cold. Such deaths occur because the chemical reactions upon which the body depends can only take place within a narrow range of body temperature, from just below to just above 37°C (98.6°F). When body temperature rises well above or drops well below normal, certain proteins (enzymes) that facilitate chemical reactions lose their normal structure and their ability to function and the chemical reactions of metabolism cannot proceed.

That said, the body can respond effectively to short-term exposure to heat (Figure 1) or cold. One of the body’s responses to heat is, of course, sweating. As sweat evaporates from skin, it removes some thermal energy from the body, cooling it. Adequate water (from the extracellular fluid in the body) is necessary to produce sweat, so adequate fluid intake is essential to balance that loss during the sweat response. Not surprisingly, the sweat response is much less effective in a humid environment because the air is already saturated with water. Thus, the sweat on the skin’s surface is not able to evaporate, and internal body temperature can get dangerously high.

[caption id="" align="aligncenter" width="420"] Figure 1. Extreme Heat. Humans adapt to some degree to repeated exposure to high temperatures. (credit: McKay Savage/flickr)[/caption]

The body can also respond effectively to short-term exposure to cold. One response to cold is shivering, which is random muscle movement that generates heat. Another response is increased breakdown of stored energy to generate heat. When that energy reserve is depleted, however, and the core temperature begins to drop significantly, red blood cells will lose their ability to give up oxygen, denying the brain of this critical component of ATP production. This lack of oxygen can cause confusion, lethargy, and eventually loss of consciousness and death. The body responds to cold by reducing blood circulation to the extremities, the hands and feet, in order to prevent blood from cooling there and so that the body’s core can stay warm. Even when core body temperature remains stable, however, tissues exposed to severe cold, especially the fingers and toes, can develop frostbite when blood flow to the extremities has been much reduced. This form of tissue damage can be permanent and lead to gangrene, requiring amputation of the affected region.

Narrow Range of Atmospheric Pressure

Pressure is a force exerted by a substance that is in contact with another substance. Atmospheric pressure is pressure exerted by the mixture of gases (primarily nitrogen and oxygen) in the Earth’s atmosphere. Although you may not perceive it, atmospheric pressure is constantly pressing down on your body. This pressure keeps gases within your body, such as the gaseous nitrogen in body fluids, dissolved. If you were suddenly ejected from a space ship above Earth’s atmosphere, you would go from a situation of normal pressure to one of very low pressure. The pressure of the nitrogen gas in your blood would be much higher than the pressure of nitrogen in the space surrounding your body. As a result, the nitrogen gas in your blood would expand, forming bubbles that could block blood vessels and even cause cells to break apart.

Atmospheric pressure does more than just keep blood gases dissolved. Your ability to breathe—that is, to take in oxygen and release carbon dioxide—also depends upon a precise atmospheric pressure. Altitude sickness occurs in part because the atmosphere at high altitudes exerts less pressure, reducing the exchange of these gases, and causing shortness of breath, confusion, headache, lethargy, and nausea. Mountain climbers carry oxygen to reduce the effects of both low oxygen levels and low barometric pressure at higher altitudes (Figure 2).

[caption id="" align="aligncenter" width="380"] Figure 2. Harsh Conditions. Climbers on Mount Everest must accommodate extreme cold, low oxygen levels, and low barometric pressure in an environment hostile to human life. (credit: Melanie Ko/flickr)[/caption]

1.5 Homeostasis

barkerj1 — Wed, 06 Sep 2017 01:19:12 +0000

Learning Objectives

By the end of this section, you will be able to:

Define the term "homeostasis"
Define the term "internal environment"

Homeostasis refers to a relatively stable set of conditions within an organism's internal environment. Within the human body, maintaining a healthy environment for living cells requires maintaining appropriate conditions in the extracellular fluids - interstitial fluid and blood plasma - for each living cell to be able to function properly.

Maintaining homeostasis requires that the body continuously monitor its internal conditions. From body temperature to blood pressure to levels of certain nutrients, each physiological condition has a particular set point. A set point is the physiological value around which the normal range fluctuates. A normal range is the restricted set of values that is optimally healthful and stable. For example, the set point for normal human body temperature is approximately 37°C (98.6°F) Physiological parameters, such as body temperature and blood pressure, tend to fluctuate within a normal range a few degrees above and below that point. Control centers in the brain and other parts of the body monitor and react to deviations from homeostasis using negative feedback. Negative feedback is a mechanism that reverses a deviation from the set point. Therefore, negative feedback maintains body parameters within their normal range. The maintenance of homeostasis by negative feedback goes on throughout the body at all times, and an understanding of negative feedback is thus fundamental to an understanding of human physiology.

Negative Feedback

A negative feedback system has three basic components (Figure 1a). A sensor, also referred to a receptor, is a component of a feedback system that monitors a physiological value. This value is reported to the control center. The control center is the component in a feedback system that compares the value to the normal range. If the value deviates too much from the set point, then the control center activates an effector. An effector is the component in a feedback system that causes a change to reverse the situation and return the value to the normal range.

[caption id="" align="aligncenter" width="450"] Figure 1. Negative Feedback Loop. In a negative feedback loop, a stimulus—a deviation from a set point—is resisted through a physiological process that returns the body to homeostasis. (a) A negative feedback loop has four basic parts. (b) Body temperature is regulated by negative feedback.[/caption]

In order to set the system in motion, a stimulus must drive a physiological parameter beyond its normal range (that is, beyond homeostasis). This stimulus is “heard” by a specific sensor. For example, in the control of blood glucose, specific endocrine cells in the pancreas detect excess glucose (the stimulus) in the bloodstream. These pancreatic beta cells respond to the increased level of blood glucose by releasing the hormone insulin into the bloodstream. The insulin signals skeletal muscle fibers, fat cells (adipocytes), and liver cells to take up the excess glucose, removing it from the bloodstream. As glucose concentration in the bloodstream drops, the decrease in concentration—the actual negative feedback—is detected by pancreatic alpha cells, and insulin release stops. This prevents blood sugar levels from continuing to drop below the normal range.

Humans have a similar temperature regulation feedback system that works by promoting either heat loss or heat gain (Figure 1b). When the brain’s temperature regulation center receives data from the sensors indicating that the body’s temperature exceeds its normal range, it stimulates a cluster of brain cells referred to as the “heat-loss center.” This stimulation has three major effects:

Blood vessels in the skin begin to dilate allowing more blood from the body core to flow to the surface of the skin allowing the heat to radiate into the environment.
As blood flow to the skin increases, sweat glands are activated to increase their output. As the sweat evaporates from the skin surface into the surrounding air, it takes heat with it.
The depth of respiration increases, and a person may breathe through an open mouth instead of through the nasal passageways. This further increases heat loss from the lungs.

In contrast, activation of the brain’s heat-gain center by exposure to cold reduces blood flow to the skin, and blood returning from the limbs is diverted into a network of deep veins. This arrangement traps heat closer to the body core and restricts heat loss. If heat loss is severe, the brain triggers an increase in random signals to skeletal muscles, causing them to contract and producing shivering. The muscle contractions of shivering release heat while using up ATP. The brain triggers the thyroid gland in the endocrine system to release thyroid hormone, which increases metabolic activity and heat production in cells throughout the body. The brain also signals the adrenal glands to release epinephrine (adrenaline), a hormone that causes the breakdown of glycogen into glucose, which can be used as an energy source. The breakdown of glycogen into glucose also results in increased metabolism and heat production.

[caption id="attachment_2988" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about homeostasis.[/caption]

Positive Feedback

Positive feedback intensifies a change in the body’s physiological condition rather than reversing it. A deviation from the normal range results in more change, and the system moves farther away from the normal range. Positive feedback in the body is normal only when there is a definite end point. Childbirth and the body’s response to blood loss are two examples of positive feedback loops that are normal but are activated only when needed.

Childbirth at full term is an example of a situation in which the maintenance of the existing body state is not desired. Enormous changes in the mother’s body are required to expel the baby at the end of pregnancy. And the events of childbirth, once begun, must progress rapidly to a conclusion or the life of the mother and the baby are at risk. The extreme muscular work of labor and delivery are the result of a positive feedback system (Figure 2).

[caption id="" align="aligncenter" width="380"] Figure 2. Positive Feedback Loop. Normal childbirth is driven by a positive feedback loop. A positive feedback loop results in a change in the body’s status, rather than a return to homeostasis.[/caption] The first contractions of labor (the stimulus) push the baby toward the cervix (the lowest part of the uterus). The cervix contains stretch-sensitive nerve cells that monitor the degree of stretching (the sensors). These nerve cells send messages to the brain, which in turn causes the pituitary gland at the base of the brain to release the hormone oxytocin into the bloodstream. Oxytocin causes stronger contractions of the smooth muscles in of the uterus (the effectors), pushing the baby further down the birth canal. This causes even greater stretching of the cervix. The cycle of stretching, oxytocin release, and increasingly more forceful contractions stops only when the baby is born. At this point, the stretching of the cervix halts, stopping the release of oxytocin.

A second example of positive feedback centers on reversing extreme damage to the body. Following a penetrating wound, the most immediate threat is excessive blood loss. Less blood circulating means reduced blood pressure and reduced perfusion (penetration of blood) to the brain and other vital organs. If perfusion is severely reduced, vital organs will shut down and the person will die. The body responds to this potential catastrophe by releasing substances in the injured blood vessel wall that begin the process of blood clotting. As each step of clotting occurs, it stimulates the release of more clotting substances. This accelerates the processes of clotting and sealing off the damaged area. Clotting is contained in a local area based on the tightly controlled availability of clotting proteins. This is an adaptive, life-saving cascade of events.

2.1 Elements and Atoms: the Building Blocks of Matter

barkerj1 — Wed, 06 Sep 2017 01:19:14 +0000

Learning Objectives

By the end of this section, you will be able to:

Review 1103/1109 material

The substance of the universe—from a grain of sand to a star—is called matter. Scientists define matter as anything that occupies space and has mass. An object’s mass and its weight are related concepts, but not quite the same. An object’s mass is the amount of matter contained in the object, and the object’s mass is the same whether that object is on Earth or in the zero-gravity environment of outer space. An object’s weight, on the other hand, is its mass as affected by the pull of gravity. Where gravity strongly pulls on an object’s mass its weight is greater than it is where gravity is less strong. An object of a certain mass weighs less on the moon, for example, than it does on Earth because the gravity of the moon is less than that of Earth. In other words, weight is variable, and is influenced by gravity. A piece of cheese that weighs a pound on Earth weighs only a few ounces on the moon.

Elements and Compounds

All matter in the natural world is composed of one or more of the 92 fundamental substances called elements. An element is a pure substance that is distinguished from all other matter by the fact that it cannot be created or broken down by ordinary chemical means. While your body can assemble many of the chemical compounds needed for life from their constituent elements, it cannot make elements. They must come from the environment. A familiar example of an element that you must take in is calcium (Ca⁺⁺). Calcium is essential to the human body; it is absorbed and used for a number of processes, including strengthening bones. When you consume dairy products your digestive system breaks down the food into components small enough to cross into the bloodstream. Among these is calcium, which, because it is an element, cannot be broken down further. The elemental calcium in cheese, therefore, is the same as the calcium that forms your bones. Some other elements you might be familiar with are oxygen, sodium, and iron. The elements in the human body are shown in Figure 1, beginning with the most abundant: oxygen (O), carbon (C), hydrogen (H), and nitrogen (N). Each element’s name can be replaced by a one- or two-letter symbol; you will become familiar with some of these during this course. All the elements in your body are derived from the foods you eat and the air you breathe.

[caption id="" align="aligncenter" width="520"] Figure 1. Elements of the Human Body. The main elements that compose the human body are shown from most abundant to least abundant.[/caption]

In nature, elements rarely occur alone. Instead, they combine to form compounds. A compound is a substance composed of two or more elements joined by chemical bonds. For example, the compound glucose is an important body fuel. It is always composed of the same three elements: carbon, hydrogen, and oxygen. Moreover, the elements that make up any given compound always occur in the same relative amounts. In glucose, there are always six carbon and six oxygen units for every twelve hydrogen units. But what, exactly, are these “units” of elements?

Atoms and Subatomic Particles

An atom is the smallest quantity of an element that retains the unique properties of that element. In other words, an atom of hydrogen is a unit of hydrogen—the smallest amount of hydrogen that can exist. As you might guess, atoms are almost unfathomably small. The period at the end of this sentence is millions of atoms wide.

Atomic Structure and Energy

Atoms are made up of even smaller subatomic particles, three types of which are important: the proton, neutron, and electron. The number of positively-charged protons and non-charged (“neutral”) neutrons, gives mass to the atom, and the number of each in the nucleus of the atom determine the element. The number of negatively-charged electrons that “spin” around the nucleus at close to the speed of light equals the number of protons. An electron has about 1/2000th the mass of a proton or neutron.

Figure 2 shows two models that can help you imagine the structure of an atom—in this case, helium (He). In the planetary model, helium’s two electrons are shown circling the nucleus in a fixed orbit depicted as a ring. Although this model is helpful in visualizing atomic structure, in reality, electrons do not travel in fixed orbits, but whiz around the nucleus erratically in a so-called electron cloud.

[caption id="" align="alignleft" width="285"] Figure 2. Two Models of Atomic Structure. (a) In the planetary model, the electrons of helium are shown in fixed orbits, depicted as rings, at a precise distance from the nucleus, somewhat like planets orbiting the sun. (b) In the electron cloud model, the electrons of carbon are shown in the variety of locations they would have at different distances from the nucleus over time.[/caption]

An atom’s protons and electrons carry electrical charges. Protons, with their positive charge, are designated p⁺. Electrons, which have a negative charge, are designated e^–. An atom’s neutrons have no charge: they are electrically neutral. Just as a magnet sticks to a steel refrigerator because their opposite charges attract, the positively charged protons attract the negatively charged electrons. This mutual attraction gives the atom some structural stability. The attraction by the positively charged nucleus helps keep electrons from straying far. The number of protons and electrons within a neutral atom are equal, thus, the atom’s overall charge is balanced.

Atomic Number and Mass Number

An atom of carbon is unique to carbon, but a proton of carbon is not. One proton is the same as another, whether it is found in an atom of carbon, sodium (Na), or iron (Fe). The same is true for neutrons and electrons. So, what gives an element its distinctive properties—what makes carbon so different from sodium or iron? The answer is the unique quantity of protons each contains. Carbon by definition is an element whose atoms contain six protons. No other element has exactly six protons in its atoms. Moreover, all atoms of carbon, whether found in your liver or in a lump of coal, contain six protons. Thus, the atomic number, which is the number of protons in the nucleus of the atom, identifies the element. Because an atom usually has the same number of electrons as protons, the atomic number identifies the usual number of electrons as well.

In their most common form, many elements also contain the same number of neutrons as protons. The most common form of carbon, for example, has six neutrons as well as six protons, for a total of 12 subatomic particles in its nucleus. An element’s mass number is the sum of the number of protons and neutrons in its nucleus. So the most common form of carbon’s mass number is 12. (Electrons have so little mass that they do not appreciably contribute to the mass of an atom.) Carbon is a relatively light element. Uranium (U), in contrast, has a mass number of 238 and is referred to as a heavy metal. Its atomic number is 92 (it has 92 protons) but it contains 146 neutrons; it has the most mass of all the naturally occurring elements.

The periodic table of the elements, shown in Figure 3, is a chart identifying the 92 elements found in nature, as well as several larger, unstable elements discovered experimentally. The elements are arranged in order of their atomic number, with hydrogen and helium at the top of the table, and the more massive elements below. The periodic table is a useful device because for each element, it identifies the chemical symbol, the atomic number, and the mass number, while organizing elements according to their propensity to react with other elements. The number of protons and electrons in an element are equal. The number of protons and neutrons may be equal for some elements, but are not equal for all.

[caption id="" align="aligncenter" width="650"] Figure 3. The Periodic Table of the Elements. (credit: R.A. Dragoset, A. Musgrove, C.W. Clark, W.C. Martin)[/caption]

In the periodic table of the elements, elements in a single column have the same number of electrons that can participate in a chemical reaction. These electrons are known as “valence electrons.” For example, the elements in the first column all have a single valence electron, an electron that can be “donated” in a chemical reaction with another atom.

Isotopes

Although each element has a unique number of protons, it can exist as different isotopes. An isotope is one of the different forms of an element, distinguished from one another by different numbers of neutrons. The standard isotope of carbon is ¹²C, commonly called carbon twelve. ¹²C has six protons and six neutrons, for a mass number of twelve. All of the isotopes of carbon have the same number of protons; therefore,¹³C has seven neutrons, and ¹⁴C has eight neutrons. The different isotopes of an element can also be indicated with the mass number hyphenated (for example, C-12 instead of ¹²C). Hydrogen has three common isotopes, shown in Figure 4.

[caption id="" align="aligncenter" width="380"] Figure 4. Isotopes of Hydrogen. Protium, designated 1H, has one proton and no neutrons. It is by far the most abundant isotope of hydrogen in nature. Deuterium, designated 2H, has one proton and one neutron. Tritium, designated 3H, has two neutrons.[/caption]

An isotope that contains more than the usual number of neutrons is referred to as a heavy isotope. An example is ¹⁴C. Heavy isotopes tend to be unstable, and unstable isotopes are radioactive. A radioactive isotope is an isotope whose nucleus readily decays, giving off subatomic particles and electromagnetic energy. Different radioactive isotopes (also called radioisotopes) differ in their half-life, the time it takes for half of any size sample of an isotope to decay. For example, the half-life of tritium—a radioisotope of hydrogen—is about 12 years, indicating it takes 12 years for half of the tritium nuclei in a sample to decay. Excessive exposure to radioactive isotopes can damage human cells and even cause cancer and birth defects, but when exposure is controlled, some radioactive isotopes can be useful in medicine. For more information, see the Career Connections.

The Behavior of Electrons

In the human body, atoms do not exist as independent entities. Rather, they are constantly reacting with other atoms to form and to break down more complex substances. To fully understand anatomy and physiology you must grasp how atoms participate in such reactions. The key is understanding the behavior of electrons.

Although electrons do not follow rigid orbits a set distance away from the atom’s nucleus, they do tend to stay within certain regions of space called electron shells. An electron shell is a layer of electrons that encircle the nucleus at a distinct energy level.

The atoms of the elements found in the human body have from one to five electron shells, and all electron shells hold eight electrons except the first shell, which can only hold two. This configuration of electron shells is the same for all atoms. The precise number of shells depends on the number of electrons in the atom. Hydrogen and helium have just one and two electrons, respectively. If you take a look at the periodic table of the elements, you will notice that hydrogen and helium are placed alone on either sides of the top row; they are the only elements that have just one electron shell (Figure 6). A second shell is necessary to hold the electrons in all elements larger than hydrogen and helium.

Lithium (Li), whose atomic number is 3, has three electrons. Two of these fill the first electron shell, and the third spills over into a second shell. The second electron shell can accommodate as many as eight electrons. Carbon, with its six electrons, entirely fills its first shell, and half-fills its second. With ten electrons, neon (Ne) entirely fills its two electron shells. Again, a look at the periodic table reveals that all of the elements in the second row, from lithium to neon, have just two electron shells. Atoms with more than ten electrons require more than two shells. These elements occupy the third and subsequent rows of the periodic table.

[caption id="" align="aligncenter" width="420"] Figure 6. Electron Shells. Electrons orbit the atomic nucleus at distinct levels of energy called electron shells. (a) With one electron, hydrogen only half-fills its electron shell. Helium also has a single shell, but its two electrons completely fill it. (b) The electrons of carbon completely fill its first electron shell, but only half-fills its second. (c) Neon, an element that does not occur in the body, has 10 electrons, filling both of its electron shells.[/caption]

The factor that most strongly governs the tendency of an atom to participate in chemical reactions is the number of electrons in its valence shell. A valence shell is an atom’s outermost electron shell. If the valence shell is full, the atom is stable; meaning its electrons are unlikely to be pulled away from the nucleus by the electrical charge of other atoms. If the valence shell is not full, the atom is reactive; meaning it will tend to react with other atoms in ways that make the valence shell full. Consider hydrogen, with its one electron only half-filling its valence shell. This single electron is likely to be drawn into relationships with the atoms of other elements, so that hydrogen’s single valence shell can be stabilized.

All atoms (except hydrogen and helium with their single electron shells) are most stable when there are exactly eight electrons in their valence shell. This principle is referred to as the octet rule, and it states that an atom will give up, gain, or share electrons with another atom so that it ends up with eight electrons in its own valence shell. For example, oxygen, with six electrons in its valence shell, is likely to react with other atoms in a way that results in the addition of two electrons to oxygen’s valence shell, bringing the number to eight. When two hydrogen atoms each share their single electron with oxygen, covalent bonds are formed, resulting in a molecule of water, H₂O.

In nature, atoms of one element tend to join with atoms of other elements in characteristic ways. For example, carbon commonly fills its valence shell by linking up with four atoms of hydrogen. In so doing, the two elements form the simplest of organic molecules, methane, which also is one of the most abundant and stable carbon-containing compounds on Earth. As stated above, another example is water; oxygen needs two electrons to fill its valence shell. It commonly interacts with two atoms of hydrogen, forming H₂O. Incidentally, the name “hydrogen” reflects its contribution to water (hydro- = “water”; -gen = “maker”). Thus, hydrogen is the “water maker.”

2.2 Chemical Bonds

barkerj1 — Wed, 06 Sep 2017 01:19:15 +0000

Learning Objectives

By the end of this section, you will be able to:

Review 1103/1109 material

Atoms separated by a great distance cannot link; rather, they must come close enough for the electrons in their valence shells to interact. But do atoms ever actually touch one another? Most physicists would say no, because the negatively charged electrons in their valence shells repel one another. No force within the human body—or anywhere in the natural world—is strong enough to overcome this electrical repulsion. So when you read about atoms linking together or colliding, bear in mind that the atoms are not merging in a physical sense.

Instead, atoms link by forming a chemical bond. A bond is a weak or strong electrical attraction that holds atoms in the same vicinity. The new grouping is typically more stable—less likely to react again—than its component atoms were when they were separate. A more or less stable grouping of two or more atoms held together by chemical bonds is called a molecule. The bonded atoms may be of the same element, as in the case of H₂, which is called molecular hydrogen or hydrogen gas. When a molecule is made up of two or more atoms of different elements, it is called a chemical compound. Thus, a unit of water, or H₂O, is a compound, as is a single molecule of the gas methane, or CH₄.

Three types of chemical bonds are important in human physiology, because they hold together substances that are used by the body for critical aspects of homeostasis, signaling, and energy production, to name just a few important processes. These are ionic bonds, covalent bonds, and hydrogen bonds.

Ions and Ionic Bonds

Recall that an atom typically has the same number of positively charged protons and negatively charged electrons. As long as this situation remains, the atom is electrically neutral. But when an atom participates in a chemical reaction that results in the donation or acceptance of one or more electrons, the atom will then become positively or negatively charged. This happens frequently for most atoms in order to have a full valence shell, as described previously. This can happen either by gaining electrons to fill a shell that is more than half-full, or by giving away electrons to empty a shell than is less than half-full, thereby leaving the next smaller electron shell as the new, full, valence shell. An atom that has an electrical charge—whether positive or negative—is an ion.

[caption id="attachment_2990" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about electric charges.[/caption]

Potassium (K), for instance, is an important element in all body cells. Its atomic number is 19. It has just one electron in its valence shell. This characteristic makes potassium highly likely to participate in chemical reactions in which it donates one electron. (It is easier for potassium to donate one electron than to gain seven electrons.) The loss will cause the positive charge of potassium’s protons to be more influential than the negative charge of potassium’s electrons. In other words, the resulting potassium ion will be slightly positive. A potassium ion is written K⁺, indicating that it has lost a single electron. A positively charged ion is known as a cation.

Now consider fluorine (F), a component of bones and teeth. Its atomic number is nine, and it has seven electrons in its valence shell. Thus, it is highly likely to bond with other atoms in such a way that fluorine accepts one electron (it is easier for fluorine to gain one electron than to donate seven electrons). When it does, its electrons will outnumber its protons by one, and it will have an overall negative charge. The ionized form of fluorine is called fluoride, and is written as F^–. A negatively charged ion is known as an anion.

Atoms that have more than one electron to donate or accept will end up with stronger positive or negative charges. A cation that has donated two electrons has a net charge of +2. Using magnesium (Mg) as an example, this can be written Mg⁺⁺ or Mg²⁺. An anion that has accepted two electrons has a net charge of –2. The ionic form of selenium (Se), for example, is typically written Se^2–.

The opposite charges of cations and anions exert a moderately strong mutual attraction that keeps the atoms in close proximity forming an ionic bond. An ionic bond is an ongoing, close association between ions of opposite charge. The table salt you sprinkle on your food owes its existence to ionic bonding. As shown in Figure 1, sodium commonly donates an electron to chlorine, becoming the cation Na⁺. When chlorine accepts the electron, it becomes the chloride anion, Cl^–. With their opposing charges, these two ions strongly attract each other.

[caption id="" align="aligncenter" width="420"] Figure 1. Ionic Bonding. (a) Sodium readily donates the solitary electron in its valence shell to chlorine, which needs only one electron to have a full valence shell. (b) The opposite electrical charges of the resulting sodium cation and chloride anion result in the formation of a bond of attraction called an ionic bond. (c) The attraction of many sodium and chloride ions results in the formation of large groupings called crystals.[/caption]

Water is an essential component of life because it is able to break the ionic bonds in salts to free the ions. In fact, in biological fluids, most individual atoms exist as ions. These dissolved ions produce electrical charges within the body. The behavior of these ions produces the tracings of heart and brain function observed as waves on an electrocardiogram (EKG or ECG) or an electroencephalogram (EEG). The electrical activity that derives from the interactions of the charged ions is why they are also called electrolytes.

Covalent Bonds

Unlike ionic bonds formed by the attraction between a cation’s positive charge and an anion’s negative charge, molecules formed by a covalent bond share electrons in a mutually stabilizing relationship. Like next-door neighbors whose kids hang out first at one home and then at the other, the atoms do not lose or gain electrons permanently. Instead, the electrons move back and forth between the elements. Because of the close sharing of pairs of electrons (one electron from each of two atoms), covalent bonds are stronger than ionic bonds.

Nonpolar Covalent Bonds

Figure 2 shows several common types of covalent bonds. Notice that the two covalently bonded atoms typically share just one or two electron pairs, though larger sharings are possible. The important concept to take from this is that in covalent bonds, electrons in the outermost valence shell are shared to fill the valence shells of both atoms, ultimately stabilizing both of the atoms involved. In a single covalent bond, a single electron is shared between two atoms, while in a double covalent bond, two pairs of electrons are shared between two atoms. There even are triple covalent bonds, where three atoms are shared.

[caption id="" align="aligncenter" width="550"] Figure 2. Covalent Bonding.[/caption] You can see that the covalent bonds shown in Figure 2 are balanced. The sharing of the negative electrons is relatively equal, as is the electrical pull of the positive protons in the nucleus of the atoms involved. This is why covalently bonded molecules that are electrically balanced in this way are described as nonpolar; that is, no region of the molecule is either more positive or more negative than any other.

Polar Covalent Bonds

Groups of legislators with completely opposite views on a particular issue are often described as “polarized” by news writers. In chemistry, a polar molecule is a molecule that contains regions that have opposite electrical charges. Polar molecules occur when atoms share electrons unequally, in polar covalent bonds.

The most familiar example of a polar molecule is water (Figure 3). The molecule has three parts: one atom of oxygen, the nucleus of which contains eight protons, and two hydrogen atoms, whose nuclei each contain only one proton. Because every proton exerts an identical positive charge, a nucleus that contains eight protons exerts a charge eight times greater than a nucleus that contains one proton. This means that the negatively charged electrons present in the water molecule are more strongly attracted to the oxygen nucleus than to the hydrogen nuclei. Each hydrogen atom’s single negative electron therefore migrates toward the oxygen atom, making the oxygen end of their bond slightly more negative than the hydrogen end of their bond.

[caption id="" align="aligncenter" width="380"] Figure 3. Polar Covalent Bonds in a Water Molecule.[/caption]

What is true for the bonds is true for the water molecule as a whole; that is, the oxygen region has a slightly negative charge and the regions of the hydrogen atoms have a slightly positive charge. These charges are often referred to as “partial charges” because the strength of the charge is less than one full electron, as would occur in an ionic bond. As shown in Figure 3, regions of weak polarity are indicated with the Greek letter delta (∂) and a plus (+) or minus (–) sign.

Even though a single water molecule is unimaginably tiny, it has mass, and the opposing electrical charges on the molecule pull that mass in such a way that it creates a shape somewhat like a triangular tent (see Figure 3b). This dipole, with the positive charges at one end formed by the hydrogen atoms at the “bottom” of the tent and the negative charge at the opposite end (the oxygen atom at the “top” of the tent) makes the charged regions highly likely to interact with charged regions of other polar molecules. For human physiology, the resulting bond is one of the most important formed by water—the hydrogen bond.

Hydrogen Bonds

A hydrogen bond is formed when a weakly positive hydrogen atom already bonded to one electronegative atom (for example, the oxygen in the water molecule) is attracted to another electronegative atom from another molecule. In other words, hydrogen bonds always include hydrogen that is already part of a polar molecule.

The most common example of hydrogen bonding in the natural world occurs between molecules of water. It happens before your eyes whenever two raindrops merge into a larger bead, or a creek spills into a river. Hydrogen bonding occurs because the weakly negative oxygen atom in one water molecule is attracted to the weakly positive hydrogen atoms of two other water molecules (Figure 4).

[caption id="" align="aligncenter" width="280"] Figure 4. Hydrogen Bonds between Water Molecules. Notice that the bonds occur between the weakly positive charge on the hydrogen atoms and the weakly negative charge on the oxygen atoms. Hydrogen bonds are relatively weak, and therefore are indicated with a dotted (rather than a solid) line.[/caption]

Water molecules also strongly attract other types of charged molecules as well as ions. This explains why “table salt,” for example, actually is a molecule called a “salt” in chemistry, which consists of equal numbers of positively-charged sodium (Na⁺) and negatively-charged chloride (Cl^–), dissolves so readily in water, in this case forming dipole-ion bonds between the water and the electrically-charged ions (electrolytes). Water molecules also repel molecules with nonpolar covalent bonds, like fats, lipids, and oils. You can demonstrate this with a simple kitchen experiment: pour a teaspoon of vegetable oil, a compound formed by nonpolar covalent bonds, into a glass of water. Instead of instantly dissolving in the water, the oil forms a distinct bead because the polar water molecules repel the nonpolar oil.

2.4 Inorganic Compounds Essential to Human Functioning

barkerj1 — Wed, 06 Sep 2017 01:19:16 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the difference between compounds that are electrolytes and those that are non-electrolytes
Define the following terms:
- Acid
- Base
- Buffer
Describe pH and the pH scale
Describe some sources of acids and bases in the body
Define acidosis, and specify two general causes of acidosis
Define alkalosis, and specify two general causes of alkalosis

The concepts you have learned so far in this chapter govern all forms of matter, and would work as a foundation for geology as well as biology. This section of the chapter narrows the focus to the chemistry of human life; that is, the compounds important for the body’s structure and function. In general, these compounds are either inorganic or organic.

An inorganic compound is a substance that does not contain both carbon and hydrogen. A great many inorganic compounds do contain hydrogen atoms, such as water (H₂O) and the hydrochloric acid (HCl) produced by your stomach. In contrast, only a handful of inorganic compounds contain carbon atoms. Carbon dioxide (CO₂) is one of the few examples.
An organic compound, then, is a substance that contains both carbon and hydrogen. Organic compounds are synthesized via covalent bonds within living organisms, including the human body. Recall that carbon and hydrogen are the second and third most abundant elements in your body. You will soon discover how these two elements combine in the foods you eat, in the compounds that make up your body structure, and in the chemicals that fuel your functioning.

The following section examines the three groups of inorganic compounds essential to life: water, salts, acids, and bases. Organic compounds are covered later in the chapter.

Water

As much as 70 percent of an adult’s body weight is water. This water is contained both within the cells and between the cells that make up tissues and organs. Its several roles make water indispensable to human functioning.

Water as a Lubricant and Cushion

Water is a major component of many of the body’s lubricating fluids. Just as oil lubricates the hinge on a door, water in synovial fluid lubricates the actions of body joints, and water in pleural fluid helps the lungs expand and recoil with breathing. Watery fluids help keep food flowing through the digestive tract, and ensure that the movement of adjacent abdominal organs is friction free.

Water also protects cells and organs from physical trauma, cushioning the brain within the skull, for example, and protecting the delicate nerve tissue of the eyes. Water cushions a developing fetus in the mother’s womb as well.

Water as a Heat Sink

A heat sink is a substance or object that absorbs and dissipates heat but does not experience a corresponding increase in temperature. In the body, water absorbs the heat generated by chemical reactions without greatly increasing in temperature. Moreover, when environmental temperature soars, the water stored in the body helps keep the body cool. This cooling effect happens as warm blood from the body’s core flows to the blood vessels just under the skin and is transferred out to the environment as radiant heat. At the same time, sweat glands release warm water in sweat. For evaporation of this water to occur, the hydrogen bonds between the water molecules must be broken, requiring a relatively high amount of energy that in part includes heat. This removal of heat by evaporation results in a cooling of the blood in the body's periphery, near the surface of the skin, which then circulates back to the body core and cools the body.

Water as a Component of Liquid Mixtures

A mixture is a combination of two or more substances, each of which maintains its own chemical identity. In other words, the constituent substances are not chemically bonded into a new, larger chemical compound. The concept is easy to imagine if you think of powdery substances such as flour and sugar; when you stir them together in a bowl, they obviously do not bond to form a new compound. The room air you breathe is a gaseous mixture, containing three discrete elements—nitrogen, oxygen, and argon—and one compound, carbon dioxide. There are three types of liquid mixtures, all of which contain water as a key component. These are solutions, colloids, and suspensions.

For cells in the body to survive, they must be kept moist in a water-based liquid called a solution. In chemistry, a liquid solution consists of a solvent that dissolves a substance called a solute. An important characteristic of solutions is that they are homogeneous; that is, the solute molecules are distributed evenly throughout the solution. If you were to stir a teaspoon of sugar into a glass of water, the sugar would dissolve into sugar molecules separated by water molecules. The ratio of sugar to water in the left side of the glass would be the same as the ratio of sugar to water in the right side of the glass. If you were to add more sugar, the ratio of sugar to water would change, but the distribution—provided you had stirred well—would still be even.

Water is considered the “universal solvent” and it is believed that life cannot exist without water because of this. Water is certainly the most abundant solvent in the body; essentially all of the body’s chemical reactions occur among compounds dissolved in water. Because water molecules are polar, with regions of positive and negative electrical charge, water readily dissolves ionic compounds and polar covalent compounds. Such compounds are referred to as hydrophilic, or “water-loving.” As mentioned above, sugar dissolves well in water. This is because sugar molecules contain regions of hydrogen-oxygen polar bonds, making it hydrophilic. Nonpolar molecules, which do not readily dissolve in water, are called hydrophobic, or “water-fearing.”

Concentrations of Solutes

Various mixtures of solutes and water are described in chemistry. The concentration of a given solute is the number of particles of that solute in a given space (oxygen makes up about 21 percent of atmospheric air). In the bloodstream of humans, glucose concentration is usually measured in milligram (mg) per deciliter (dL), and in a healthy adult averages about 100 mg/dL. Another method of measuring the concentration of a solute is by its molarilty—which is moles (M) of the molecules per liter (L). The mole of an element is its atomic weight, while a mole of a compound is the sum of the atomic weights of its components, called the molecular weight. An often-used example is calculating a mole of glucose, with the chemical formula C₆H₁₂O₆. Using the periodic table, the atomic weight of carbon (C) is 12.011 grams (g), and there are six carbons in glucose, for a total atomic weight of 72.066 g. Doing the same calculations for hydrogen (H) and oxygen (O), the molecular weight equals 180.156g (the “gram molecular weight” of glucose). When water is added to make one liter of solution, you have one mole (1M) of glucose. This is particularly useful in chemistry because of the relationship of moles to “Avogadro’s number.” A mole of any solution has the same number of particles in it: 6.02 × 10²³. Many substances in the bloodstream and other tissue of the body are measured in thousandths of a mole, or millimoles (mM).

A colloid is a mixture that is somewhat like a heavy solution. The solute particles consist of tiny clumps of molecules large enough to make the liquid mixture opaque (because the particles are large enough to scatter light). Familiar examples of colloids are milk and cream. In the thyroid glands, the thyroid hormone is stored as a thick protein mixture also called a colloid.

A suspension is a liquid mixture in which a heavier substance is suspended temporarily in a liquid, but over time, settles out. This separation of particles from a suspension is called sedimentation. An example of sedimentation occurs in the blood test that establishes sedimentation rate, or sed rate. The test measures how quickly red blood cells in a test tube settle out of the watery portion of blood (known as plasma) over a set period of time. Rapid sedimentation of blood cells does not normally happen in the healthy body, but aspects of certain diseases can cause blood cells to clump together, and these heavy clumps of blood cells settle to the bottom of the test tube more quickly than do normal blood cells.

The Role of Water in Chemical Reactions

Two types of chemical reactions involve the creation or the consumption of water: dehydration synthesis and hydrolysis.

In dehydration synthesis, one reactant gives up an atom of hydrogen and another reactant gives up a hydroxyl group (OH) in the synthesis of a new product. In the formation of their covalent bond, a molecule of water is released as a byproduct (Figure 1). This is also sometimes referred to as a condensation reaction.
In hydrolysis, a molecule of water disrupts a compound, breaking its bonds. The water is itself split into H and OH. One portion of the severed compound then bonds with the hydrogen atom, and the other portion bonds with the hydroxyl group.

These reactions are reversible, and play an important role in the chemistry of organic compounds (which will be discussed shortly).

[caption id="" align="aligncenter" width="520"] Figure 1. Dehydration Synthesis and Hydrolysis. Monomers, the basic units for building larger molecules, form polymers (two or more chemically-bonded monomers). (a) In dehydration synthesis, two monomers are covalently bonded in a reaction in which one gives up a hydroxyl group and the other a hydrogen atom. A molecule of water is released as a byproduct during dehydration reactions. (b) In hydrolysis, the covalent bond between two monomers is split by the addition of a hydrogen atom to one and a hydroxyl group to the other, which requires the contribution of one molecule of water.[/caption]

[caption id="attachment_3037" align="aligncenter" width="150"] Watch this amoeba sisters video to learn more about the properties of water![/caption] [caption id="attachment_2951" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about the importance of water![/caption]

Salts

Recall that salts are formed when ions form ionic bonds. In these reactions, one atom gives up one or more electrons, and thus becomes positively charged, whereas the other accepts one or more electrons and becomes negatively charged. You can now define a salt as a substance that, when dissolved in water, dissociates into ions other than H⁺ or OH^–. This fact is important in distinguishing salts from acids and bases, discussed next.

A typical salt, NaCl, dissociates completely in water (Figure 2). The positive and negative regions on the water molecule (the hydrogen and oxygen ends respectively) attract the negative chloride and positive sodium ions, pulling them away from each other. Again, whereas nonpolar and polar covalently bonded compounds break apart into molecules in solution, salts dissociate into ions. These ions are electrolytes; they are capable of conducting an electrical current in solution. This property is critical to the function of ions in transmitting nerve impulses and prompting muscle contraction.

[caption id="" align="aligncenter" width="480"] Figure 2. Dissociation of Sodium Chloride in Water. Notice that the crystals of sodium chloride dissociate not into molecules of NaCl, but into Na+ cations and Cl– anions, each completely surrounded by water molecules.[/caption]

Many other salts are important in the body. For example, bile salts produced by the liver help break apart dietary fats, and calcium phosphate salts form the mineral portion of teeth and bones.

Acids and Bases

Acids and bases, like salts, dissociate in water into electrolytes. Acids and bases can very much change the properties of the solutions in which they are dissolved.

Acids

An acid is a substance that releases hydrogen ions (H⁺) in solution (Figure 3a). Because an atom of hydrogen has just one proton and one electron, a positively charged hydrogen ion is simply a proton. This solitary proton is highly likely to participate in chemical reactions. Strong acids are compounds that release all of their H⁺in solution; that is, they ionize completely. Hydrochloric acid (HCl), which is released from cells in the lining of the stomach, is a strong acid because it releases all of its H⁺in the stomach’s watery environment. This strong acid aids in digestion and kills ingested microbes. Weak acids do not ionize completely; that is, some of their hydrogen ions remain bound within a compound in solution. An example of a weak acid is vinegar, or acetic acid; it is called acetate after it gives up a proton.

Acids and Bases

(a) In aqueous solution, an acid dissociates into hydrogen ions (H⁺) and anions. Nearly every molecule of a strong acid dissociates, producing a high concentration of H⁺. (b) In aqueous solution, a base dissociates into hydroxyl ions (OH^–) and cations. Nearly every molecule of a strong base dissociates, producing a high concentration of OH^–.

[caption id="" align="aligncenter" width="420"] Figure 3. Acids and Bases. (a) In aqueous solution, an acid dissociates into hydrogen ions (H+) and anions. Nearly every molecule of a strong acid dissociates, producing a high concentration of H+. (b) In aqueous solution, a base dissociates into hydroxyl ions (OH–) and cations. Nearly every molecule of a strong base dissociates, producing a high concentration of OH–.[/caption]

Bases

A base is a substance that releases hydroxyl ions (OH^–) in solution, or one that accepts H⁺ already present in solution (see Figure 3b). The hydroxyl ions (also known as hydroxide ions) or other basic substances combine with H⁺present to form a water molecule, thereby removing H⁺ and reducing the solution’s acidity. Strong bases release most or all of their hydroxyl ions; weak bases release only some hydroxyl ions or absorb only a few H⁺. Food mixed with hydrochloric acid from the stomach would burn the small intestine, the next portion of the digestive tract after the stomach, if it were not for the release of bicarbonate (HCO₃^–), a weak base that attracts H⁺. Bicarbonate accepts some of the H⁺ protons, thereby reducing the acidity of the solution.

The Concept of pH

The relative acidity or alkalinity of a solution can be indicated by its pH. A solution’s pH is the negative, base-10 logarithm of the hydrogen ion (H⁺) concentration of the solution. As an example, a pH 4 solution has an H⁺ concentration that is ten times greater than that of a pH 5 solution. That is, a solution with a pH of 4 is ten times more acidic than a solution with a pH of 5. The concept of pH will begin to make more sense when you study the pH scale, like that shown in [link]. The scale consists of a series of increments ranging from 0 to 14. A solution with a pH of 7 is considered neutral—neither acidic nor basic. Pure water has a pH of 7. The lower the number below 7, the more acidic the solution, or the greater the concentration of H⁺. The concentration of hydrogen ions at each pH value is 10 times different than the next pH. For instance, a pH value of 4 corresponds to a proton concentration of 10^–4 M, or 0.0001M, while a pH value of 5 corresponds to a proton concentration of 10^–5 M, or 0.00001M. The higher the number above 7, the more basic (alkaline) the solution, or the lower the concentration of H⁺. Human urine, for example, is ten times more acidic than pure water, and HCl is 10,000,000 times more acidic than water.

[caption id="" align="aligncenter" width="320"] Figure 4. The pH Scale[/caption]

Buffers

The pH of human blood normally ranges from 7.35 to 7.45, although it is typically identified as pH 7.4. At this slightly basic pH, blood can reduce the acidity resulting from the carbon dioxide (CO₂) constantly being released into the bloodstream by the trillions of cells in the body. Homeostatic mechanisms (along with exhaling CO₂ while breathing) normally keep the pH of blood within this narrow range. This is critical, because fluctuations—either too acidic or too alkaline—can lead to life-threatening disorders.

All cells of the body depend on homeostatic regulation of acid–base balance at a pH of approximately 7.4. The body therefore has several mechanisms for this regulation, involving breathing, the excretion of chemicals in urine, and the internal release of chemicals collectively called buffers into body fluids. A buffer is a solution of a weak acid and its conjugate base. A buffer can neutralize small amounts of acids or bases in body fluids. For example, if there is even a slight decrease below 7.35 in the pH of a bodily fluid, the buffer in the fluid—in this case, acting as a weak base—will bind the excess hydrogen ions. In contrast, if pH rises above 7.45, the buffer will act as a weak acid and contribute hydrogen ions.

Homeostatic Imbalance of Acids and Bases Excessive acidity of the blood and other body fluids is known as acidosis. Common causes of acidosis are situations and disorders that reduce the effectiveness of breathing, especially the person’s ability to exhale fully, which causes a buildup of CO₂ (and H⁺) in the bloodstream. Acidosis can also be caused by metabolic problems that reduce the level or function of buffers that act as bases, or that promote the production of acids. For instance, with severe diarrhea, too much bicarbonate can be lost from the body, allowing acids to build up in body fluids. In people with poorly managed diabetes (ineffective regulation of blood sugar), acids called ketones are produced as a form of body fuel. These can build up in the blood, causing a serious condition called diabetic ketoacidosis. Kidney failure, liver failure, heart failure, cancer, and other disorders also can prompt metabolic acidosis.

In contrast, alkalosis is a condition in which the blood and other body fluids are too alkaline (basic). As with acidosis, respiratory disorders are a major cause; however, in respiratory alkalosis, carbon dioxide levels fall too low. Lung disease, aspirin overdose, shock, and ordinary anxiety can cause respiratory alkalosis, which reduces the normal concentration of H⁺.

Metabolic alkalosis often results from prolonged, severe vomiting, which causes a loss of hydrogen and chloride ions (as components of HCl). Medications also can prompt alkalosis. These include diuretics that cause the body to lose potassium ions, as well as antacids when taken in excessive amounts, for instance by someone with persistent heartburn or an ulcer.

2.5 Organic Compounds Essential to Human Functioning

barkerj1 — Wed, 06 Sep 2017 01:19:17 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the three major groups of carbohydrates
Describe the general structure of a lipid molecule
Specify the major groups of lipids
Distinguish between saturated, unsaturated, and polyunsaturated fats
Describe the basic structure of proteins
Describe several major functional groups of proteins
Describe the general structure and importance of adenosine triphosphate (ATP)

Organic compounds typically consist of groups of carbon atoms covalently bonded to hydrogen, usually oxygen, and often other elements as well. Created by living things, they are found throughout the world, in soils and seas, commercial products, and every cell of the human body. The four types most important to human structure and function are carbohydrates, lipids, proteins, and nucleotides. Before exploring these compounds, you need to first understand the chemistry of carbon.

The Chemistry of Carbon

What makes organic compounds ubiquitous is the chemistry of their carbon core. Recall that carbon atoms have four electrons in their valence shell, and that the octet rule dictates that atoms tend to react in such a way as to complete their valence shell with eight electrons. Carbon atoms do not complete their valence shells by donating or accepting four electrons. Instead, they readily share electrons via covalent bonds.

Commonly, carbon atoms share with other carbon atoms, often forming a long carbon chain referred to as a carbon skeleton. When they do share, however, they do not share all their electrons exclusively with each other. Rather, carbon atoms tend to share electrons with a variety of other elements, one of which is always hydrogen. Carbon and hydrogen groupings are called hydrocarbons. If you study the figures of organic compounds in the remainder of this chapter, you will see several with chains of hydrocarbons in one region of the compound.

Many combinations are possible to fill carbon’s four “vacancies.” Carbon may share electrons with oxygen or nitrogen or other atoms in a particular region of an organic compound. Moreover, the atoms to which carbon atoms bond may also be part of a functional group. A functional group is a group of atoms linked by strong covalent bonds and tending to function in chemical reactions as a single unit. You can think of functional groups as tightly knit “cliques” whose members are unlikely to be parted. Five functional groups are important in human physiology; these are the hydroxyl, carboxyl, amino, methyl and phosphate groups (Table 1).

Functional Groups Important in Human Physiology
Functional group	Structural formula	Importance
Hydroxyl	—O—H	Hydroxyl groups are polar. They are components of all four types of organic compounds discussed in this chapter. They are involved in dehydration synthesis and hydrolysis reactions.
Carboxyl	O—C—OH	Carboxyl groups are found within fatty acids, amino acids, and many other acids.
Amino	—N—H₂	Amino groups are found within amino acids, the building blocks of proteins.
Methyl	—C—H₃	Methyl groups are found within amino acids.
Phosphate	—P—O₄^2–	Phosphate groups are found within phospholipids and nucleotides.

Carbon’s affinity for covalent bonding means that many distinct and relatively stable organic molecules nevertheless readily form larger, more complex molecules. Any large molecule is referred to as macromolecule (macro- = “large”), and the organic compounds in this section all fit this description. However, some macromolecules are made up of several “copies” of single units called monomer (mono- = “one”; -mer = “part”). Like beads in a long necklace, these monomers link by covalent bonds to form long polymers (poly- = “many”). There are many examples of monomers and polymers among the organic compounds.

Monomers form polymers by engaging in dehydration synthesis (see Chapter 2.4 Figure 1). As was noted earlier, this reaction results in the release of a molecule of water. Each monomer contributes: One gives up a hydrogen atom and the other gives up a hydroxyl group. Polymers are split into monomers by hydrolysis (-lysis = “rupture”). The bonds between their monomers are broken, via the donation of a molecule of water, which contributes a hydrogen atom to one monomer and a hydroxyl group to the other.

Carbohydrates

The term carbohydrate means “hydrated carbon.” Recall that the root hydro- indicates water. A carbohydrate is a molecule composed of carbon, hydrogen, and oxygen; in most carbohydrates, hydrogen and oxygen are found in the same two-to-one relative proportions they have in water. In fact, the chemical formula for a “generic” molecule of carbohydrate is (CH₂O)_n.

Carbohydrates are referred to as saccharides, a word meaning “sugars.” Three forms are important in the body. Monosaccharides are the monomers of carbohydrates. Disaccharides (di- = “two”) are made up of two monomers. Polysaccharides are the polymers, and can consist of hundreds to thousands of monomers.

Monosaccharides

A monosaccharide is a monomer of carbohydrates. Five monosaccharides are particularly important in the body. Three of these are the hexose sugars, so called because they each contain six atoms of carbon. These include glucose, fructose, and galactose, shown in Figure 1a. These are typically disassembled to generate adenosine triphosphate (ATP), a process that will be described in detail elsewhere in this textbook. The remaining monosaccharides are two pentose sugars, each of which contains five atoms of carbon. They are the ribose and deoxyribose (Figure 2b) molecules that make up a major component of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), respectively.

[caption id="" align="aligncenter" width="420"] Figure 1. Five Important Monosaccharides.[/caption]

Disaccharides

A disaccharide is a pair of monosaccharides. Disaccharides are formed via dehydration synthesis, and the bond linking them is referred to as a glycosidic bond (glyco- = “sugar”). Three disaccharides (shown in Figure 2) are important to humans. These are sucrose, commonly referred to as table sugar; lactose, or milk sugar; and maltose, or malt sugar. As you can tell from their common names, you consume these in your diet; however, your body cannot use them directly. Instead, in the digestive tract, they are split into their component monosaccharides via hydrolysis.

[caption id="" align="aligncenter" width="420"] Figure 2. Three Important Disaccharides. All three important disaccharides form by dehydration synthesis.[/caption]

Polysaccharides

Polysaccharides can contain a few to a thousand or more monosaccharides. Three are important to the body (Figure 3):

Starches are polymers of glucose. They occur in long chains called amylose or branched chains called amylopectin, both of which are stored in plant-based foods and are relatively easy to digest.
Glycogen is also a polymer of glucose, but it is stored in the tissues of animals, especially in the muscles and liver. It is not considered a dietary carbohydrate because very little glycogen remains in animal tissues after slaughter; however, the human body stores excess glucose as glycogen in the muscles and liver.
Cellulose, a polysaccharide that is the primary component of the cell wall of green plants, is the component of plant food referred to as “fiber”. In humans, cellulose/fiber is not digestible; however, dietary fiber has many health benefits. It helps you feel full so you eat less, it promotes a healthy digestive tract, and a diet high in fiber is thought to reduce the risk of heart disease and possibly some forms of cancer.

[caption id="" align="aligncenter" width="420"] Figure 3. Three Important Polysaccharides. Three important polysaccharides are starches, glycogen, and fiber.[/caption]

Functions of Carbohydrates

The body obtains carbohydrates from plant-based foods. Grains, fruits, and legumes and other vegetables provide most of the carbohydrate in the human diet, although lactose is found in dairy products.

Although most body cells can break down other organic compounds for fuel, all body cells can use glucose. Moreover, nerve cells (neurons) in the brain, spinal cord, and through the peripheral nervous system, as well as red blood cells, can use only glucose for fuel. In the breakdown of glucose for energy, molecules of adenosine triphosphate (ATP) are produced. ATP consists of a ribose molecule bound to an adenine base and three phosphate groups, and releases free energy when its phosphate bonds are broken, supplying chemical energy to the cell. More ATP is produced in the presence of oxygen (O₂) than in carbohydrate-metabolizing pathways that do not use oxygen. The overall reaction for the conversion of the energy in glucose to energy stored in ATP can be written:

C₆H₁₂O₆ + 6 O₂ → 6 CO₂ + 6 H₂O + ATP

In addition to being a critical fuel source, carbohydrates are used in small amounts as part of a cell's structure. For instance, some carbohydrate molecules bind with proteins to produce glycoproteins, and others combine with lipids to produce glycolipids, both of which are found in the membrane that encloses the contents of body cells. The carbohydrate chains protrude outward from the cell membrane, creating a structure known as the glycocalyx ("sugar coat") of a cell that is used in cell adhesion and recognition. Pentose sugars are critical structural components of ATP and the nucleotides that make up RNA and DNA.

Lipids

A lipid is one of a highly diverse group of compounds made up mostly of hydrocarbons. The few oxygen atoms they contain are often at the periphery of the molecule. Their nonpolar hydrocarbons make all lipids hydrophobic. In water, lipids do not form a true solution, but they may form an emulsion, which is the term for a mixture of solutions that do not mix well.

Triglycerides

A triglyceride is one of the most common dietary lipid groups, and the type found most abundantly in body tissues. This compound, which is commonly referred to as a fat, is formed from the synthesis of two types of molecules (Figure 4):

A glycerol backbone at the core of triglycerides, consists of three carbon atoms.
Three fatty acids, long chains of hydrocarbons with a carboxyl group and a methyl group at opposite ends, extend from each of the carbons of the glycerol.

[caption id="" align="aligncenter" width="550"] Figure 4. Triglycerides. Triglycerides are composed of glycerol attached to three fatty acids via dehydration synthesis. Notice that glycerol gives up a hydrogen atom, and the carboxyl groups on the fatty acids each give up a hydroxyl group.[/caption]

Triglycerides form via dehydration synthesis. Glycerol gives up hydrogen atoms from its hydroxyl groups at each bond, and the carboxyl group on each fatty acid chain gives up a hydroxyl group. A total of three water molecules are thereby released.

Fatty acid chains that have no double carbon bonds anywhere along their length and therefore contain the maximum number of hydrogen atoms are called saturated fatty acids. These straight, rigid chains pack tightly together and are solid or semi-solid at room temperature (Figure 5a). Butter and lard are examples, as is the fat found on a steak or in your own body. In contrast, fatty acids with one double carbon bond are kinked at that bond (Figure 5b). These monounsaturated fatty acids are therefore unable to pack together tightly, and are liquid at room temperature. Polyunsaturated fatty acids contain two or more double carbon bonds, and are also liquid at room temperature. Plant oils such as olive oil typically contain both mono- and polyunsaturated fatty acids.

[caption id="" align="aligncenter" width="380"] Figure 5. Fatty Acid Shapes. The level of saturation of a fatty acid affects its shape. (a) Saturated fatty acid chains are straight. (b) Unsaturated fatty acid chains are kinked.[/caption]

Whereas a diet high in saturated fatty acids increases the risk of heart disease, a diet high in unsaturated fatty acids is thought to reduce the risk. This is especially true for the omega-3 unsaturated fatty acids found in cold-water fish such as salmon. These fatty acids have their first double carbon bond at the third hydrocarbon from the methyl group (referred to as the omega end of the molecule). Omega-6 unsaturated fatty acids has their first double carbon bond at the sixth hydrocarbon from the methyl group.

Finally, trans fatty acids found in some processed foods, including some stick and tub margarines, are thought to be even more harmful to the heart and blood vessels than saturated fatty acids. Trans fats are created from unsaturated fatty acids (such as corn oil) when chemically treated to produce partially hydrogenated fats. These molecules contain double carbon bonds that are formed by removal of hydrogen atoms from opposite sides of the hydrocarbon chain, leaving the hydrocarbon chain straight rather than kinked as in the cis unsaturated fatty acids (where the hydrogens are removed from the same side of adjacent carbons) more commonly produced by living cells.

As a group, triglycerides are a major fuel source for the body. When you are resting or asleep, a majority of the energy used to keep you alive is derived from triglycerides stored in your fat (adipose) tissues. Triglycerides also fuel long, slow physical activity such as gardening or hiking, and contribute a modest percentage of energy for vigorous physical activity. Dietary fat also assists the absorption and transport of the nonpolar fat-soluble vitamins A, D, E, and K. Additionally, stored body fat protects and cushions the body’s bones and internal organs, and acts as insulation to retain body heat.

Fatty acids are also components of glycolipids, which are sugar-fat compounds found in the cell membrane. Lipoproteins are compounds in which the hydrophobic triglycerides are packaged in protein envelopes for transport in body fluids.

Phospholipids

As its name suggests, a phospholipid is a bond between the glycerol component of a lipid and a phosphorous molecule. In fact, phospholipids are similar in structure to triglycerides. However, instead of having three fatty acids, a phospholipid is generated from a diglyceride, a glycerol with just two fatty acid chains (Figure 6). The third binding site on the glycerol is taken up by the phosphate group, which in turn is attached to a polar “head” region of the molecule. Recall that triglycerides are nonpolar and hydrophobic. This still holds for the fatty acid portion of a phospholipid compound. However, the head of a phospholipid contains charges on the phosphate groups, as well as on the nitrogen atom. These charges make the phospholipid head hydrophilic. Therefore, phospholipids are said to have hydrophobic tails, containing the neutral fatty acids, and hydrophilic heads, containing the charged phosphate groups and nitrogen atom.

[caption id="" align="aligncenter" width="600"] Figure 6. Other Important Lipids. (a) Phospholipids are composed of two fatty acids, glycerol, and a phosphate group. (b) Sterols are ring-shaped lipids. Shown here is cholesterol. (c) Prostaglandins are derived from unsaturated fatty acids. Prostaglandin E2 (PGE2) includes hydroxyl and carboxyl groups.[/caption]

Steroids

A steroid compound (referred to as a sterol) has as its foundation a set of four hydrocarbon rings bonded to a variety of other atoms and molecules (see Figure 6b). Although both plants and animals synthesize sterols, the type that makes the most important contribution to human structure and function is cholesterol, which is synthesized by the liver in humans and animals and is also present in most animal-based foods. Like other lipids, cholesterol’s hydrocarbons make it hydrophobic; however, it has a polar hydroxyl head that is hydrophilic. Cholesterol is an important component of bile acids, compounds that help emulsify dietary fats. In fact, the word root chole- refers to bile. Cholesterol is also a building block of the steroid hormones, one class of signaling molecules that the body releases to regulate processes at distant sites (endocrine signalling). Finally, like phospholipids, cholesterol molecules are found in the cell membrane, where their hydrophobic and hydrophilic regions help regulate the flow of substances into and out of the cell.

Eicosanoids

The eicosanoids are lipids that are derived from polyunsaturated fatty acids with 20 carbon atoms in their hydrocarbon chain, primarily arachidonic acid. Like the steroid hormones, they are used as signalling molecules in the body, and include prostaglandins (see Figure 6c), leukotrienes, and thromboxanes. They are often used for shorter-range signalling than steroid hormones, however, typically acting in an autocrine (affecting the cell that released them) or paracrine (affecting nearby cells) fashion. Prostaglandins are produced by almost all nucleated cells, and serve a variety of functions. One reason that the omega-3 fatty acids found in fish are beneficial is that they stimulate the production of certain prostaglandins that help regulate aspects of blood pressure and inflammation, and thereby reduce the risk for heart disease. Some prostaglandins also sensitize nerves to pain. One class of pain-relieving medications called nonsteroidal anti-inflammatory drugs (NSAIDs) works by reducing the effects of prostaglandins. Leukotrienes are produced by leukocytes, and primarily mediate inflammation. Thromboxanes are derived from a particular prostaglandin in platelets, and stimulate blood clot formation ("thrombosis"), vasoconstriction, and bronchoconstriction.

Proteins

You might associate proteins with muscle tissue, but in fact, proteins are critical components of all tissues and organs. A protein is an organic molecule composed of amino acids linked by peptide bonds. Proteins include the keratin in the epidermis of skin that protects underlying tissues, the collagen found in the dermis of skin, in bones, and in the meninges that cover the brain and spinal cord. Proteins are also components of many of the body’s functional chemicals, including digestive enzymes in the digestive tract, antibodies, the neurotransmitters that neurons use to communicate with other cells, and the peptide-based hormones that regulate certain body functions (for instance, growth hormone). While carbohydrates and lipids are composed of hydrocarbons and oxygen, all proteins also contain nitrogen (N), and many contain sulfur (S), in addition to carbon, hydrogen, and oxygen.

Microstructure of Proteins

Proteins are polymers made up of nitrogen-containing monomers called amino acids. An amino acid is a molecule composed of an amino group and a carboxyl group, together with a variable side chain. Just 20 different amino acids contribute to nearly all of the thousands of different proteins important in human structure and function. Body proteins contain a unique combination of a few dozen to a few hundred of these 20 amino acid monomers. All 20 of these amino acids share a similar structure (Figure 7). All consist of a central carbon atom to which the following are bonded:

a hydrogen atom
an alkaline (basic) amino group NH₂ (see Table 1)
an acidic carboxyl group COOH (see Table 1)
a variable group

[caption id="" align="aligncenter" width="320"] Figure 8. Structure of an Amino Acid[/caption]

Notice that all amino acids contain both an acid (the carboxyl group) and a base (the amino group) (amine = “nitrogen-containing”). For this reason, they make excellent buffers, helping the body regulate acid–base balance. What distinguishes the 20 amino acids from one another is their variable group, which is referred to as a side chain or an R-group. This group can vary in size and can be polar or nonpolar, giving each amino acid its unique characteristics. For example, the side chains of two amino acids—cysteine and methionine—contain sulfur. Sulfur does not readily participate in hydrogen bonds, whereas all other amino acids do. This variation influences the way that proteins containing cysteine and methionine are assembled.

Amino acids join via dehydration synthesis to form protein polymers (Figure 8). The unique bond holding amino acids together is called a peptide bond. A peptide bond is a covalent bond between two amino acids that forms by dehydration synthesis. A peptide, in fact, is a very short chain of amino acids. Strands containing fewer than about 100 amino acids are generally referred to as polypeptides rather than proteins.

[caption id="" align="aligncenter" width="280"] Figure 8.Peptide Bond. Different amino acids join together to form peptides, polypeptides, or proteins via dehydration synthesis. The bonds between the amino acids are peptide bonds.[/caption]

The body is able to synthesize most of the amino acids from components of other molecules; however, nine cannot be synthesized and have to be consumed in the diet. These are known as the essential amino acids.

Free amino acids available for protein construction are said to reside in the amino acid pool within cells. Structures within cells use these amino acids when assembling proteins. If a particular essential amino acid is not available in sufficient quantities in the amino acid pool, however, synthesis of proteins containing it can slow or even cease.

Shape of Proteins

Just as a fork cannot be used to eat soup and a spoon cannot be used to spear meat, a protein’s shape is essential to its function. A protein’s shape is determined, most fundamentally, by the sequence of amino acids of which it is made (Figure 9a). The sequence is called the primary structure of the protein.

[caption id="" align="aligncenter" width="480"] Figure 9. The Shape of Proteins. (a) The primary structure is the sequence of amino acids that make up the polypeptide chain. (b) The secondary structure, which can take the form of an alpha-helix or a beta-pleated sheet, is maintained by hydrogen bonds between amino acids in different regions of the original polypeptide strand. (c) The tertiary structure occurs as a result of further folding and bonding of the secondary structure. (d) The quaternary structure occurs as a result of interactions between two or more tertiary subunits. The example shown here is hemoglobin, a protein in red blood cells which transports oxygen to body tissues.[/caption]

Although some polypeptides exist as linear chains, most are twisted or folded into more complex secondary structures that form when bonding occurs between amino acids with different properties at different regions of the polypeptide. The most common secondary structure is a spiral called an alpha-helix. If you were to take a length of string and simply twist it into a spiral, it would not hold the shape. Similarly, a strand of amino acids could not maintain a stable spiral shape without the help of hydrogen bonds, which create bridges between different regions of the same strand (see Figure 9b). Less commonly, a polypeptide chain can form a beta-pleated sheet, in which hydrogen bonds form bridges between different regions of a single polypeptide that has folded back upon itself, or between two or more adjacent polypeptide chains.

The secondary structure of proteins further folds into a compact three-dimensional shape, referred to as the protein’s tertiary structure (see Figure 9c). In this configuration, amino acids that had been very distant in the primary chain can be brought quite close via hydrogen bonds or, in proteins containing cysteine, via disulfide bonds. A disulfide bond is a covalent bond between sulfur atoms in a polypeptide. Often, two or more separate polypeptides bond to form an even larger protein with a quaternary structure (see Figure 9d). The polypeptide subunits forming a quaternary structure can be identical or different. For instance, hemoglobin, the protein found in red blood cells is composed of four tertiary polypeptides, two of which are called alpha chains and two of which are called beta chains.

When they are exposed to extreme heat, acids, bases, and certain other substances, proteins will denature. Denaturation is a change in the structure of a molecule through physical or chemical means. Denatured proteins lose their functional shape and are no longer able to carry out their jobs. An everyday example of protein denaturation is the curdling of milk when acidic lemon juice is added.

The contribution of the shape of a protein to its function can hardly be exaggerated. For example, the long, slender shape of protein strands that make up muscle tissue is essential to their ability to contract (shorten) and relax (lengthen). As another example, bones contain long threads of a protein called collagen that acts as scaffolding upon which bone minerals are deposited. These elongated proteins, called fibrous proteins, are strong and durable and typically hydrophobic. Fibrous proteins are used for movement, from muscle cell contraction (actin and myosin) down to intracellular transport (e.g. actin). They are also used to provide a structural framework or mechanical support of connective tissues (e.g. collagen, keratin, elastin), individual cells (e.g. titin), and plasma membranes (e.g. spectrin, dystrophin).

In contrast, globular proteins are shaped like globes or spheres that tend to be highly reactive and are hydrophilic. Globular proteins are abundant throughout the body, playing critical roles in most body functions. Enzymes, introduced earlier as protein catalysts, are examples of this; the next section takes a closer look at the catalytic action of enzymes, but globular proteins serve many other functions in the human body as well.

Some globular proteins are used to transport specific molecules (e.g. hormones or gases) or ions (e.g. iron or calcium) in blood. The hemoglobin proteins packed into red blood cells for example (see Figure 9d) are used to transport the oxygen gas molecules from the lungs to other body cells. Others (e.g. albumin, hemoglobin) can help regulate body fluid pH by reversibly functioning as acids or bases, thus acting as buffers. Some globular proteins act as hormones to regulate metabolism, and are referred to as peptide hormones or protein hormones (e.g. insulin, growth hormone, oxytocin). Others are used to defend the body against foreign substances including invading pathogens and toxins (e.g. antibodies, complement proteins). Finally, some globular proteins known as molecular chaperones are essential to the production of other proteins and the appropriate breakdown of damaged proteins.

Proteins Function as Enzymes

If you were trying to type a paper, and every time you hit a key on your laptop there was a delay of six or seven minutes before you got a response, you would probably get a new laptop. In a similar way, without enzymes to catalyze chemical reactions, the human body would be nonfunctional. It functions only because enzymes function.

Enzymatic reactions—chemical reactions catalyzed by enzymes—begin when substrates bind to the enzyme. A substrate is a reactant in an enzymatic reaction. This occurs on regions of the enzyme known as active sites (Figure 10). Any given enzyme catalyzes just one type of chemical reaction. This characteristic, called specificity, is due to the fact that a substrate with a particular shape and electrical charge can bind only to an active site corresponding to that substrate.

[caption id="" align="aligncenter" width="520"] Figure 10. Steps in an Enzymatic Reaction. (a) Substrates approach active sites on enzyme. (b) Substrates bind to active sites, producing an enzyme–substrate complex. (c) Changes internal to the enzyme–substrate complex facilitate interaction of the substrates. (d) Products are released and the enzyme returns to its original form, ready to facilitate another enzymatic reaction.[/caption]

Binding of a substrate produces an enzyme–substrate complex. It is likely that enzymes speed up chemical reactions in part because the enzyme–substrate complex undergoes a set of temporary and reversible changes that cause the substrates to be oriented toward each other in an optimal position to facilitate their interaction. This promotes increased reaction speed. The enzyme then releases the product(s), and resumes its original shape. The enzyme is then free to engage in the process again, and will do so as long as substrate remains.

Other Functions of Proteins

Advertisements for protein bars, powders, and shakes all say that protein is important in building, repairing, and maintaining muscle tissue, but the truth is that proteins contribute to all body tissues, from the skin to the brain cells. Also, certain proteins act as hormones, chemical messengers that help regulate body functions, For example, growth hormone is important for skeletal growth, among other roles.

As was noted earlier, the basic and acidic components enable proteins to function as buffers in maintaining acid–base balance, but they also help regulate fluid–electrolyte balance. Proteins attract fluid, and a healthy concentration of proteins in the blood, the cells, and the spaces between cells helps ensure a balance of fluids in these various “compartments.” Moreover, proteins in the cell membrane help to transport electrolytes in and out of the cell, keeping these ions in a healthy balance. Like lipids, proteins can bind with carbohydrates. They can thereby produce glycoproteins or proteoglycans, both of which have many functions in the body.

The body can use proteins for energy when carbohydrate and fat intake is inadequate, and stores of glycogen and adipose tissue become depleted. However, since there is no storage site for protein except functional tissues, using protein for energy causes tissue breakdown, and results in body wasting.

Nucleotides

The fourth type of organic compound important to human structure and function are the nucleotides (Figure 11). A nucleotide is one of a class of organic compounds composed of three subunits:

one or more phosphate groups
a pentose sugar: either deoxyribose or ribose
a nitrogen-containing base: adenine, cytosine, guanine, thymine, or uracil

Nucleotides can be assembled into nucleic acids (DNA or RNA) or the energy compound adenosine triphosphate.

[caption id="" align="aligncenter" width="520"] Figure 11. Nucleotides. (a) The building blocks of all nucleotides are one or more phosphate groups, a pentose sugar, and a nitrogen-containing base. (b) The nitrogen-containing bases of nucleotides. (c) The two pentose sugars of DNA and RNA.[/caption]

Nucleic Acids

The nucleic acids differ in their type of pentose sugar. Deoxyribonucleic acid (DNA) is nucleotide that stores genetic information. DNA contains deoxyribose (so-called because it has one less atom of oxygen than ribose) plus one phosphate group and one nitrogen-containing base. The “choices” of base for DNA are adenine, cytosine, guanine, and thymine. Ribonucleic acid (RNA) is a ribose-containing nucleotide that helps manifest the genetic code as protein. RNA contains ribose, one phosphate group, and one nitrogen-containing base, but the “choices” of base for RNA are adenine, cytosine, guanine, and uracil.

The nitrogen-containing bases adenine and guanine are classified as purines. A purine is a nitrogen-containing molecule with a double ring structure, which accommodates several nitrogen atoms. The bases cytosine, thymine (found in DNA only) and uracil (found in RNA only) are pyramidines. A pyramidine is a nitrogen-containing base with a single ring structure

Bonds formed by dehydration synthesis between the pentose sugar of one nucleic acid monomer and the phosphate group of another form a “backbone,” from which the components’ nitrogen-containing bases protrude. In DNA, two such backbones attach at their protruding bases via hydrogen bonds. These twist to form a shape known as a double helix (Figure 12). The sequence of nitrogen-containing bases within a strand of DNA form the genes that act as a molecular code instructing cells in the assembly of amino acids into proteins. Humans have almost 22,000 genes in their DNA, locked up in the 46 chromosomes inside the nucleus of each cell (except red blood cells which lose their nuclei during development). These genes carry the genetic code to build one’s body, and are unique for each individual except identical twins.

[caption id="" align="aligncenter" width="320"] Figure 12. DNA. In the DNA double helix, two strands attach via hydrogen bonds between the bases of the component nucleotides.[/caption]

In contrast, RNA consists of a single strand of sugar-phosphate backbone studded with bases. Messenger RNA (mRNA) is created during protein synthesis to carry the genetic instructions from the DNA to the cell’s protein manufacturing plants in the cytoplasm, the ribosomes.

Adenosine Triphosphate

The nucleotide adenosine triphosphate (ATP), is composed of a ribose sugar, an adenine base, and three phosphate groups (Figure 13). ATP is classified as a high energy compound because the two covalent bonds linking its three phosphates store a significant amount of potential energy. In the body, the energy released from these high energy bonds helps fuel the body’s activities, from muscle contraction to the transport of substances in and out of cells to anabolic chemical reactions.

[caption id="" align="aligncenter" width="420"] Figure 13. Structure of Adenosine Triphosphate (ATP).[/caption]

When a phosphate group is cleaved from ATP, the products are adenosine diphosphate (ADP) and inorganic phosphate (P_i). This hydrolysis reaction can be written:

ATP + H₂O → ADP + P_i + energy

Removal of a second phosphate leaves adenosine monophosphate (AMP) and two phosphate groups. Again, these reactions also liberate the energy that had been stored in the phosphate-phosphate bonds. They are reversible, too, as when ADP undergoes phosphorylation. Phosphorylation is the addition of a phosphate group to an organic compound, in this case, resulting in ATP. In such cases, the same level of energy that had been released during hydrolysis must be reinvested to power dehydration synthesis.

Cells can also transfer a phosphate group from ATP to another organic compound. For example, when glucose first enters a cell, a phosphate group is transferred from ATP, forming glucose phosphate (C₆H₁₂O₆—P) and ADP. Once glucose is phosphorylated in this way, it can be stored as glycogen or metabolized for immediate energy.

[caption id="attachment_3052" align="aligncenter" width="150"] Watch this amoeba sisters video to learn more about biomolecules![/caption]

3.5 Cell Growth and Division

barkerj1 — Wed, 06 Sep 2017 01:19:19 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the location of chromosomes and genes
Describe the complement of chromosomes found in normal males and females
Describe the behavior of chromosomes during meiosis
Describe the behavior of chromosomes during mitosis
Explain the significance of crossing over and random alignment during meiosis

So far in this chapter, you have read numerous times of the importance and prevalence of cell division. While there are a few cells in the body that do not undergo cell division (such as gametes, red blood cells, most neurons, and some muscle cells), most somatic cells divide regularly. A somatic cell is a general term for a body cell, and all human cells, except for the cells that produce eggs and sperm (which are referred to as germ cells), are somatic cells. Somatic cells contain two copies of each of their chromosomes (one copy received from each parent). A homologous pair of chromosomes is the two copies of a single chromosome found in each somatic cell. The human is a diploid organism, having 23 homologous pairs of chromosomes in each of the somatic cells. The condition of having pairs of chromosomes is known as diploidy.

Cells in the body replace themselves over the lifetime of a person. For example, the cells lining the gastrointestinal tract must be frequently replaced when constantly “worn off” by the movement of food through the gut. But what triggers a cell to divide, and how does it prepare for and complete cell division? The cell cycle is the sequence of events in the life of the cell from the moment it is created at the end of a previous cycle of cell division until it then divides itself, generating two new cells.

The Cell Cycle

One “turn” or cycle of the cell cycle consists of two general phases: interphase, followed by mitosis and cytokinesis. Interphase is the period of the cell cycle during which the cell is not dividing. The majority of cells are in interphase most of the time. Mitosis is the division of genetic material, during which the cell nucleus breaks down and two new, fully functional, nuclei are formed. Cytokinesis divides the cytoplasm into two distinctive cells.

Interphase

A cell grows and carries out all normal metabolic functions and processes in a period called G₁ (Figure 1). G₁ phase (gap 1 phase) is the first gap, or growth phase in the cell cycle. For cells that will divide again, G₁ is followed by replication of the DNA, during the S phase. The S phase (synthesis phase) is period during which a cell replicates its DNA.

[caption id="" align="aligncenter" width="280"] Figure 1. Cell Cycle. The two major phases of the cell cycle include mitosis (cell division), and interphase, when the cell grows and performs all of its normal functions. Interphase is further subdivided into G1, S, and G2 phases.[/caption]

After the synthesis phase, the cell proceeds through the G₂ phase. The G₂ phase is a second gap phase, during which the cell continues to grow and makes the necessary preparations for mitosis. Between G₁, S, and G₂ phases, cells will vary the most in their duration of the G1 phase. It is here that a cell might spend a couple of hours, or many days. The S phase typically lasts between 8-10 hours and the G₂ phase approximately 5 hours. In contrast to these phases, the G₀ phase is a resting phase of the cell cycle. Cells that have temporarily stopped dividing and are resting (a common condition) and cells that have permanently ceased dividing (like nerve cells) are said to be in G₀.

The Structure of Chromosomes

Billions of cells in the human body divide every day. During the synthesis phase (S, for DNA synthesis) of interphase, the amount of DNA within the cell precisely doubles. Therefore, after DNA replication but before cell division, each cell actually contains two copies of each chromosome. Each copy of the chromosome is referred to as a sister chromatid and is physically bound to the other copy. The centromere is the structure that attaches one sister chromatid to another. Because a human cell has 46 chromosomes, during this phase, there are 92 chromatids (46 × 2) in the cell. Make sure not to confuse the concept of a pair of chromatids (one chromosome and its exact copy attached during mitosis) and a homologous pair of chromosomes (two paired chromosomes which were inherited separately, one from each parent) (Figure 2).

[caption id="" align="aligncenter" width="250"] Figure 2. A Homologous Pair of Chromosomes with their Attached Sister Chromatids. The red and blue colors correspond to a homologous pair of chromosomes. Each member of the pair was separately inherited from one parent. Each chromosome in the homologous pair is also bound to an identical sister chromatid, which is produced by DNA replication, and results in the familiar “X” shape.[/caption]

Mitosis and Cytokinesis

The mitotic phase of the cell typically takes between 1 and 2 hours. During this phase, a cell undergoes two major processes. First, it completes mitosis, during which the contents of the nucleus are equitably pulled apart and distributed between its two halves. Cytokinesis then occurs, dividing the cytoplasm and cell body into two new cells. Mitosis is divided into four major stages that take place after interphase (Figure 3) and in the following order: prophase, metaphase, anaphase, and telophase. The process is then followed by cytokinesis.

[caption id="attachment_1512" align="aligncenter" width="600"] Figure 3. Cell Division: Mitosis Followed by Cytokinesis. The stages of cell division oversee the separation of identical genetic material into two new nuclei, followed by the division of the cytoplasm.[/caption]

Prophase is the first phase of mitosis, during which the loosely packed chromatin coils and condenses into visible chromosomes. During prophase, each chromosome becomes visible with its identical partner attached, forming the familiar X-shape of sister chromatids. The nucleolus disappears early during this phase, and the nuclear envelope also disintegrates.A major occurrence during prophase concerns a very important structure that contains the origin site for microtubule growth. Recall the cellular structures called centrioles that serve as origin points from which microtubules extend. These tiny structures also play a very important role during mitosis. A centrosome is a pair of centrioles together. The cell contains two centrosomes side-by-side, which begin to move apart during prophase. As the centrosomes migrate to two different sides of the cell, microtubules begin to extend from each like long fingers from two hands extending toward each other. The mitotic spindle is the structure composed of the centrosomes and their emerging microtubules.

Near the end of prophase there is an invasion of the nuclear area by microtubules from the mitotic spindle. The nuclear membrane has disintegrated, and the microtubules attach themselves to the centromeres that adjoin pairs of sister chromatids. The kinetochore is a protein structure on the centromere that is the point of attachment between the mitotic spindle and the sister chromatids. This stage is referred to as late prophase or “prometaphase” to indicate the transition between prophase and metaphase.

Metaphase is the second stage of mitosis. During this stage, the sister chromatids, with their attached microtubules, line up along a linear plane in the middle of the cell. A metaphase plate forms between the centrosomes that are now located at either end of the cell. The metaphase plate is the name for the plane through the center of the spindle on which the sister chromatids are positioned. The microtubules are now poised to pull apart the sister chromatids and bring one from each pair to each side of the cell.

Anaphase is the third stage of mitosis. Anaphase takes place over a few minutes, when the pairs of sister chromatids are separated from one another, forming individual chromosomes once again. These chromosomes are pulled to opposite ends of the cell by their kinetochores, as the microtubules shorten. Each end of the cell receives one partner from each pair of sister chromatids, ensuring that the two new daughter cells will contain identical genetic material.

Telophase is the final stage of mitosis. Telophase is characterized by the formation of two new daughter nuclei at either end of the dividing cell. These newly formed nuclei surround the genetic material, which uncoils such that the chromosomes return to loosely packed chromatin. Nucleoli also reappear within the new nuclei, and the mitotic spindle breaks apart, each new cell receiving its own complement of DNA, organelles, membranes, and centrioles. At this point, the cell is already beginning to split in half as cytokinesis begins.

The cleavage furrow is a contractile band made up of microfilaments that forms around the midline of the cell during cytokinesis. (Recall that microfilaments consist of actin.) This contractile band squeezes the two cells apart until they finally separate. Two new cells are now formed. One of these cells (the “stem cell”) enters its own cell cycle; able to grow and divide again at some future time. The other cell transforms into the functional cell of the tissue, typically replacing an “old” cell there.

Imagine a cell that completed mitosis but never underwent cytokinesis. In some cases, a cell may divide its genetic material and grow in size, but fail to undergo cytokinesis. This results in larger cells with more than one nucleus. Usually this is an unwanted aberration and can be a sign of cancerous cells.

Cell Cycle Control

A very elaborate and precise system of regulation controls direct the way cells proceed from one phase to the next in the cell cycle and begin mitosis. The control system involves molecules within the cell as well as external triggers. These internal and external control triggers provide “stop” and “advance” signals for the cell. Precise regulation of the cell cycle is critical for maintaining the health of an organism, and loss of cell cycle control can lead to cancer.

Mechanisms of Cell Cycle Control

As the cell proceeds through its cycle, each phase involves certain processes that must be completed before the cell should advance to the next phase. A checkpoint is a point in the cell cycle at which the cycle can be signaled to move forward or stopped. At each of these checkpoints, different varieties of molecules provide the stop or go signals, depending on certain conditions within the cell. A cyclin is one of the primary classes of cell cycle control molecules (Figure 4). A cyclin-dependent kinase (CDK) is one of a group of molecules that work together with cyclins to determine progression past cell checkpoints. By interacting with many additional molecules, these triggers push the cell cycle forward unless prevented from doing so by “stop” signals, if for some reason the cell is not ready. At the G₁checkpoint, the cell must be ready for DNA synthesis to occur. At the G₂ checkpoint the cell must be fully prepared for mitosis. Even during mitosis, a crucial stop and go checkpoint in metaphase ensures that the cell is fully prepared to complete cell division. The metaphase checkpoint ensures that all sister chromatids are properly attached to their respective microtubules and lined up at the metaphase plate before the signal is given to separate them during anaphase.

[caption id="" align="aligncenter" width="350"] Figure 4. Control of the Cell Cycle. Cells proceed through the cell cycle under the control of a variety of molecules, such as cyclins and cyclin-dependent kinases. These control molecules determine whether or not the cell is prepared to move into the following stage.[/caption]

The Cell Cycle Out of Control: Implications

Most people understand that cancer or tumors are caused by abnormal cells that multiply continuously. If the abnormal cells continue to divide unstopped, they can damage the tissues around them, spread to other parts of the body, and eventually result in death. In healthy cells, the tight regulation mechanisms of the cell cycle prevent this from happening, while failures of cell cycle control can cause unwanted and excessive cell division. Failures of control may be caused by inherited genetic abnormalities that compromise the function of certain “stop” and “go” signals. Environmental insult that damages DNA can also cause dysfunction in those signals. Often, a combination of both genetic predisposition and environmental factors lead to cancer.

The process of a cell escaping its normal control system and becoming cancerous may actually happen throughout the body quite frequently. Fortunately, certain cells of the immune system are capable of recognizing cells that have become cancerous and destroying them. However, in certain cases the cancerous cells remain undetected and continue to proliferate. If the resulting tumor does not pose a threat to surrounding tissues, it is said to be benign and can usually be easily removed. If capable of damage, the tumor is considered malignant and the patient is diagnosed with cancer.

Cancer Arises from Dysregulated Mitosis

Cancer is an extremely complex condition, capable of arising from a wide variety of genetic and environmental causes. Typically, mutations or aberrations in a cell’s DNA that compromise normal cell cycle control systems lead to cancerous tumors. Cell cycle control is an example of a homeostatic mechanism that maintains proper cell function and health. While progressing through the phases of the cell cycle, a large variety of intracellular molecules provide stop and go signals to regulate movement forward to the next phase. These signals are maintained in an intricate balance so that the cell only proceeds to the next phase when it is ready. This homeostatic control of the cell cycle can be thought of like a car’s cruise control. Cruise control will continually apply just the right amount of acceleration to maintain a desired speed, unless the driver hits the brakes, in which case the car will slow down. Similarly, the cell includes molecular messengers, such as cyclins, that push the cell forward in its cycle.

In addition to cyclins, a class of proteins that are encoded by genes called proto-oncogenes provide important signals that regulate the cell cycle and move it forward. Examples of proto-oncogene products include cell-surface receptors for growth factors, or cell-signaling molecules, two classes of molecules that can promote DNA replication and cell division. In contrast, a second class of genes known as tumor suppressor genes sends stop signals during a cell cycle. For example, certain protein products of tumor suppressor genes signal potential problems with the DNA and thus stop the cell from dividing, while other proteins signal the cell to die if it is damaged beyond repair. Some tumor suppressor proteins also signal a sufficient surrounding cellular density, which indicates that the cell need not presently divide. The latter function is uniquely important in preventing tumor growth: normal cells exhibit a phenomenon called “contact inhibition;” thus, extensive cellular contact with neighboring cells causes a signal that stops further cell division.

These two contrasting classes of genes, proto-oncogenes and tumor suppressor genes, are like the accelerator and brake pedal of the cell’s own “cruise control system,” respectively. Under normal conditions, these stop and go signals are maintained in a homeostatic balance. Generally speaking, there are two ways that the cell’s cruise control can lose control: a malfunctioning (overactive) accelerator, or a malfunctioning (underactive) brake. When compromised through a mutation, or otherwise altered, proto-oncogenes can be converted to oncogenes, which produce oncoproteins that push a cell forward in its cycle and stimulate cell division even when it is undesirable to do so. For example, a cell that should be programmed to self-destruct (a process called apoptosis) due to extensive DNA damage might instead be triggered to proliferate by an oncoprotein. On the other hand, a dysfunctional tumor suppressor gene may fail to provide the cell with a necessary stop signal, also resulting in unwanted cell division and proliferation.

A delicate homeostatic balance between the many proto-oncogenes and tumor suppressor genes delicately controls the cell cycle and ensures that only healthy cells replicate. Therefore, a disruption of this homeostatic balance can cause aberrant cell division and cancerous growths.

Meiosis

Meiosis, unlike mitosis, is not considered part of the normal cell cycle. The daughter cells generated by meiosis are not genetically identical to the parent cell and so cannot continue going through the cell cycle stages on their own.

[caption id="attachment_1151" align="aligncenter" width="2809"] Figure 5. Cell Division: Meiosis. The stages of cell division oversee the separation of a cell's genetic material into two new nuclei that each contain half of the genetic material of the parent cell. Image credit: Ali Zifan, Wikimedia Commons[/caption] Meiosis is divided into two major stages, meiosis I and meiosis II, that each further divided into four main stages that are similar to those of mitosis: prophase, metaphase, anaphase, and telophase (Figure 5). Prophase I is the first phase of meiosis, during which the loosely packed chromatin coils and condenses into visible chromosomes, in a manner similar to prophase of mitosis. In prophase I, however, homologous chromosomes - chromosomes that contain the same genes - pair together and exchange genetic information with each other. Although pairs of chromosomes contain the same genes, they may contain different variants of those genes known as alleles. This process, known as crossing over, can occur at many points along a chromosome's length and results in chromosomes that may contain chromatids that are no longer identical to each other.

Metaphase I is the second stage of meiosis. During this stage, the pairs of homologous chromosomes line up along a linear plane in the middle of the cell. Similar to mitosis, the central location where the chromosomes line up is called a metaphase plate. However, unlike mitosis the chromosomes are lined up in pairs. These pairs are arranged in somewhat random orientations relative to each other, in that although they are all lined up at the metaphase plate, the material and paternal chromosomes are not necessarily all on the same side of the plate. This lack of regard to the orientation of other chromosomes results in the independent assortment of maternal and paternal genetic information into separate daughter cells.

Anaphase I is the third stage of meiosis. Microtubules pull entire chromosomes to opposite sides of the cell, while leaving the individual chromatids paired. This results in half as many chromosomes being delivered to either side of the cell as were found in the original parent cell.

Telophase I is the final stage of meiosis I; much like telophase of mitosis, telophase I results in the formation of two new daughter nuclei at either end of the dividing cell, surrounding the genetic material. However, in this case each daughter cell has only half of the number of chromosomes of the parent cell, and may have a different complement of alleles than the parent cell. Each chromosome at this stage still consists of two chromatids that then need to be separated.

Each of the two cells resulting from meiosis I will therefore need to go through a second round of division known as meiosis II. The behaviour of chromosomes in meiosis II is remarkably similar to that of chromosomes during mitosis. However, cells that enter meiosis II have half as many chromosomes as a cell entering mitosis. Prophase II is the fifth phase of meiosis and the first phase of meiosis II. Again, chromatin is condensed into visible chromosomes and spindle fibers form.

Metaphase II is the second stage of meiosis II. During this stage, the chromosomes line up along the metaphase plate. As in mitosis, the chromosomes are unpaired and simply line up along the central region of the cell.

Anaphase II is the third stage of meiosis II. Microtubules pull the two chromatids of each chromosome to opposite ends of the cell.

Telophase II is the final stage of meiosis. Since the original parent cell produced two cells that then went on to divide a second time, there are now a total of four daughter cells, each having half the genetic material of the original parental cell. Due to crossing-over between chromosomes and the independent assortment of chromosomes that occurred during meiosis, the four resulting daughter cells are likely to be genetically different from each other.

[caption id="attachment_2992" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about the process of mitosis![/caption] [caption id="attachment_3039" align="aligncenter" width="150"] Watch this amoeba sisters video to learn more about mitosis![/caption] [caption id="attachment_3040" align="aligncenter" width="150"] Watch this amoeba sisters video to learn about the process of meiosis![/caption]

4.2 Epithelial Tissue

barkerj1 — Wed, 06 Sep 2017 01:19:20 +0000

Learning Objectives

By the end of this section, you will be able to:

Define 'gland'
Specify the difference between endocrine and exocrine glands

Most epithelial tissues are essentially large sheets of cells covering all the surfaces of the body exposed to the outside world and lining the outside of organs. Epithelium also forms much of the glandular tissue of the body. Skin is not the only area of the body exposed to the outside. Other areas include the airways, the digestive tract, as well as the urinary and reproductive systems, all of which are lined by an epithelium. Hollow organs and body cavities that do not connect to the exterior of the body, which includes, blood vessels and serous membranes, are lined by endothelium (plural = endothelia), which is a type of epithelium.

Epithelial cells derive from all three major embryonic layers. The epithelia lining the skin, parts of the mouth and nose, and the anus develop from the ectoderm. Cells lining the airways and most of the digestive system originate in the endoderm. The epithelium that lines vessels in the lymphatic and cardiovascular system derives from the mesoderm and is called an endothelium.

All epithelia share some important structural and functional features. This tissue is highly cellular, with little or no extracellular material present between cells. Adjoining cells form a specialized intercellular connection between their cell membranes called a cell junction. The epithelial cells exhibit polarity with differences in structure and function between the exposed or apical facing surface of the cell and the basal surface close to the underlying body structures. The basal lamina, a mixture of glycoproteins and collagen, provides an attachment site for the epithelium, separating it from underlying connective tissue. The basal lamina attaches to a reticular lamina, which is secreted by the underlying connective tissue, forming a basement membrane that helps hold it all together.

Epithelial tissues are nearly completely avascular. For instance, no blood vessels cross the basement membrane to enter the tissue, and nutrients must come by diffusion or absorption from underlying tissues or the surface. Many epithelial tissues are capable of rapidly replacing damaged and dead cells. Sloughing off of damaged or dead cells is a characteristic of surface epithelium and allows our airways and digestive tracts to rapidly replace damaged cells with new cells.

Generalized Functions of Epithelial Tissue

Epithelial tissues provide the body’s first line of protection from physical, chemical, and biological wear and tear. The cells of an epithelium act as gatekeepers of the body controlling permeability and allowing selective transfer of materials across a physical barrier. All substances that enter the body must cross an epithelium. Some epithelia often include structural features that allow the selective transport of molecules and ions across their cell membranes.

Many epithelial cells are capable of secretion and release mucous and specific chemical compounds onto their apical surfaces. The epithelium of the small intestine releases digestive enzymes, for example. Cells lining the respiratory tract secrete mucous that traps incoming microorganisms and particles. A glandular epithelium contains many secretory cells.

The Epithelial Cell

Epithelial cells are typically characterized by the polarized distribution of organelles and membrane-bound proteins between their basal and apical surfaces. Particular structures found in some epithelial cells are an adaptation to specific functions. Certain organelles are segregated to the basal sides, whereas other organelles and extensions, such as cilia, when present, are on the apical surface.

Cilia are microscopic extensions of the apical cell membrane that are supported by microtubules. They beat in unison and move fluids as well as trapped particles. Ciliated epithelium lines the ventricles of the brain where it helps circulate the cerebrospinal fluid. The ciliated epithelium of your airway forms a mucociliary escalator that sweeps particles of dust and pathogens trapped in the secreted mucous toward the throat. It is called an escalator because it continuously pushes mucous with trapped particles upward. In contrast, nasal cilia sweep the mucous blanket down towards your throat. In both cases, the transported materials are usually swallowed, and end up in the acidic environment of your stomach.

Cell to Cell Junctions

Cells of epithelia are closely connected and are not separated by intracellular material. Three basic types of connections allow varying degrees of interaction between the cells: tight junctions, anchoring junctions, and gap junctions (Figure 1).

[caption id="" align="aligncenter" width="500"] Figure 1. Types of Cell Junctions. The three basic types of cell-to-cell junctions are tight junctions, gap junctions, and anchoring junctions.[/caption]

At one end of the spectrum is the tight junction, which separates the cells into apical and basal compartments. An anchoring junction includes several types of cell junctions that help stabilize epithelial tissues. Anchoring junctions are common on the lateral and basal surfaces of cells where they provide strong and flexible connections. There are three types of anchoring junctions: desmosomes, hemidesmosomes, and adherens. Desmosomes occur in patches on the membranes of cells. The patches are structural proteins on the inner surface of the cell’s membrane. The adhesion molecule, cadherin, is embedded in these patches and projects through the cell membrane to link with the cadherin molecules of adjacent cells. These connections are especially important in holding cells together. Hemidesmosomes, which look like half a desmosome, link cells to the extracellular matrix, for example, the basal lamina. While similar in appearance to desmosomes, they include the adhesion proteins called integrins rather than cadherins. Adherens junctions use either cadherins or integrins depending on whether they are linking to other cells or matrix. The junctions are characterized by the presence of the contractile protein actin located on the cytoplasmic surface of the cell membrane. The actin can connect isolated patches or form a belt-like structure inside the cell. These junctions influence the shape and folding of the epithelial tissue.

In contrast with the tight and anchoring junctions, a gap junction forms an intercellular passageway between the membranes of adjacent cells to facilitate the movement of small molecules and ions between the cytoplasm of adjacent cells. These junctions allow electrical and metabolic coupling of adjacent cells, which coordinates function in large groups of cells.

Classification of Epithelial Tissues

Epithelial tissues are classified according to the shape of the cells and number of the cell layers formed (Figure 2). Cell shapes can be squamous (flattened and thin), cuboidal (boxy, as wide as it is tall), or columnar (rectangular, taller than it is wide). Similarly, the number of cell layers in the tissue can be one—where every cell rests on the basal lamina—which is a simple epithelium, or more than one, which is a stratified epithelium and only the basal layer of cells rests on the basal lamina. Pseudostratified (pseudo- = “false”) describes tissue with a single layer of irregularly shaped cells that give the appearance of more than one layer. Transitional describes a form of specialized stratified epithelium in which the shape of the cells can vary.

[caption id="" align="aligncenter" width="520"] Figure 2. Cells of Epithelial Tissue. Simple epithelial tissue is organized as a single layer of cells and stratified epithelial tissue is formed by several layers of cells.[/caption]

Simple Epithelium

The shape of the cells in the single cell layer of simple epithelium reflects the functioning of those cells. The cells in simple squamous epithelium have the appearance of thin scales. Squamous cell nuclei tend to be flat, horizontal, and elliptical, mirroring the form of the cell. The endothelium is the epithelial tissue that lines vessels of the lymphatic and cardiovascular system, and it is made up of a single layer of squamous cells. Simple squamous epithelium, because of the thinness of the cell, is present where rapid passage of chemical compounds is observed. The alveoli of lungs where gases diffuse, segments of kidney tubules, and the lining of capillaries are also made of simple squamous epithelial tissue. The mesothelium is a simple squamous epithelium that forms the surface layer of the serous membrane that lines body cavities and internal organs. Its primary function is to provide a smooth and protective surface. Mesothelial cells are squamous epithelial cells that secrete a fluid that lubricates the mesothelium.

In simple cuboidal epithelium, the nucleus of the box-like cells appears round and is generally located near the center of the cell. These epithelia are active in the secretion and absorptions of molecules. Simple cuboidal epithelia are observed in the lining of the kidney tubules and in the ducts of glands.

In simple columnar epithelium, the nucleus of the tall column-like cells tends to be elongated and located in the basal end of the cells. Like the cuboidal epithelia, this epithelium is active in the absorption and secretion of molecules. Simple columnar epithelium forms the lining of some sections of the digestive system and parts of the female reproductive tract. Ciliated columnar epithelium is composed of simple columnar epithelial cells with cilia on their apical surfaces. These epithelial cells are found in the lining of the fallopian tubes and parts of the respiratory system, where the beating of the cilia helps remove particulate matter.

Pseudostratified columnar epithelium is a type of epithelium that appears to be stratified but instead consists of a single layer of irregularly shaped and differently sized columnar cells. In pseudostratified epithelium, nuclei of neighboring cells appear at different levels rather than clustered in the basal end. The arrangement gives the appearance of stratification; but in fact all the cells are in contact with the basal lamina, although some do not reach the apical surface. Pseudostratified columnar epithelium is found in the respiratory tract, where some of these cells have cilia.

Both simple and pseudostratified columnar epithelia are heterogeneous epithelia because they include additional types of cells interspersed among the epithelial cells. For example, a goblet cell is a mucous-secreting unicellular “gland” interspersed between the columnar epithelial cells of mucous membranes (Figure 3).

[caption id="" align="aligncenter" width="250"] Figure 3. Goblet Cell. (a) In the lining of the small intestine, columnar epithelium cells are interspersed with goblet cells. (b) The arrows in this micrograph point to the mucous-secreting goblet cells. LM × 1600. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Stratified Epithelium

A stratified epithelium consists of several stacked layers of cells. This epithelium protects against physical and chemical wear and tear. The stratified epithelium is named by the shape of the most apical layer of cells, closest to the free space. Stratified squamous epithelium is the most common type of stratified epithelium in the human body. The apical cells are squamous, whereas the basal layer contains either columnar or cuboidal cells. The top layer may be covered with dead cells filled with keratin. Mammalian skin is an example of this dry, keratinized, stratified squamous epithelium. The lining of the mouth cavity is an example of an unkeratinized, stratified squamous epithelium. Stratified cuboidal epithelium and stratified columnar epithelium can also be found in certain glands and ducts, but are uncommon in the human body.

Another kind of stratified epithelium is transitional epithelium, so-called because of the gradual changes in the shapes of the apical cells as the bladder fills with urine. It is found only in the urinary system, specifically the ureters and urinary bladder. When the bladder is empty, this epithelium is convoluted and has cuboidal apical cells with convex, umbrella shaped, apical surfaces. As the bladder fills with urine, this epithelium loses its convolutions and the apical cells transition from cuboidal to squamous. It appears thicker and more multi-layered when the bladder is empty, and more stretched out and less stratified when the bladder is full and distended. Figure 4 summarizes the different categories of epithelial cell tissue cells.

[caption id="" align="aligncenter" width="500"] Figure 4. Summary of Epithelial Tissue Cells.[/caption]

[caption id="attachment_2994" align="aligncenter" width="150"] Watch this CrashCourse video to get an overview of epithelial tissue.[/caption]

Glandular Epithelium

A gland is a structure made up of one or more cells modified to synthesize and secrete chemical substances. Most glands consist of groups of epithelial cells. A gland can be classified as an endocrine gland, a ductless gland that releases secretions directly into surrounding tissues and fluids (endo- = “inside”), or an exocrine gland whose secretions leave through a duct that opens directly, or indirectly, to the external environment (exo- = “outside”).

Endocrine Glands

The secretions of endocrine glands are called hormones. Hormones are released into the interstitial fluid, diffused into the bloodstream, and delivered to targets, in other words, cells that have receptors to bind the hormones. The endocrine system is part of a major regulatory system coordinating the regulation and integration of body responses. A few examples of endocrine glands include the anterior pituitary, thymus, adrenal cortex, and gonads.

Exocrine Glands

Exocrine glands release their contents through a duct that leads to the epithelial surface. Mucous, sweat, saliva, and breast milk are all examples of secretions from exocrine glands. They are all discharged through tubular ducts. Secretions into the lumen of the gastrointestinal tract, technically outside of the body, are of the exocrine category.

Glandular Structure

Exocrine glands are classified as either unicellular or multicellular. The unicellular glands are scattered single cells, such as goblet cells, found in the mucous membranes of the small and large intestine.

The multicellular exocrine glands known as serous glands develop from simple epithelium to form a secretory surface that secretes directly into an inner cavity. These glands line the internal cavities of the abdomen and chest and release their secretions directly into the cavities. Other multicellular exocrine glands release their contents through a tubular duct. The duct is single in a simple gland but in compound glands is divided into one or more branches (Figure 5). In tubular glands, the ducts can be straight or coiled, whereas tubes that form pockets are alveolar (acinar), such as the exocrine portion of the pancreas. Combinations of tubes and pockets are known as tubuloalveolar (tubuloacinar) compound glands. In a branched gland, a duct is connected to more than one secretory group of cells.

[caption id="" align="aligncenter" width="550"] Figure 5. Types of Exocrine Glands. Exocrine glands are classified by their structure.[/caption]

Methods and Types of Secretion

Exocrine glands can be classified by their mode of secretion and the nature of the substances released, as well as by the structure of the glands and shape of ducts (Figure 6). Merocrine secretion is the most common type of exocrine secretion. The secretions are enclosed in vesicles that move to the apical surface of the cell where the contents are released by exocytosis. For example, watery mucous containing the glycoprotein mucin, a lubricant that offers some pathogen protection is a merocrine secretion. The eccrine glands that produce and secrete sweat are another example.

[caption id="" align="aligncenter" width="400"] Figure 6. Modes of Glandular Secretion. (a) In merocrine secretion, the cell remains intact. (b) In apocrine secretion, the apical portion of the cell is released, as well. (c) In holocrine secretion, the cell is destroyed as it releases its product and the cell itself becomes part of the secretion.[/caption]

Apocrine secretion accumulates near the apical portion of the cell. That portion of the cell and its secretory contents pinch off from the cell and are released. The sweat glands of the armpit are classified as apocrine glands. Both merocrine and apocrine glands continue to produce and secrete their contents with little damage caused to the cell because the nucleus and golgi regions remain intact after secretion.

In contrast, the process of holocrine secretion involves the rupture and destruction of the entire gland cell. The cell accumulates its secretory products and releases them only when it bursts. New gland cells differentiate from cells in the surrounding tissue to replace those lost by secretion. The sebaceous glands that produce the oils on the skin and hair are holocrine glands/cells (Figure 7).

[caption id="" align="aligncenter" width="520"] Figure 7. Sebaceous Glands. These glands secrete oils that lubricate and protect the skin. They are holocrine glands and they are destroyed after releasing their contents. New glandular cells form to replace the cells that are lost. LM × 400. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Glands are also named after the products they produce. The serous gland produces watery, blood-plasma-like secretions rich in enzymes such as alpha amylase, whereas the mucous gland releases watery to viscous products rich in the glycoprotein mucin. Both serous and mucous glands are common in the salivary glands of the mouth. Mixed exocrine glands contain both serous and mucous glands and release both types of secretions.

Introduction

barkerj1 — Wed, 06 Sep 2017 01:19:21 +0000

[caption id="" align="aligncenter" width="500"] Figure 1. Robotic Arms Playing Foosball. As the neural circuitry of the nervous system has become more fully understood and robotics more sophisticated, it is now possible to integrate technology with the body and restore abilities following traumatic events. At some point in the future, will this type of technology lead to the ability to augment our nervous systems? (credit: U.S. Army/Wikimedia Commons)[/caption] The nervous system is a very complex organ system. In Peter D. Kramer’s book Listening to Prozac, a pharmaceutical researcher is quoted as saying, “If the human brain were simple enough for us to understand, we would be too simple to understand it” (1994). That quote is from the early 1990s; in the two decades since, progress has continued at an amazing rate within the scientific disciplines of neuroscience. It is an interesting conundrum to consider that the complexity of the nervous system may be too complex for it (that is, for us) to completely unravel. But our current level of understanding is probably nowhere close to that limit. One easy way to begin to understand the structure of the nervous system is to start with the large divisions and work through to a more in-depth understanding. In other chapters, the finer details of the nervous system will be explained, but first looking at an overview of the system will allow you to begin to understand how its parts work together. The focus of this chapter is on nervous (neural) tissue, both its structure and its function. But before you learn about that, you will see a big picture of the system—actually, a few big pictures.

12.1 Basic Structure and Function of the Nervous System

barkerj1 — Wed, 06 Sep 2017 01:19:21 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the structure of each of the following:
- Ganglion
- Nerve
- Gray matter
- Tract
- White matter
Describe the organization of the nervous system
Explain the functions of the principle components of the nervous system

The picture you have in your mind of the nervous system probably includes the brain, the nervous tissue contained within the cranium, and the spinal cord, the extension of nervous tissue within the vertebral column. That suggests it is made of two organs—and you may not even think of the spinal cord as an organ—but the nervous system is a very complex structure. Within the brain, many different and separate regions are responsible for many different and separate functions. It is as if the nervous system is composed of many organs that all look similar and can only be differentiated using tools such as the microscope or electrophysiology. In comparison, it is easy to see that the stomach is different than the esophagus or the liver, so you can imagine the digestive system as a collection of specific organs.

The Central and Peripheral Nervous Systems

The nervous system can be divided into two major regions: the central and peripheral nervous systems. The central nervous system (CNS) is the brain and spinal cord, and the peripheral nervous system (PNS) is everything else (Figure 1). The brain is contained within the cranial cavity of the skull, and the spinal cord is contained within the vertebral cavity of the vertebral column. It is a bit of an oversimplification to say that the CNS is what is inside these two cavities and the peripheral nervous system is outside of them, but that is one way to start to think about it. In actuality, there are some elements of the peripheral nervous system that are within the cranial or vertebral cavities. The peripheral nervous system is so named because it is on the periphery—meaning beyond the brain and spinal cord. Depending on different aspects of the nervous system, the dividing line between central and peripheral is not necessarily universal.

[caption id="" align="aligncenter" width="380"] Figure 1. Central and Peripheral Nervous System. The structures of the PNS are referred to as ganglia and nerves, which can be seen as distinct structures. The equivalent structures in the CNS are not obvious from this overall perspective and are best examined in prepared tissue under the microscope.[/caption]

Nervous tissue, present in both the CNS and PNS, contains two basic types of cells: neurons and glial cells. A glial cell is one of a variety of cells that provide a framework of tissue that supports the neurons and their activities. The neuron is the more functionally important of the two, in terms of the communicative function of the nervous system. To describe the functional divisions of the nervous system, it is important to understand the structure of a neuron. Neurons are cells and therefore have a soma, or cell body, but they also have extensions of the cell; each extension is generally referred to as a process. There is one important process that every neuron has called an axon, which is the fiber that connects a neuron with its target. Another type of process that branches off from the soma is the dendrite. Dendrites are responsible for receiving most of the input from other neurons. Looking at nervous tissue, there are regions that predominantly contain cell bodies and regions that are largely composed of just axons. These two regions within nervous system structures are often referred to as gray matter (the regions with many cell bodies and dendrites) or white matter (the regions with many axons). Figure 2 demonstrates the appearance of these regions in the brain and spinal cord. The colors ascribed to these regions are what would be seen in “fresh,” or unstained, nervous tissue. Gray matter is not necessarily gray. It can be pinkish because of blood content, or even slightly tan, depending on how long the tissue has been preserved. But white matter is white because axons are insulated by a lipid-rich substance called myelin. Lipids can appear as white (“fatty”) material, much like the fat on a raw piece of chicken or beef. Actually, gray matter may have that color ascribed to it because next to the white matter, it is just darker—hence, gray.

The distinction between gray matter and white matter is most often applied to central nervous tissue, which has large regions that can be seen with the unaided eye. When looking at peripheral structures, often a microscope is used and the tissue is stained with artificial colors. That is not to say that central nervous tissue cannot be stained and viewed under a microscope, but unstained tissue is most likely from the CNS—for example, a frontal section of the brain or cross section of the spinal cord.

[caption id="" align="aligncenter" width="380"] Figure 2. Gray Matter and White Matter. A brain removed during an autopsy, with a partial section removed, shows white matter surrounded by gray matter. Gray matter makes up the outer cortex of the brain. (credit: modification of work by “Suseno”/Wikimedia Commons)[/caption]

Regardless of the appearance of stained or unstained tissue, the cell bodies of neurons or axons can be located in discrete anatomical structures that need to be named. Those names are specific to whether the structure is central or peripheral. A localized collection of neuron cell bodies in the CNS is referred to as a nucleus. In the PNS, a cluster of neuron cell bodies is referred to as a ganglion. Figure 3 indicates how the term nucleus has a few different meanings within anatomy and physiology. It is the center of an atom, where protons and neutrons are found; it is the center of a cell, where the DNA is found; and it is a center of some function in the CNS. There is also a potentially confusing use of the word ganglion (plural = ganglia) that has a historical explanation. In the central nervous system, there is a group of nuclei that are connected together and were once called the basal ganglia before “ganglion” became accepted as a description for a peripheral structure. Some sources refer to this group of nuclei as the “basal nuclei” to avoid confusion.

[caption id="" align="aligncenter" width="395"] Figure 3. What Is a Nucleus? (a) The nucleus of an atom contains its protons and neutrons. (b) The nucleus of a cell is the organelle that contains DNA. (c) A nucleus in the CNS is a localized center of function with the cell bodies of several neurons, shown here circled in red. (credit c: “Was a bee”/Wikimedia Commons)[/caption]

Terminology applied to bundles of axons also differs depending on location. A bundle of axons, or fibers, found in the CNS is called a tract whereas the same thing in the PNS would be called a nerve. There is an important point to make about these terms, which is that they can both be used to refer to the same bundle of axons. When those axons are in the PNS, the term is nerve, but if they are CNS, the term is tract. The most obvious example of this is the axons that project from the retina into the brain. Those axons are called the optic nerve as they leave the eye, but when they are inside the cranium, they are referred to as the optic tract. There is a specific place where the name changes, which is the optic chiasm, but they are still the same axons (Figure 4). A similar situation outside of science can be described for some roads. Imagine a road called “Broad Street” in a town called “Anyville.” The road leaves Anyville and goes to the next town over, called “Hometown.” When the road crosses the line between the two towns and is in Hometown, its name changes to “Main Street.” That is the idea behind the naming of the retinal axons. In the PNS, they are called the optic nerve, and in the CNS, they are the optic tract. Table 1 helps to clarify which of these terms apply to the central or peripheral nervous systems.

[caption id="" align="aligncenter" width="380"] Figure 4. Optic Nerve Versus Optic Tract. This drawing of the connections of the eye to the brain shows the optic nerve extending from the eye to the chiasm, where the structure continues as the optic tract. The same axons extend from the eye to the brain through these two bundles of fibers, but the chiasm represents the border between peripheral and central.[/caption]

Structures of the CNS and PNS (Table 1)
	CNS	PNS
Group of Neuron Cell Bodies (i.e., gray matter)	Nucleus	Ganglion
Bundle of Axons (i.e., white matter)	Tract	Nerve

Functional Divisions of the Nervous System

The nervous system can also be divided on the basis of its functions, but anatomical divisions and functional divisions are different. The CNS and the PNS both contribute to the same functions, but those functions can be attributed to different regions of the brain (such as the cerebral cortex or the hypothalamus) or to different ganglia in the periphery. The problem with trying to fit functional differences into anatomical divisions is that sometimes the same structure can be part of several functions. For example, the optic nerve carries signals from the retina that are either used for the conscious perception of visual stimuli, which takes place in the cerebral cortex, or for the reflexive responses of smooth muscle tissue that are processed through the hypothalamus.

There are two ways to consider how the nervous system is divided functionally. First, the basic functions of the nervous system are sensation, integration, and response. Secondly, control of the body can be somatic or autonomic—divisions that are largely defined by the structures that are involved in the response. There is also a region of the peripheral nervous system that is called the enteric nervous system that is responsible for a specific set of the functions within the realm of autonomic control related to gastrointestinal functions.

Basic Functions

The nervous system is involved in receiving information about the environment around us (sensation) and generating responses to that information (motor responses). The nervous system can be divided into regions that are responsible for sensation (sensory functions) and for the response (motor functions). But there is a third function that needs to be included. Sensory input needs to be integrated with other sensations, as well as with memories, emotional state, or learning (cognition). Some regions of the nervous system are termed integration or association areas. The process of integration combines sensory perceptions and higher cognitive functions such as memories, learning, and emotion to produce a response.

Sensation. The first major function of the nervous system is sensation—receiving information about the environment to gain input about what is happening outside the body (or, sometimes, within the body). The sensory functions of the nervous system register the presence of a change from homeostasis or a particular event in the environment, known as a stimulus. The senses most people think of most are the “big five”: taste, smell, touch, sight, and hearing. The stimuli for taste and smell are chemical substances (molecules, compounds, ions, etc.), touch is the perception of a variety of physical or mechanical stimuli that interact with the skin, sight is the perception of light stimuli, and hearing is the perception of sound, which is a physical stimulus similar to some aspects of touch. There are actually more senses than just those, that will be discussed in a later chapter. The five noted here are all senses that receive stimuli from the outside world and of which there is conscious perception. Additional senses include the detection (which may or may not be perceived) of sensory stimuli arising from the internal environment, such as the stretch of an organ wall or the concentration of certain ions in the blood, or the detection and perception of the body's position in space.

Response. The nervous system produces a response on the basis of the stimuli perceived by sensory structures. An obvious response would be the movement of muscles, such as withdrawing a hand from a hot stove, but there are broader uses of the term. The nervous system can cause the contraction of all three types of muscle tissue. For example, skeletal muscle contracts to move the skeleton, cardiac muscle is influenced as heart rate increases during exercise, and smooth muscle contracts as the digestive system moves food along the digestive tract. Responses also include the neural control of glands in the body as well, such as the production and secretion of sweat by the eccrine and merocrine sweat glands found in the skin to lower body temperature.

Responses can be divided into those that are voluntary or conscious (contraction of skeletal muscle) and those that are involuntary (contraction of smooth muscles, regulation of cardiac muscle, activation of glands). Voluntary responses are governed by the somatic nervous system and involuntary responses are governed by the autonomic nervous system, which are discussed in the next section.

Integration. Stimuli that are received by sensory structures are communicated to the nervous system where that information is processed. This is called integration. Stimuli are compared with, or integrated with, other stimuli, memories of previous stimuli, or the state of a person at a particular time. This leads to the specific response that will be generated. Seeing a baseball pitched to a batter will not automatically cause the batter to swing. The trajectory of the ball and its speed will need to be considered. Maybe the count is three balls and one strike, and the batter wants to let this pitch go by in the hope of getting a walk to first base. Or maybe the batter’s team is so far ahead, it would be fun to just swing away.

Controlling the Body

The nervous system can be divided into two parts mostly on the basis of a functional difference in responses. The somatic nervous system (SNS) is responsible for conscious perception and voluntary motor responses. Voluntary motor response means the contraction of skeletal muscle, but those contractions are not always voluntary in the sense that you have to want to perform them. Some somatic motor responses are reflexes, and often happen without a conscious decision to perform them. If your friend jumps out from behind a corner and yells “Boo!” you will be startled and you might scream or leap back. You didn’t decide to do that, and you may not have wanted to give your friend a reason to laugh at your expense, but it is a reflex involving skeletal muscle contractions. Other motor responses become automatic (in other words, unconscious) as a person learns motor skills (referred to as “habit learning” or “procedural memory”).

The autonomic nervous system (ANS) is responsible for involuntary control of the body, usually for the sake of homeostasis (regulation of the internal environment). Sensory input for autonomic functions can be from sensory structures tuned to external or internal environmental stimuli. The motor output extends to smooth and cardiac muscle as well as glandular tissue. The role of the autonomic system is to regulate the organ systems of the body, which usually means to control homeostasis. Sweat glands, for example, are controlled by the autonomic system. When you are hot, sweating helps cool your body down. That is a homeostatic mechanism. But when you are nervous, you might start sweating also. That is not homeostatic, it is the physiological response to an emotional state.

There is another division of the nervous system that describes functional responses. The enteric nervous system (ENS) is responsible for controlling the smooth muscle and glandular tissue in your digestive system. It is a large part of the PNS, and is not dependent on the CNS. It is sometimes valid, however, to consider the enteric system to be a part of the autonomic system because the neural structures that make up the enteric system are a component of the autonomic output that regulates digestion. There are some differences between the two, but for our purposes here there will be a good bit of overlap. See Figure 5 for examples of where these divisions of the nervous system can be found.

[caption id="" align="aligncenter" width="580"] Figure 5. Somatic, Autonomic, and Enteric Structures of the Nervous System. Somatic structures include the spinal nerves, both motor and sensory fibers, as well as the sensory ganglia (posterior root ganglia and cranial nerve ganglia). Autonomic structures are found in the nerves also, but include the sympathetic and parasympathetic ganglia. The enteric nervous system includes the nervous tissue within the organs of the digestive tract.[/caption]

[caption id="attachment_2996" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of the nervous system![/caption]

12.2 Nervous Tissue

barkerj1 — Wed, 06 Sep 2017 01:19:22 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the structure of each of the following:
- Neuron
- Neuroglia
- Sensory neuron
- Motor neuron

Nervous tissue is composed of two types of cells, neurons and glial cells. Neurons are the primary type of cell that most anyone associates with the nervous system. They are responsible for the computation and communication that the nervous system provides. They are electrically active and release chemical signals to target cells. Glial cells, or glia, are known to play a supporting role for nervous tissue. Ongoing research pursues an expanded role that glial cells might play in signaling, but neurons are still considered the basis of this function. Neurons are important, but without glial support they would not be able to perform their function.

Neurons

Neurons are the cells considered to be the basis of nervous tissue. They are responsible for the electrical signals that communicate information about sensations, and that produce movements in response to those stimuli, along with inducing thought processes within the brain. An important part of the function of neurons is in their structure, or shape. The three-dimensional shape of these cells makes the immense numbers of connections within the nervous system possible.

Parts of a Neuron

As you learned in the first section, the main part of a neuron is the cell body, which is also known as the soma (soma = “body”). The cell body contains the nucleus and most of the major organelles. But what makes neurons special is that they have many extensions of their cell membranes, which are generally referred to as processes. Neurons are usually described as having one, and only one, axon—a fiber that emerges from the cell body and projects to target cells. That single axon can branch repeatedly to communicate with many target cells. It is the axon that propagates the nerve impulse, which is communicated to one or more cells. The other processes of the neuron are dendrites, which receive information from other neurons at specialized areas of contact called synapses. The dendrites are usually highly branched processes, providing locations for other neurons to communicate with the cell body. Information flows through a neuron from the dendrites, across the cell body, and down the axon. This gives the neuron a polarity—meaning that information flows in this one direction. Figure 1 shows the relationship of these parts to one another.

[caption id="" align="aligncenter" width="380"] Figure 1. Parts of a Neuron. The major parts of the neuron are labeled on a multipolar neuron from the CNS.[/caption]

Where the axon emerges from the cell body, there is a special region referred to as the axon hillock. This is a tapering of the cell body toward the axon fiber. Within the axon hillock, the cytoplasm changes to a solution of limited components called axoplasm. Because the axon hillock represents the beginning of the axon, it is also referred to as the initial segment.

Many axons are wrapped by an insulating substance called myelin, which is actually made from glial cells. Myelin acts as insulation much like the plastic or rubber that is used to insulate electrical wires. A key difference between myelin and the insulation on a wire is that there are gaps in the myelin covering of an axon. Each gap is called a node of Ranvier and is important to the way that electrical signals travel down the axon. The length of the axon between each gap, which is wrapped in myelin, is referred to as an axon segment. At the end of the axon is the axon terminal, where there are usually several branches extending toward the target cell, each of which ends in an enlargement called a synaptic end bulb. These bulbs are what make the connection with the target cell at the synapse.

Types of Neurons

There are many neurons in the nervous system—a number in the trillions. And there are many different types of neurons. They can be classified by many different criteria. The first way to classify them is by the number of processes attached to the cell body. Using the standard model of neurons, one of these processes is the axon, and the rest are dendrites. Because information flows through the neuron from dendrites or cell bodies toward the axon, these names are based on the neuron's polarity (Figure 2).

[caption id="" align="aligncenter" width="420"] Figure 2. Neuron Classification by Shape. Unipolar cells have one process that includes both the axon and dendrite. Bipolar cells have two processes, the axon and a dendrite. Multipolar cells have more than two processes, the axon and two or more dendrites.[/caption]

Unipolar cells have only one process emerging from the cell. True unipolar cells are only found in invertebrate animals, so the unipolar cells in humans are more appropriately called “pseudo-unipolar” cells. Invertebrate unipolar cells do not have dendrites. Human unipolar cells have an axon that emerges from the cell body, but it splits so that the axon can extend along a very long distance. At one end of the axon are dendrites, and at the other end, the axon forms synaptic connections with a target. Unipolar cells are exclusively sensory neurons and have two unique characteristics. First, their dendrites are receiving sensory information, sometimes directly from the stimulus itself. Secondly, the cell bodies of unipolar neurons are always found in ganglia. Sensory reception is a peripheral function (those dendrites are in the periphery, perhaps in the skin) so the cell body is in the periphery, though closer to the CNS in a ganglion. The axon projects from the dendrite endings, past the cell body in a ganglion, and into the central nervous system.

Bipolar cells have two processes, which extend from each end of the cell body, opposite to each other. One is the axon and one the dendrite. Bipolar cells are not very common. They are found mainly in the olfactory epithelium (where smell stimuli are sensed), and as part of the retina.

Multipolar neurons are all of the neurons that are not unipolar or bipolar. They have one axon and two or more dendrites (usually many more). With the exception of the unipolar sensory ganglion cells, and the two specific bipolar cells mentioned above, all other neurons are multipolar. Some cutting edge research suggests that certain neurons in the CNS do not conform to the standard model of “one, and only one” axon. Some sources describe a fourth type of neuron, called an anaxonic neuron. The name suggests that it has no axon (an- = “without”), but this is not accurate. Anaxonic neurons are very small, and if you look through a microscope at the standard resolution used in histology (approximately 400X to 1000X total magnification), you will not be able to distinguish any process specifically as an axon or a dendrite. Any of those processes can function as an axon depending on the conditions at any given time. Nevertheless, even if they cannot be easily seen, and one specific process is definitively the axon, these neurons have multiple processes and are therefore multipolar.

Neurons can also be classified on the basis of where they are found, who found them, what they do, or even what chemicals they use to communicate with each other. Some neurons referred to in this section on the nervous system are named on the basis of those sorts of classifications (Figure 3). For example, a multipolar neuron that has a very important role to play in a part of the brain called the cerebellum is known as a Purkinje (commonly pronounced per-KIN-gee) cell. It is named after the anatomist who discovered it (Jan Evangilista Purkinje, 1787–1869).

[caption id="" align="aligncenter" width="450"] Figure 3. Other Neuron Classifications. Three examples of neurons that are classified on the basis of other criteria. (a) The pyramidal cell is a multipolar cell with a cell body that is shaped something like a pyramid. (b) The Purkinje cell in the cerebellum was named after the scientist who originally described it. (c) Olfactory neurons are named for the functional group with which they belong.[/caption]

Glial Cells

Glial cells, or neuroglia or simply glia, are the other type of cell found in nervous tissue. They are considered to be supporting cells, and many functions are directed at helping neurons complete their function for communication. The name glia comes from the Greek word that means “glue,” and was coined by the German pathologist Rudolph Virchow, who wrote in 1856: “This connective substance, which is in the brain, the spinal cord, and the special sense nerves, is a kind of glue (neuroglia) in which the nervous elements are planted.” Today, research into nervous tissue has shown that there are many deeper roles that these cells play. And research may find much more about them in the future.

There are six types of glial cells. Four of them are found in the CNS and two are found in the PNS. Table 2 outlines some common characteristics and functions.

Glial Cell Types by Location and Basic Function (Table 2)
CNS glia	PNS glia	Basic function
Astrocyte	Satellite cell	Support
Oligodendrocyte	Schwann cell	Insulation, myelination
Microglia	-	Immune surveillance and phagocytosis
Ependymal cell	-	Creating CSF

Glial Cells of the CNS

One cell providing support to neurons of the CNS is the astrocyte, so named because it appears to be star-shaped under the microscope (astro- = “star”). Astrocytes have many processes extending from their main cell body (not axons or dendrites like neurons, just cell extensions). Those processes extend to interact with neurons, blood vessels, or the connective tissue covering the CNS that is called the pia mater (Figure 4). Generally, they are supporting cells for the neurons in the central nervous system. Some ways in which they support neurons in the central nervous system are by maintaining the concentration of chemicals in the extracellular space, removing excess signaling molecules, reacting to tissue damage, and contributing to the blood-brain barrier (BBB). The blood-brain barrier is a physiological barrier that keeps many substances that circulate in the rest of the body from getting into the central nervous system, restricting what can cross from circulating blood into the CNS. Nutrient molecules, such as glucose or amino acids, can pass through the BBB, but other molecules cannot. This actually causes problems with drug delivery to the CNS. Pharmaceutical companies are challenged to design drugs that can cross the BBB as well as have an effect on the nervous system.

[caption id="" align="aligncenter" width="420"] Figure 4. Glial Cells of the CNS. The CNS has astrocytes, oligodendrocytes, microglia, and ependymal cells that support the neurons of the CNS in several ways.[/caption]

Like a few other parts of the body, the brain has a privileged blood supply. Very little can pass through by diffusion. Most substances that cross the wall of a blood vessel into the CNS must do so through an active transport process. Because of this, only specific types of molecules can enter the CNS. Glucose—the primary energy source—is allowed, as are amino acids. Water and some other small particles, like gases and ions, can enter. But most everything else cannot, including white blood cells, which are one of the body’s main lines of defense. While this barrier protects the CNS from exposure to toxic or pathogenic substances, it also keeps out the cells that could protect the brain and spinal cord from disease and damage. The BBB also makes it harder for pharmaceuticals to be developed that can affect the nervous system. Aside from finding efficacious substances, the means of delivery is also crucial.

Also found in CNS tissue is the oligodendrocyte, sometimes called just “oligo,” which is the glial cell type that insulates axons in the CNS. The name means “cell of a few branches” (oligo- = “few”; dendro- = “branches”; -cyte = “cell”). There are a few processes that extend from the cell body. Each one reaches out and surrounds an axon to insulate it in myelin. One oligodendrocyte will provide the myelin for multiple axon segments, either for the same axon or for separate axons. The function of myelin will be discussed below.

Microglia are, as the name implies, smaller than most of the other glial cells. Ongoing research into these cells, although not entirely conclusive, suggests that they may originate as white blood cells, called macrophages, that become part of the CNS during early development. While their origin is not conclusively determined, their function is related to what macrophages do in the rest of the body. When macrophages encounter diseased or damaged cells in the rest of the body, they ingest and digest those cells or the pathogens that cause disease. Microglia are the cells in the CNS that can do this in normal, healthy tissue, and they are therefore also referred to as CNS-resident macrophages.

The ependymal cell is a glial cell that filters blood to make cerebrospinal fluid (CSF), the fluid that circulates through the CNS. Because of the privileged blood supply inherent in the BBB, the extracellular space in nervous tissue does not easily exchange components with the blood. Ependymal cells line each ventricle, one of four central cavities that are remnants of the hollow center of the neural tube formed during the embryonic development of the brain. The choroid plexus is a specialized structure in the ventricles where ependymal cells come in contact with blood vessels and filter and absorb components of the blood to produce cerebrospinal fluid. Because of this, ependymal cells can be considered a component of the BBB, or a place where the BBB breaks down. These glial cells appear similar to epithelial cells, making a single layer of cells with little intracellular space and tight connections between adjacent cells. They also have cilia on their apical surface to help move the CSF through the ventricular space. The relationship of these glial cells to the structure of the CNS is seen in Figure 4.

Glial Cells of the PNS

One of the two types of glial cells found in the PNS is the satellite cell. Satellite cells are found in sensory and autonomic ganglia, where they surround the cell bodies of neurons. This accounts for the name, based on their appearance under the microscope. They provide support, performing similar functions in the periphery as astrocytes do in the CNS—except, of course, for establishing the BBB.

The second type of glial cell is the Schwann cell, which insulate axons with myelin in the periphery. Schwann cells are different than oligodendrocytes, in that a Schwann cell wraps around a portion of only one axon segment and no others. Oligodendrocytes have processes that reach out to multiple axon segments, whereas the entire Schwann cell surrounds just one axon segment. The nucleus and cytoplasm of the Schwann cell are on the edge of the myelin sheath. The relationship of these two types of glial cells to ganglia and nerves in the PNS is seen in Figure 5.

[caption id="" align="aligncenter" width="420"] Figure 5. Glial Cells of the PNS. The PNS has satellite cells and Schwann cells.[/caption]

Myelin

The insulation for axons in the nervous system is provided by glial cells, oligodendrocytes in the CNS, and Schwann cells in the PNS. Whereas the manner in which either cell is associated with the axon segment, or segments, that it insulates is different, the means of myelinating an axon segment is mostly the same in the two situations. Myelin is a lipid-rich sheath that surrounds the axon and by doing so creates a myelin sheath that facilitates the transmission of electrical signals along the axon. The lipids are essentially the phospholipids of the glial cell membrane. Myelin, however, is more than just the membrane of the glial cell. It also includes important proteins that are integral to that membrane. Some of the proteins help to hold the layers of the glial cell membrane closely together.

The appearance of the myelin sheath can be thought of as similar to the pastry wrapped around a hot dog for “pigs in a blanket” or a similar food. The glial cell is wrapped around the axon several times with little to no cytoplasm between the glial cell layers. For oligodendrocytes, the rest of the cell is separate from the myelin sheath as a cell process extends back toward the cell body. A few other processes provide the same insulation for other axon segments in the area. For Schwann cells, the outermost layer of the cell membrane contains cytoplasm and the nucleus of the cell as a bulge on one side of the myelin sheath. During development, the glial cell is loosely or incompletely wrapped around the axon (Figure 6a). The edges of this loose enclosure extend toward each other, and one end tucks under the other. The inner edge wraps around the axon, creating several layers, and the other edge closes around the outside so that the axon is completely enclosed.

Myelin sheaths can extend for one or two millimeters, depending on the diameter of the axon. Axon diameters can be as small as 1 to 20 micrometers. Because a micrometer is 1/1000 of a millimeter, this means that the length of a myelin sheath can be 100–1000 times the diameter of the axon. Figure 1, Figure 4, and Figure 5 show the myelin sheath surrounding an axon segment, but are not to scale. If the myelin sheath were drawn to scale, the neuron would have to be immense—possibly covering an entire wall of the room in which you are sitting.

[caption id="" align="aligncenter" width="550"] Figure 6. The Process of Myelination. Myelinating glia wrap several layers of cell membrane around the cell membrane of an axon segment. A single Schwann cell insulates a segment of a peripheral nerve, whereas in the CNS, an oligodendrocyte may provide insulation for a few separate axon segments. EM × 1,460,000. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Disorders of Nervous Tissue

Several diseases can result from the demyelination of axons. The causes of these diseases are not the same; some have genetic causes, some are caused by pathogens, and others are the result of autoimmune disorders. Though the causes are varied, the results are largely similar. The myelin insulation of axons is compromised, making electrical signaling slower.

Multiple sclerosis (MS) is one such disease. It is an example of an autoimmune disease. The antibodies produced by lymphocytes (a type of white blood cell) mark myelin as something that should not be in the body. This causes inflammation and the destruction of the myelin in the central nervous system. As the insulation around the axons is destroyed by the disease, scarring becomes obvious. This is where the name of the disease comes from; sclerosis means hardening of tissue, which is what a scar is. Multiple scars are found in the white matter of the brain and spinal cord. The symptoms of MS include both somatic and autonomic deficits. Control of the musculature is compromised, as is control of organs such as the bladder.

Guillain-Barré (pronounced gee-YAN bah-RAY) syndrome is an example of a demyelinating disease of the peripheral nervous system. It is also the result of an autoimmune reaction, but the inflammation is in peripheral nerves. Sensory symptoms or motor deficits are common, and autonomic failures can lead to changes in the heart rhythm or a drop in blood pressure, especially when standing, which causes dizziness.

12.3 The Function of Nervous Tissue

barkerj1 — Wed, 06 Sep 2017 01:19:23 +0000

Learning Objectives

By the end of this section, you will be able to:

Having looked at the components of nervous tissue, and the basic anatomy of the nervous system, next comes an understanding of how nervous tissue is capable of communicating within the nervous system. Before getting to the nuts and bolts of how this works, an illustration of how the components come together will be helpful. An example is summarized in Figure 1.

[caption id="" align="aligncenter" width="450"] Figure 1. Testing the Water. (1) The sensory neuron has endings in the skin that sense a stimulus such as water temperature. The strength of the signal that starts here is dependent on the strength of the stimulus. (2) The graded potential from the sensory endings, if strong enough, will initiate an action potential at the initial segment of the axon (which is immediately adjacent to the sensory endings in the skin). (3) The axon of the peripheral sensory neuron enters the spinal cord and contacts another neuron in the gray matter. The contact is a synapse where another graded potential is caused by the release of a chemical signal from the axon terminals. (4) An action potential is initiated at the initial segment of this neuron and travels up the sensory pathway to a region of the brain called the thalamus. Another synapse passes the information along to the next neuron. (5) The sensory pathway ends when the signal reaches the cerebral cortex. (6) After integration with neurons in other parts of the cerebral cortex, a motor command is sent from the precentral gyrus of the frontal cortex. (7) The upper motor neuron sends an action potential down to the spinal cord. The target of the upper motor neuron is the dendrites of the lower motor neuron in the gray matter of the spinal cord. (8) The axon of the lower motor neuron emerges from the spinal cord in a nerve and connects to a muscle through a neuromuscular junction to cause contraction of the target muscle.[/caption]

Imagine you are about to take a shower in the morning before going to school. You have turned on the faucet to start the water as you prepare to get in the shower. After a few minutes, you expect the water to be a temperature that will be comfortable to enter. So you put your hand out into the spray of water. What happens next depends on how your nervous system interacts with the stimulus of the water temperature and what you do in response to that stimulus.

Found in the skin of your fingers or toes is a type of sensory receptor that is sensitive to temperature, called a thermoreceptor. When you place your hand under the shower (Figure 2), the cell membrane of the thermoreceptors changes its electrical state (voltage). The amount of change is dependent on the strength of the stimulus (how hot the water is). This is called a graded potential. If the stimulus is strong, the voltage of the cell membrane will change enough to generate an electrical signal that will travel down the axon. You have learned about this type of signaling before, with respect to the interaction of nerves and muscles at the neuromuscular junction. The voltage at which such a signal is generated is called the threshold, and the resulting electrical signal is called an action potential. In this example, the action potential travels—a process known as propagation—along the axon from the axon hillock to the axon terminals and into the synaptic end bulbs. When this signal reaches the end bulbs, it causes the release of a signaling molecule called a neurotransmitter.

[caption id="" align="aligncenter" width="380"] Figure 2. The Sensory Input. Receptors in the skin sense the temperature of the water.[/caption]

The neurotransmitter diffuses across the short distance of the synapse and binds to a receptor protein of the target neuron. When the molecular signal binds to the receptor, the cell membrane of the target neuron changes its electrical state and a new graded potential begins. If that graded potential is strong enough to reach threshold, the second neuron generates an action potential at its axon hillock. The target of this neuron is another neuron in the thalamus of the brain, the part of the CNS that acts as a relay for sensory information. At another synapse, neurotransmitter is released and binds to its receptor. The thalamus then sends the sensory information to the cerebral cortex, the outermost layer of gray matter in the brain, where conscious perception of that water temperature begins.

Within the cerebral cortex, information is processed among many neurons, integrating the stimulus of the water temperature with other sensory stimuli, with your emotional state (you just aren't ready to wake up; the bed is calling to you), memories (perhaps of the lab notes you have to study before a quiz). Finally, a plan is developed about what to do, whether that is to turn the temperature up, turn the whole shower off and go back to bed, or step into the shower. To do any of these things, the cerebral cortex has to send a command out to your body to move muscles (Figure 3).

[caption id="" align="aligncenter" width="380"] Figure 3. The Motor Response. On the basis of the sensory input and the integration in the CNS, a motor response is formulated and executed.[/caption]

A region of the cortex is specialized for sending signals down to the spinal cord for movement. The upper motor neuron is in this region, called the precentral gyrus of the frontal cortex, which has an axon that extends all the way down the spinal cord. At the level of the spinal cord at which this axon makes a synapse, a graded potential occurs in the cell membrane of a lower motor neuron. This second motor neuron is responsible for causing muscle fibers to contract. In the manner described in the chapter on muscle tissue, an action potential travels along the motor neuron axon into the periphery. The axon terminates on muscle fibers at the neuromuscular junction. Acetylcholine is released at this specialized synapse, which causes the muscle action potential to begin, following a large potential known as an end plate potential. When the lower motor neuron excites the muscle fiber, it contracts. All of this occurs in a fraction of a second, but this story is the basis of how the nervous system functions.

12.4 The Action Potential

barkerj1 — Wed, 06 Sep 2017 01:19:23 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the resting state of a neuron
Explain how an action potential is generated and travels down a neuron
Describe how a neuron is returned to the resting state

The functions of the nervous system—sensation, integration, and response—depend on the functions of the neurons underlying these pathways. To understand how neurons are able to communicate, it is necessary to describe the role of an excitable membrane in generating these signals. The basis of this communication is the action potential, which demonstrates how changes in the membrane can constitute a signal. Looking at the way these signals work in more variable circumstances involves a look at graded potentials, which will be covered in the next section.

Electrically Active Cell Membranes

Most cells in the body make use of charged particles, ions, to build up a charge across the cell membrane. Previously, this was shown to be a part of how muscle cells work. For skeletal muscles to contract, based on excitation–contraction coupling, requires input from a neuron. Both of the cells make use of the cell membrane to regulate ion movement between the extracellular fluid and cytosol.

As you learned in the chapter on cells, the cell membrane is primarily responsible for regulating what can cross the membrane and what stays on only one side. The cell membrane is a phospholipid bilayer, so only substances that can pass directly through the hydrophobic core can diffuse through unaided. Charged particles, which are hydrophilic by definition, cannot pass through the cell membrane without assistance (Figure 1). Transmembrane proteins, specifically channel proteins, make this possible. Several passive transport channels, as well as active transport pumps, are necessary to generate a transmembrane potential and an action potential. Of special interest is the carrier protein referred to as the sodium/potassium pump that moves sodium ions (Na⁺) out of a cell and potassium ions (K⁺) into a cell, thus regulating ion concentration on both sides of the cell membrane.

[caption id="" align="aligncenter" width="550"] Figure 1. Cell Membrane and Transmembrane Proteins. The cell membrane is composed of a phospholipid bilayer and has many transmembrane proteins, including different types of channel proteins that serve as ion channels.[/caption]

The sodium/potassium pump requires energy in the form of adenosine triphosphate (ATP), so it is also referred to as an ATPase. As was explained in the cell chapter, the concentration of Na⁺ is higher outside the cell than inside, and the concentration of K⁺ is higher inside the cell than outside. That means that this pump is moving the ions against the concentration gradients for sodium and potassium, which is why it requires energy. In fact, the pump basically maintains those concentration gradients.

Ion channels are pores that allow specific charged particles to cross the membrane in response to an existing concentration gradient. Proteins are capable of spanning the cell membrane, including its hydrophobic core, and can interact with the charge of ions because of the varied properties of amino acids found within specific domains or regions of the protein channel. Hydrophobic amino acids are found in the domains that are apposed to the hydrocarbon tails of the phospholipids. Hydrophilic amino acids are exposed to the fluid environments of the extracellular fluid and cytosol. Additionally, the ions will interact with the hydrophilic amino acids, which will be selective for the charge of the ion. Channels for cations (positive ions) will have negatively charged side chains in the pore. Channels for anions (negative ions) will have positively charged side chains in the pore. This is called electrochemical exclusion, meaning that the channel pore is charge-specific.

Ion channels can also be specified by the diameter of the pore. The distance between the amino acids will be specific for the diameter of the ion when it dissociates from the water molecules surrounding it. Because of the surrounding water molecules, larger pores are not ideal for smaller ions because the water molecules will interact, by hydrogen bonds, more readily than the amino acid side chains. This is called size exclusion. Some ion channels are selective for charge but not necessarily for size, and thus are called a nonspecific channel. These nonspecific channels allow cations—particularly Na⁺, K⁺, and Ca²⁺—to cross the membrane, but exclude anions.

Ion channels do not always freely allow ions to diffuse across the membrane. Some are opened by certain events, meaning the channels are gated. So another way that channels can be categorized is on the basis of how they are gated. Although these classes of ion channels are found primarily in the cells of nervous or muscular tissue, they also can be found in the cells of epithelial and connective tissues.

A ligand-gated channel opens because a signaling molecule, a ligand, binds to the extracellular region of the channel. This type of channel is also known as an ionotropic receptor because when the ligand, known as a neurotransmitter in the nervous system, binds to the protein, ions cross the membrane changing its charge (Figure 2).

[caption id="" align="aligncenter" width="580"] Figure 2. Ligand-Gated Channels. When the ligand, in this case the neurotransmitter acetylcholine, binds to a specific location on the extracellular surface of the channel protein, the pore opens to allow select ions through. The ions, in this case, are cations of sodium, calcium, and potassium.[/caption]

A mechanically gated channel opens because of a physical distortion of the cell membrane. Many channels associated with the sense of touch (somatosensation) are mechanically gated. For example, as pressure is applied to the skin, these channels open and allow ions to enter the cell. Similar to this type of channel would be the channel that opens on the basis of temperature changes, as in testing the water in the shower (Figure 3).

[caption id="" align="aligncenter" width="580"] Figure 3. Mechanically Gated Channels. When a mechanical change occurs in the surrounding tissue, such as pressure or touch, the channel is physically opened. Thermoreceptors work on a similar principle. When the local tissue temperature changes, the protein reacts by physically opening the channel.[/caption]

A voltage-gated channel is a channel that responds to changes in the electrical properties of the membrane in which it is embedded. Normally, the inner portion of the membrane is at a negative voltage. When that voltage becomes less negative, the channel begins to allow ions to cross the membrane (Figure 4).

[caption id="" align="aligncenter" width="500"] Figure 4. Voltage-Gated Channels. Voltage-gated channels open when the transmembrane voltage changes around them. Amino acids in the structure of the protein are sensitive to charge and cause the pore to open to the selected ion.[/caption]

A leakage channel is randomly gated, meaning that it opens and closes at random, hence the reference to leaking. There is no actual event that opens the channel; instead, it has an intrinsic rate of switching between the open and closed states. Leakage channels contribute to the resting transmembrane voltage of the excitable membrane (Figure 5).

[caption id="" align="aligncenter" width="550"] Figure 5. Leakage Channels. In certain situations, ions need to move across the membrane randomly. The particular electrical properties of certain cells are modified by the presence of this type of channel.[/caption]

The Membrane Potential

The electrical state of the cell membrane can have several variations. These are all variations in the membrane potential. A potential is a distribution of charge across the cell membrane, measured in millivolts (mV). The standard is to compare the inside of the cell relative to the outside, so the membrane potential is a value representing the charge on the intracellular side of the membrane based on the outside being zero, relatively speaking (Figure 6).

[caption id="" align="aligncenter" width="550"] Figure 6. Measuring Charge across a Membrane with a Voltmeter. A recording electrode is inserted into the cell and a reference electrode is outside the cell. By comparing the charge measured by these two electrodes, the transmembrane voltage is determined. It is conventional to express that value for the cytosol relative to the outside.[/caption]

The concentration of ions in extracellular and intracellular fluids is largely balanced, with a net neutral charge. However, a slight difference in charge occurs right at the membrane surface, both internally and externally. It is the difference in this very limited region that has all the power in neurons (and muscle cells) to generate electrical signals, including action potentials.

Before these electrical signals can be described, the resting state of the membrane must be explained. When the cell is at rest, and the ion channels are closed (except for leakage channels which randomly open), ions are distributed across the membrane in a very predictable way. The concentration of Na⁺ outside the cell is 10 times greater than the concentration inside. Also, the concentration of K⁺ inside the cell is greater than outside. The cytosol contains a high concentration of anions, in the form of phosphate ions and negatively charged proteins. Large anions are a component of the inner cell membrane, including specialized phospholipids and proteins associated with the inner leaflet of the membrane (leaflet is a term used for one side of the lipid bilayer membrane). The negative charge is localized in the large anions.

With the ions distributed across the membrane at these concentrations, the difference in charge is measured at -70 mV, the value described as the resting membrane potential. The exact value measured for the resting membrane potential varies between cells, but -70 mV is most commonly used as this value. This voltage would actually be much lower except for the contributions of some important proteins in the membrane. Leakage channels allow Na⁺ to slowly move into the cell or K⁺ to slowly move out, and the Na⁺/K⁺ pump restores them. This may appear to be a waste of energy, but each has a role in maintaining the membrane potential.

The Action Potential

Resting membrane potential describes the steady state of the cell, which is a dynamic process that is balanced by ion leakage and ion pumping. Without any outside influence, it will not change. To get an electrical signal started, the membrane potential has to change.

This starts with a channel opening for Na⁺ in the membrane. Because the concentration of Na⁺ is higher outside the cell than inside the cell by a factor of 10, ions will rush into the cell that are driven largely by the concentration gradient. Because sodium is a positively charged ion, it will change the relative voltage immediately inside the cell relative to immediately outside. The resting potential is the state of the membrane at a voltage of -70 mV, so the sodium cation entering the cell will cause it to become less negative. This is known as depolarization, meaning the membrane potential moves toward zero.

The concentration gradient for Na⁺ is so strong that it will continue to enter the cell even after the membrane potential has become zero, so that the voltage immediately around the pore begins to become positive. The electrical gradient also plays a role, as negative proteins below the membrane attract the sodium ion. The membrane potential will reach +30 mV by the time sodium has entered the cell.

As the membrane potential reaches +30 mV, other voltage-gated channels are opening in the membrane. These channels are specific for the potassium ion. A concentration gradient acts on K⁺, as well. As K⁺ starts to leave the cell, taking a positive charge with it, the membrane potential begins to move back toward its resting voltage. This is called repolarization, meaning that the membrane voltage moves back toward the -70 mV value of the resting membrane potential.

Repolarization returns the membrane potential to the -70 mV value that indicates the resting potential, but it actually overshoots that value. Potassium ions reach equilibrium when the membrane voltage is below -70 mV, so a period of hyperpolarization occurs while the K⁺ channels are open. Those K⁺ channels are slightly delayed in closing, accounting for this short overshoot.

What has been described here is the action potential, which is presented as a graph of voltage over time in Figure 7. It is the electrical signal that nervous tissue generates for communication. The change in the membrane voltage from -70 mV at rest to +30 mV at the end of depolarization is a 100-mV change. That can also be written as a 0.1-V change. To put that value in perspective, think about a battery. An AA battery that you might find in a television remote has a voltage of 1.5 V, or a 9-V battery (the rectangular battery with two posts on one end) is, obviously, 9 V. The change seen in the action potential is one or two orders of magnitude less than the charge in these batteries. In fact, the membrane potential can be described as a battery. A charge is stored across the membrane that can be released under the correct conditions. A battery in your remote has stored a charge that is “released” when you push a button.

[caption id="" align="aligncenter" width="380"] Figure 7. Graph of Action Potential. Plotting voltage measured across the cell membrane against time, the action potential begins with depolarization, followed by repolarization, which goes past the resting potential into hyperpolarization, and finally the membrane returns to rest.[/caption]

[caption id="attachment_2998" align="aligncenter" width="150"] Watch this Crashcourse video to learn more about the action potential![/caption]

The question is, now, what initiates the action potential? The description above conveniently glosses over that point. But it is vital to understanding what is happening. The membrane potential will stay at the resting voltage until something changes. The description above just says that a Na⁺ channel opens. Now, to say “a channel opens” does not mean that one individual transmembrane protein changes. Instead, it means that one kind of channel opens. There are a few different types of channels that allow Na⁺ to cross the membrane. A ligand-gated Na⁺ channel will open when a neurotransmitter binds to it and a mechanically gated Na⁺ channel will open when a physical stimulus affects a sensory receptor (like pressure applied to the skin compresses a touch receptor). Whether it is a neurotransmitter binding to its receptor protein or a sensory stimulus activating a sensory receptor cell, some stimulus gets the process started. Sodium starts to enter the cell and the membrane becomes less negative.

A third type of channel that is an important part of depolarization in the action potential is the voltage-gated Na⁺ channel. The channels that start depolarizing the membrane because of a stimulus help the cell to depolarize from -70 mV to -55 mV. Once the membrane reaches that voltage, the voltage-gated Na⁺ channels open. This is what is known as the threshold. Any depolarization that does not change the membrane potential to -55 mV or higher will not reach threshold and thus will not result in an action potential. Also, any stimulus that depolarizes the membrane to -55 mV or beyond will cause a large number of channels to open and an action potential will be initiated.

Because of the threshold, the action potential can be likened to a digital event—it either happens or it does not. If the threshold is not reached, then no action potential occurs. If depolarization reaches -55 mV, then the action potential continues and runs all the way to +30 mV, at which K⁺ causes repolarization, including the hyperpolarizing overshoot. Also, those changes are the same for every action potential, which means that once the threshold is reached, the exact same thing happens. A stronger stimulus, which might depolarize the membrane well past threshold, will not make a “bigger” action potential. Action potentials are “all or none.” Either the membrane reaches the threshold and everything occurs as described above, or the membrane does not reach the threshold and nothing else happens. All action potentials peak at the same voltage (+30 mV), so one action potential is not bigger than another. Stronger stimuli will initiate multiple action potentials more quickly, but the individual signals are not bigger. Thus, for example, you will not feel a greater sensation of pain, or have a stronger muscle contraction, because of the size of the action potential because they are not different sizes.

As we have seen, the depolarization and repolarization of an action potential are dependent on two types of channels (the voltage-gated Na⁺ channel and the voltage-gated K⁺ channel). The voltage-gated Na⁺ channel actually has two gates. One is the activation gate, which opens when the membrane potential crosses -55 mV. The other gate is the inactivation gate, which closes after a specific period of time—on the order of a fraction of a millisecond. When a cell is at rest, the activation gate is closed and the inactivation gate is open. However, when the threshold is reached, the activation gate opens, allowing Na⁺ to rush into the cell. Timed with the peak of depolarization, the inactivation gate closes. During repolarization, no more sodium can enter the cell. When the membrane potential passes -55 mV again, the activation gate closes. After that, the inactivation gate re-opens, making the channel ready to start the whole process over again.

The voltage-gated K⁺ channel has only one gate, which is sensitive to a membrane voltage of -50 mV. However, it does not open as quickly as the voltage-gated Na⁺ channel does. It might take a fraction of a millisecond for the channel to open once that voltage has been reached. The timing of this coincides exactly with when the Na⁺ flow peaks, so voltage-gated K⁺ channels open just as the voltage-gated Na⁺ channels are being inactivated. As the membrane potential repolarizes and the voltage passes -50 mV again, the channel closes—again, with a little delay. Potassium continues to leave the cell for a short while and the membrane potential becomes more negative, resulting in the hyperpolarizing overshoot. Then the channel closes again and the membrane can return to the resting potential because of the ongoing activity of the non-gated channels and the Na⁺/K⁺ pump.

All of this takes place within approximately 2 milliseconds (Figure 8). While an action potential is in progress, another one cannot be initiated. That effect is referred to as the refractory period. There are two phases of the refractory period: the absolute refractory period and the relative refractory period. During the absolute phase, another action potential will not start. This is because of the inactivation gate of the voltage-gated Na⁺ channel. Once that channel is back to its resting conformation (less than -55 mV), a new action potential could be started, but only by a stronger stimulus than the one that initiated the current action potential. This is because of the flow of K⁺ out of the cell. Because that ion is rushing out, any Na⁺ that tries to enter will not depolarize the cell, but will only keep the cell from hyperpolarizing.

[caption id="" align="aligncenter" width="380"] Figure 8. Stages of an Action Potential. Plotting voltage measured across the cell membrane against time, the events of the action potential can be related to specific changes in the membrane voltage. (1) At rest, the membrane voltage is -70 mV. (2) The membrane begins to depolarize when an external stimulus is applied. (3) The membrane voltage begins a rapid rise toward +30 mV. (4) The membrane voltage starts to return to a negative value. (5) Repolarization continues past the resting membrane voltage, resulting in hyperpolarization. (6) The membrane voltage returns to the resting value shortly after hyperpolarization.[/caption]

Propagation of the Action Potential

The action potential is initiated at the beginning of the axon, at what is called the initial segment. There is a high density of voltage-gated Na⁺ channels so that rapid depolarization can take place here. Going down the length of the axon, the action potential is propagated because more voltage-gated Na⁺ channels are opened as the depolarization spreads. This spreading occurs because Na⁺ enters through the channel and moves along the inside of the cell membrane. As the Na⁺ moves, or flows, a short distance along the cell membrane, its positive charge depolarizes a little more of the cell membrane. As that depolarization spreads, new voltage-gated Na⁺ channels open and more ions rush into the cell, spreading the depolarization a little farther.

Because voltage-gated Na⁺ channels are inactivated at the peak of the depolarization, they cannot be opened again for a brief time—the absolute refractory period. Because of this, depolarization spreading back toward previously opened channels has no effect. The action potential must propagate toward the axon terminals; as a result, the polarity of the neuron is maintained, as mentioned above.

Propagation, as described above, applies to unmyelinated axons. When myelination is present, the action potential propagates differently. Sodium ions that enter the cell at the initial segment start to spread along the length of the axon segment, but there are no voltage-gated Na⁺ channels until the first node of Ranvier. Because there is not constant opening of these channels along the axon segment, the depolarization spreads at an optimal speed. The distance between nodes is the optimal distance to keep the membrane still depolarized above threshold at the next node. As Na⁺ spreads along the inside of the membrane of the axon segment, the charge starts to dissipate. If the node were any farther down the axon, that depolarization would have fallen off too much for voltage-gated Na⁺ channels to be activated at the next node of Ranvier. If the nodes were any closer together, the speed of propagation would be slower.

Propagation along an unmyelinated axon is referred to as continuous conduction; along the length of a myelinated axon, it is saltatory conduction. Continuous conduction is slow because there are always voltage-gated Na⁺ channels opening, and more and more Na⁺ is rushing into the cell. Saltatory conduction is faster because the action potential basically jumps from one node to the next (saltare = “to leap”), and the new influx of Na⁺ renews the depolarized membrane. Along with the myelination of the axon, the diameter of the axon can influence the speed of conduction. Much as water runs faster in a wide river than in a narrow creek, Na⁺-based depolarization spreads faster down a wide axon than down a narrow one. This concept is known as resistance and is generally true for electrical wires or plumbing, just as it is true for axons, although the specific conditions are different at the scales of electrons or ions versus water in a river.

Homeostatic Imbalances

Potassium Concentration Glial cells, especially astrocytes, are responsible for maintaining the chemical environment of the CNS tissue. The concentrations of ions in the extracellular fluid are the basis for how the membrane potential is established and changes in electrochemical signaling. If the balance of ions is upset, drastic outcomes are possible.

Normally the concentration of K⁺ is higher inside the neuron than outside. After the repolarizing phase of the action potential, K⁺ leakage channels and the Na⁺/K⁺ pump ensure that the ions return to their original locations. Following a stroke or other ischemic event, extracellular K⁺ levels are elevated. The astrocytes in the area are equipped to clear excess K⁺ to aid the pump. But when the level is far out of balance, the effects can be irreversible.

Astrocytes can become reactive in cases such as these, which impairs their ability to maintain the local chemical environment. The glial cells enlarge and their processes swell. They lose their K⁺ buffering ability and the function of the pump is affected, or even reversed. One of the early signs of cell disease is this "leaking" of sodium ions into the body cells. This sodium/potassium imbalance negatively affects the internal chemistry of cells, preventing them from functioning normally.

12.5 Communication Between Neurons

barkerj1 — Wed, 06 Sep 2017 01:19:25 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the roles of neurotransmitters in conducting a nerve impulse across a synaptic cleft
Name three different neurotransmitters

The electrical changes taking place within a neuron, as described in the previous section, are similar to a light switch being turned on. A stimulus starts the depolarization, but the action potential runs on its own once a threshold has been reached. The question is now, “What flips the light switch on?” Temporary changes to the cell membrane voltage can result from neurons receiving information from the environment, or from the action of one neuron on another. These special types of potentials influence a neuron and determine whether an action potential will occur or not. Many of these transient signals originate at the synapse.

Graded Potentials

Local changes in the membrane potential are called graded potentials and are usually associated with the dendrites of a neuron. The amount of change in the membrane potential is determined by the size of the stimulus that causes it. In the example of testing the temperature of the shower, slightly warm water would only initiate a small change in a thermoreceptor, whereas hot water would cause a large amount of change in the membrane potential.

Graded potentials can be of two sorts, either they are depolarizing or hyperpolarizing (Figure 1). For a membrane at the resting potential, a graded potential represents a change in that voltage either above -70 mV or below -70 mV. Depolarizing graded potentials are often the result of Na⁺ or Ca²⁺ entering the cell. Both of these ions have higher concentrations outside the cell than inside; because they have a positive charge, they will move into the cell causing it to become less negative relative to the outside. Hyperpolarizing graded potentials can be caused by K⁺ leaving the cell or Cl^- entering the cell. If a positive charge moves out of a cell, the cell becomes more negative; if a negative charge enters the cell, the same thing happens.

[caption id="" align="aligncenter" width="500"] Figure 1. Graded Potentials. Graded potentials are temporary changes in the membrane voltage, the characteristics of which depend on the size of the stimulus. Some types of stimuli cause depolarization of the membrane, whereas others cause hyperpolarization. It depends on the specific ion channels that are activated in the cell membrane.[/caption]

Types of Graded Potentials

For the unipolar cells of sensory neurons—both those with free nerve endings and those within encapsulations—graded potentials develop in the dendrites that influence the generation of an action potential in the axon of the same cell. This is called a generator potential. For other sensory receptor cells, such as taste cells or photoreceptors of the retina, graded potentials in their membranes result in the release of neurotransmitters at synapses with sensory neurons. This is called a receptor potential.

A postsynaptic potential (PSP) is the graded potential in the dendrites of a neuron that is receiving synapses from other cells. Postsynaptic potentials can be depolarizing or hyperpolarizing. Depolarization in a postsynaptic potential is called an excitatory postsynaptic potential (EPSP) because it causes the membrane potential to move toward threshold. Hyperpolarization in a postsynaptic potential is an inhibitory postsynaptic potential (IPSP) because it causes the membrane potential to move away from threshold.

Summation

All types of graded potentials will result in small changes of either depolarization or hyperpolarization in the voltage of a membrane. These changes can lead to the neuron reaching threshold if the changes add together, or summate. The combined effects of different types of graded potentials are illustrated in Figure 2. If the total change in voltage in the membrane is a positive 15 mV, meaning that the membrane depolarizes from -70 mV to -55 mV, then the graded potentials will result in the membrane reaching threshold.

For receptor potentials, threshold is not a factor because the change in membrane potential for receptor cells directly causes neurotransmitter release. However, generator potentials can initiate action potentials in the sensory neuron axon, and postsynaptic potentials can initiate an action potential in the axon of other neurons. Graded potentials summate at a specific location at the beginning of the axon to initiate the action potential, namely the initial segment. For sensory neurons, which do not have a cell body between the dendrites and the axon, the initial segment is directly adjacent to the dendritic endings. For all other neurons, the axon hillock is essentially the initial segment of the axon, and it is where summation takes place. These locations have a high density of voltage-gated Na⁺ channels that initiate the depolarizing phase of the action potential.

Summation can be spatial or temporal, meaning it can be the result of multiple graded potentials at different locations on the neuron, or all at the same place but separated in time. Spatial summation is related to associating the activity of multiple inputs to a neuron with each other. Temporal summation is the relationship of multiple action potentials from a single cell resulting in a significant change in the membrane potential. Spatial and temporal summation can act together, as well.

[caption id="" align="aligncenter" width="380"] Figure 2. Postsynaptic Potential Summation. The result of summation of postsynaptic potentials is the overall change in the membrane potential. At point A, several different excitatory postsynaptic potentials add up to a large depolarization. At point B, a mix of excitatory and inhibitory postsynaptic potentials result in a different end result for the membrane potential.[/caption]

Synapses

There are two types of connections between electrically active cells, chemical synapses and electrical synapses. In a chemical synapse, a chemical signal—namely, a neurotransmitter—is released from one cell and it affects the other cell. In an electrical synapse, there is a direct connection between the two cells so that ions can pass directly from one cell to the next. If one cell is depolarized in an electrical synapse, the joined cell also depolarizes because the ions pass between the cells. Chemical synapses involve the transmission of chemical information from one cell to the next. This section will concentrate on the chemical type of synapse.

An example of a chemical synapse is the neuromuscular junction (NMJ) described in the chapter on muscle tissue. In the nervous system, there are many more synapses that are essentially the same as the NMJ. All synapses have common characteristics, which can be summarized in this list:

presynaptic element
neurotransmitter (packaged in vesicles)
synaptic cleft
receptor proteins
postsynaptic element
neurotransmitter elimination or re-uptake

For the NMJ, these characteristics are as follows: the presynaptic element is the motor neuron's axon terminals, the neurotransmitter is acetylcholine, the synaptic cleft is the space between the cells where the neurotransmitter diffuses, the receptor protein is the nicotinic acetylcholine receptor, the postsynaptic element is the sarcolemma of the muscle cell, and the neurotransmitter is eliminated by acetylcholinesterase. Other synapses are similar to this, and the specifics are different, but they all contain the same characteristics.

Neurotransmitter Release

When an action potential reaches the axon terminals, voltage-gated Ca²⁺ channels in the membrane of the synaptic end bulb open. The concentration of Ca²⁺ increases inside the end bulb, and the Ca²⁺ ion associates with proteins in the outer surface of neurotransmitter vesicles. The Ca²⁺ facilitates the merging of the vesicle with the presynaptic membrane so that the neurotransmitter is released through exocytosis into the small gap between the cells, known as the synaptic cleft.

Once in the synaptic cleft, the neurotransmitter diffuses the short distance to the postsynaptic membrane and can interact with neurotransmitter receptors. Receptors are specific for the neurotransmitter, and the two fit together like a key and lock. One neurotransmitter binds to its receptor and will not bind to receptors for other neurotransmitters, making the binding a specific chemical event (Figure 3).

[caption id="" align="aligncenter" width="480"] Figure 3. The Synapse. The synapse is a connection between a neuron and its target cell (which is not necessarily a neuron). The presynaptic element is the synaptic end bulb of the axon where Ca2+ enters the bulb to cause vesicle fusion and neurotransmitter release. The neurotransmitter diffuses across the synaptic cleft to bind to its receptor. The neurotransmitter is cleared from the synapse either by enzymatic degradation, neuronal reuptake, or glial reuptake.[/caption]

Neurotransmitter Systems

There are several systems of neurotransmitters that are found at various synapses in the nervous system. These groups refer to the chemicals that are the neurotransmitters, and within the groups are specific systems.

The first group, which is a neurotransmitter system of its own, is the cholinergic system. It is the system based on acetylcholine. This includes the NMJ as an example of a cholinergic synapse, but cholinergic synapses are found in other parts of the nervous system. They are in the autonomic nervous system, as well as distributed throughout the brain.

The cholinergic system has two types of receptors, the nicotinic receptor is found in the NMJ as well as other synapses. There is also an acetylcholine receptor known as the muscarinic receptor. Both of these receptors are named for drugs that interact with the receptor in addition to acetylcholine. Nicotine will bind to the nicotinic receptor and activate it similar to acetylcholine. Muscarine, a product of certain mushrooms, will bind to the muscarinic receptor. However, nicotine will not bind to the muscarinic receptor and muscarine will not bind to the nicotinic receptor.

Another group of neurotransmitters are amino acids. This includes glutamate (Glu), GABA (gamma-aminobutyric acid, a derivative of glutamate), and glycine (Gly). These amino acids have an amino group and a carboxyl group in their chemical structures. Glutamate is one of the 20 amino acids that are used to make proteins. Each amino acid neurotransmitter would be part of its own system, namely the glutamatergic, GABAergic, and glycinergic systems. They each have their own receptors and do not interact with each other. Amino acid neurotransmitters are eliminated from the synapse by reuptake. A pump in the cell membrane of the presynaptic element, or sometimes a neighboring glial cell, will clear the amino acid from the synaptic cleft so that it can be recycled, repackaged in vesicles, and released again.

Another class of neurotransmitter is the biogenic amine, a group of neurotransmitters that are enzymatically made from amino acids. They have amino groups in them, but no longer have carboxyl groups and are therefore no longer classified as amino acids. Serotonin is made from tryptophan. It is the basis of the serotonergic system, which has its own specific receptors. Serotonin is transported back into the presynaptic cell for repackaging.

Other biogenic amines are made from tyrosine, and include dopamine, norepinephrine, and epinephrine. Dopamine is part of its own system, the dopaminergic system, which has dopamine receptors. Dopamine is removed from the synapse by transport proteins in the presynaptic cell membrane. Norepinephrine and epinephrine belong to the adrenergic neurotransmitter system. The two molecules are very similar and bind to the same receptors, which are referred to as alpha and beta receptors. Norepinephrine and epinephrine are also transported back into the presynaptic cell. The chemical epinephrine (epi- = “on”; “-nephrine” = kidney) is also known as adrenaline (renal = “kidney”), and norepinephrine is sometimes referred to as noradrenaline. The adrenal gland produces epinephrine and norepinephrine to be released into the blood stream as hormones.

A neuropeptide is a neurotransmitter molecule made up of chains of amino acids connected by peptide bonds. This is what a protein is, but the term protein implies a certain length to the molecule. Some neuropeptides are quite short, such as met-enkephalin, which is five amino acids long. Others are long, such as beta-endorphin, which is 31 amino acids long. Neuropeptides are often released at synapses in combination with another neurotransmitter, and they often act as hormones in other systems of the body, such as vasoactive intestinal peptide (VIP) or substance P.

The effect of a neurotransmitter on the postsynaptic element is entirely dependent on the receptor protein. First, if there is no receptor protein in the membrane of the postsynaptic element, then the neurotransmitter has no effect. The depolarizing or hyperpolarizing effect is also dependent on the receptor. When acetylcholine binds to the nicotinic receptor, the postsynaptic cell is depolarized. This is because the receptor is a cation channel and positively charged Na⁺ will rush into the cell. However, when acetylcholine binds to the muscarinic receptor, of which there are several variants, it might cause depolarization or hyperpolarization of the target cell.

The amino acid neurotransmitters, glutamate, glycine, and GABA, are almost exclusively associated with just one effect. Glutamate is considered an excitatory amino acid, but only because Glu receptors in the adult cause depolarization of the postsynaptic cell. Glycine and GABA are considered inhibitory amino acids, again because their receptors cause hyperpolarization.

The biogenic amines have mixed effects. For example, the dopamine receptors that are classified as D1 receptors are excitatory whereas D2-type receptors are inhibitory. Biogenic amine receptors and neuropeptide receptors can have even more complex effects because some may not directly affect the membrane potential, but rather have an effect on gene transcription or other metabolic processes in the neuron. The characteristics of the various neurotransmitter systems presented in this section are organized in Table 3.

The important thing to remember about neurotransmitters, and signaling chemicals in general, is that the effect is entirely dependent on the receptor. Neurotransmitters bind to one of two classes of receptors at the cell surface, ionotropic or metabotropic (Figure 4). Ionotropic receptors are ligand-gated ion channels, such as the nicotinic receptor for acetylcholine or the glycine receptor. A metabotropic receptor involves a complex of proteins that result in metabolic changes within the cell. The receptor complex includes the transmembrane receptor protein, a G protein, and an effector protein. The neurotransmitter, referred to as the first messenger, binds to the receptor protein on the extracellular surface of the cell, and the intracellular side of the protein initiates activity of the G protein. The G protein is a guanosine triphosphate (GTP) hydrolase that physically moves from the receptor protein to the effector protein to activate the latter. An effector protein is an enzyme that catalyzes the generation of a new molecule, which acts as the intracellular mediator of the signal that binds to the receptor. This intracellular mediator is called the second messenger.

Different receptors use different second messengers. Two common examples of second messengers are cyclic adenosine monophosphate (cAMP) and inositol triphosphate (IP₃). The enzyme adenylate cyclase (an example of an effector protein) makes cAMP, and phospholipase C is the enzyme that makes IP₃. Second messengers, after they are produced by the effector protein, cause metabolic changes within the cell. These changes are most likely the activation of other enzymes in the cell. In neurons, they often modify ion channels, either opening or closing them. These enzymes can also cause changes in the cell, such as the activation of genes in the nucleus, and therefore the increased synthesis of proteins. In neurons, these kinds of changes are often the basis of stronger connections between cells at the synapse and may be the basis of learning and memory.

[caption id="" align="aligncenter" width="450"] Figure 4. Receptor Types. (a) An ionotropic receptor is a channel that opens when the neurotransmitter binds to it. (b) A metabotropic receptor is a complex that causes metabolic changes in the cell when the neurotransmitter binds to it (1). After binding, the G protein hydrolyzes GTP and moves to the effector protein (2). When the G protein contacts the effector protein, a second messenger is generated, such as cAMP (3). The second messenger can then go on to cause changes in the neuron, such as opening or closing ion channels, metabolic changes, and changes in gene transcription.[/caption]

Characteristics of Neurotransmitter Systems (Table 3)
System	Cholinergic	Amino acids	Biogenic amines	Neuropeptides
Neurotransmitters	Acetylcholine	Glutamate, glycine, GABA	Serotonin (5-HT), dopamine, norepinephrine, (epinephrine)	Met-enkephalin, beta-endorphin, VIP, Substance P, etc.
Receptors	Nicotinic and muscarinic receptors	Glu receptors, gly receptors, GABA receptors	5-HT receptors, D1 and D2 receptors, α-adrenergic and β-adrenergic receptors	Receptors are too numerous to list, but are specific to the peptides.
Elimination	Degradation by acetylcholinesterase	Reuptake by neurons or glia	Reuptake by neurons	Degradation by enzymes called peptidases
Postsynaptic effect	Nicotinic receptor causes depolarization. Muscarinic receptors can cause both depolarization or hyperpolarization depending on the subtype.	Glu receptors cause depolarization. Gly and GABA receptors cause hyperpolarization.	Depolarization or hyperpolarization depends on the specific receptor. For example, D1 receptors cause depolarization and D2 receptors cause hyperpolarization.	Depolarization or hyperpolarization depends on the specific receptor.

Disorders of the Nervous System

The underlying cause of some neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, appears to be related to proteins—specifically, to proteins behaving badly. One of the strongest theories of what causes Alzheimer’s disease is based on the accumulation of beta-amyloid plaques, dense conglomerations of a protein that is not functioning correctly. Parkinson’s disease is linked to an increase in a protein known as alpha-synuclein that is toxic to the cells of the substantia nigra nucleus in the midbrain. For proteins to function correctly, they are dependent on their three-dimensional shape. The linear sequence of amino acids folds into a three-dimensional shape that is based on the interactions between and among those amino acids. When the folding is disturbed, and proteins take on a different shape, they stop functioning correctly. But the disease is not necessarily the result of functional loss of these proteins; rather, these altered proteins start to accumulate and may become toxic. For example, in Alzheimer’s, the hallmark of the disease is the accumulation of these amyloid plaques in the cerebral cortex. The term coined to describe this sort of disease is “proteopathy” and it includes other diseases. Creutzfeld-Jacob disease, the human variant of the prion disease known as mad cow disease in the bovine, also involves the accumulation of amyloid plaques, similar to Alzheimer’s. Diseases of other organ systems can fall into this group as well, such as cystic fibrosis or type 2 diabetes. Recognizing the relationship between these diseases has suggested new therapeutic possibilities. Interfering with the accumulation of the proteins, and possibly as early as their original production within the cell, may unlock new ways to alleviate these devastating diseases.

Health Canada Eat Well plate eat-well-bien-manger-eng

barkerj1 — Sat, 28 Apr 2018 00:19:43 +0000

Eye refraction JB

barkerj1 — Wed, 09 May 2018 21:54:57 +0000

Meiosis_Stages wiki commons JB

barkerj1 — Fri, 18 May 2018 19:55:50 +0000

frame

barkerj1 — Wed, 23 May 2018 21:39:56 +0000

frame (1)

barkerj1 — Fri, 20 Jul 2018 22:54:46 +0000

13.2 The Central Nervous System

barkerj1 — Wed, 06 Sep 2017 01:19:26 +0000

Learning Objectives

By the end of this section, you will be able to:

Name, locate, and describe the functions of the:
- Cerebrum
- Diencephalon, i.e. the thalamus and hypothalamus
- Brainstem, i.e. the midbrain, pons, and medulla oblongata
- Cerebellum
Describe the structure of the spinal cord
Explain the functions of the spinal cord

The brain and the spinal cord are the central nervous system, and they represent the main organs of the nervous system. The spinal cord is a single structure, whereas the adult brain is described in terms of four major regions: the cerebrum, the diencephalon, the brain stem, and the cerebellum. A person’s conscious experiences are based on neural activity in the brain. The regulation of homeostasis is governed by a specialized region in the brain. The coordination of reflexes depends on the integration of sensory and motor pathways in the spinal cord.

The Cerebrum

The iconic grey mantle of the human brain, which appears to make up most of the mass of the brain, is the cerebrum (Figure 1). The wrinkled portion is the cerebral cortex, and the rest of the structure is beneath that outer covering. There is a large separation between the two sides of the cerebrum called the longitudinal fissure. It separates the cerebrum into two distinct halves, a right and left cerebral hemisphere. Deep within the cerebrum, the white matter of the corpus callosum provides the major pathway for communication between the two hemispheres of the cerebral cortex.

[caption id="" align="aligncenter" width="600"] Figure 1. The Cerebrum. The cerebrum is a large component of the CNS in humans, and the most obvious aspect of it is the folded surface called the cerebral cortex.[/caption]

Many of the higher neurological functions, such as memory, emotion, and consciousness, are the result of cerebral function. The complexity of the cerebrum is different across vertebrate species. The cerebrum of the most primitive vertebrates is not much more than the connection for the sense of smell. In mammals, the cerebrum comprises the outer grey matter that is the cortex (from the Latin word meaning “bark of a tree”) and several deep nuclei that belong to three important functional groups. The basal nuclei are responsible for cognitive processing, the most important function being that associated with planning movements. The basal forebrain contains nuclei that are important in learning and memory. The limbic cortex is the region of the cerebral cortex that is part of the limbic system, a collection of structures involved in emotion, memory, and behavior.

Cerebral Cortex

The cerebrum is covered by a continuous layer of grey matter that wraps around either side of the forebrain—the cerebral cortex. This thin, extensive region of wrinkled gray matter is responsible for the higher functions of the nervous system. A gyrus (plural = gyri) is the ridge of one of those wrinkles, and a sulcus (plural = sulci) is the groove between two gyri. The pattern of these folds of tissue indicates specific regions of the cerebral cortex.

The head is limited by the size of the birth canal, and the brain must fit inside the cranial cavity of the skull. Extensive folding in the cerebral cortex enables more grey matter to fit into this limited space. If the grey matter of the cortex were peeled off of the cerebrum and laid out flat, its surface area would be roughly equal to one square meter.

The folding of the cortex maximizes the amount of grey matter in the cranial cavity. During embryonic development, as the telencephalon expands within the skull, the brain goes through a regular course of growth that results in everyone’s brain having a similar pattern of folds. The surface of the brain can be mapped on the basis of the locations of large gyri and sulci. Using these landmarks, the cortex can be separated into four major regions, or lobes (Figure 2). The lateral sulcus that separates the temporal lobe from the other regions is one such landmark. Superior to the lateral sulcus are the parietal lobe and frontal lobe, which are separated from each other by the central sulcus. The posterior region of the cortex is the occipital lobe, which has no obvious anatomical border between it and the parietal or temporal lobes on the lateral surface of the brain. From the medial surface, an obvious landmark separating the parietal and occipital lobes is called the parieto-occipital sulcus. The fact that there is no obvious anatomical border between these lobes is consistent with the functions of these regions being interrelated.

[caption id="" align="aligncenter" width="380"] Figure 2. Lobes of the Cerebral Cortex. The cerebral cortex is divided into four lobes. Extensive folding increases the surface area available for cerebral functions.[/caption]

Different regions of the cerebral cortex can be associated with particular functions, a concept known as localization of function. In the early 1900s, a German neuroscientist named Korbinian Brodmann performed an extensive study of the microscopic anatomy—the cytoarchitecture—of the cerebral cortex and divided the cortex into 52 separate regions on the basis of the histology of the cortex. His work resulted in a system of classification known as Brodmann’s areas, which is still used today to describe the anatomical distinctions within the cortex (Figure 3). The results from Brodmann’s work on the anatomy align very well with the functional differences within the cortex. Areas 17 and 18 in the occipital lobe are responsible for primary visual perception. That visual information is complex, so it is processed in the temporal and parietal lobes as well.

The temporal lobe is associated with primary auditory sensation, known as Brodmann’s areas 41 and 42 in the superior temporal lobe. Because regions of the temporal lobe are part of the limbic system, memory is an important function associated with that lobe. Memory is essentially a sensory function; memories are recalled sensations such as the smell of Mom’s baking or the sound of a barking dog. Even memories of movement are really the memory of sensory feedback from those movements, such as stretching muscles or the movement of the skin around a joint. Structures in the temporal lobe are responsible for establishing long-term memory, but the ultimate location of those memories is usually in the region in which the sensory perception was processed.

The main sensation associated with the parietal lobe is somatosensation, meaning the general sensations associated with the body. Posterior to the central sulcus is the postcentral gyrus, the primary somatosensory cortex, which is identified as Brodmann’s areas 1, 2, and 3. All of the tactile senses are processed in this area, including touch, pressure, tickle, pain, itch, and vibration, as well as more general senses of the body such as proprioception and kinesthesia, which are the senses of body position and movement, respectively.

Anterior to the central sulcus is the frontal lobe, which is primarily associated with motor functions. The precentral gyrus is the primary motor cortex. Cells from this region of the cerebral cortex are the upper motor neurons that instruct cells in the spinal cord to move skeletal muscles. Anterior to this region are a few areas that are associated with planned movements. The premotor area is responsible for thinking of a movement to be made. The frontal eye fields are important in eliciting eye movements and in attending to visual stimuli. Broca’s area is responsible for the production of language, or controlling movements responsible for speech; in the vast majority of people, it is located only on the left side. Anterior to these regions is the prefrontal lobe, which serves cognitive functions that can be the basis of personality, short-term memory, and consciousness. The prefrontal lobotomy is an outdated mode of treatment for personality disorders (psychiatric conditions) that profoundly affected the personality of the patient.

[caption id="" align="aligncenter" width="550"] Figure 3. Brodmann's Areas of the Cerebral Cortex. Brodmann mapping of functionally distinct regions of the cortex was based on its cytoarchitecture at a microscopic level.[/caption]

Subcortical structures

Beneath the cerebral cortex are sets of nuclei known as subcortical nuclei that augment cortical processes. The nuclei of the basal forebrain serve as the primary location for acetylcholine production, which modulates the overall activity of the cortex, possibly leading to greater attention to sensory stimuli. Alzheimer’s disease is associated with a loss of neurons in the basal forebrain. The hippocampus and amygdala are medial-lobe structures that, along with the adjacent cortex, are involved in long-term memory formation and emotional responses. The basal nuclei are a set of nuclei in the cerebrum responsible for comparing cortical processing with the general state of activity in the nervous system to influence the likelihood of movement taking place. For example, while a student is sitting in a classroom listening to a lecture, the basal nuclei will keep the urge to jump up and scream from actually happening. (The basal nuclei are also referred to as the basal ganglia, although that is potentially confusing because the term ganglia is typically used for peripheral structures.)

The major structures of the basal nuclei that control movement are the caudate, putamen, and globus pallidus, which are located deep in the cerebrum. The caudate is a long nucleus that follows the basic C-shape of the cerebrum from the frontal lobe, through the parietal and occipital lobes, into the temporal lobe. The putamen is mostly deep in the anterior regions of the frontal and parietal lobes. Together, the caudate and putamen are called the striatum. The globus pallidus is a layered nucleus that lies just medial to the putamen; they are called the lenticular nuclei because they look like curved pieces fitting together like lenses. The globus pallidus has two subdivisions, the external and internal segments, which are lateral and medial, respectively. These nuclei are depicted in a frontal section of the brain in Figure 4.

[caption id="" align="aligncenter" width="380"] Figure 4. Frontal Section of Cerebral Cortex and Basal Nuclei. The major components of the basal nuclei, shown in a frontal section of the brain, are the caudate (just lateral to the lateral ventricle), the putamen (inferior to the caudate and separated by the large white-matter structure called the internal capsule), and the globus pallidus (medial to the putamen).[/caption]

The basal nuclei in the cerebrum are connected with a few more nuclei in the brain stem that together act as a functional group that forms a motor pathway. Two streams of information processing take place in the basal nuclei. All input to the basal nuclei is from the cortex into the striatum (Figure 5). The direct pathway is the projection of axons from the striatum to the globus pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr). The GPi/SNr then projects to the thalamus, which projects back to the cortex. The indirect pathway is the projection of axons from the striatum to the globus pallidus external segment (GPe), then to the subthalamic nucleus (STN), and finally to GPi/SNr. The two streams both target the GPi/SNr, but one has a direct projection and the other goes through a few intervening nuclei. The direct pathway causes the disinhibition of the thalamus (inhibition of one cell on a target cell that then inhibits the first cell), whereas the indirect pathway causes, or reinforces, the normal inhibition of the thalamus. The thalamus then can either excite the cortex (as a result of the direct pathway) or fail to excite the cortex (as a result of the indirect pathway).

[caption id="" align="aligncenter" width="295"] Figure 5. Connections of Basal Nuclei. Input to the basal nuclei is from the cerebral cortex, which is an excitatory connection releasing glutamate as a neurotransmitter. This input is to the striatum, or the caudate and putamen. In the direct pathway, the striatum projects to the internal segment of the globus pallidus and the substantia nigra pars reticulata (GPi/SNr). This is an inhibitory pathway, in which GABA is released at the synapse, and the target cells are hyperpolarized and less likely to fire. The output from the basal nuclei is to the thalamus, which is an inhibitory projection using GABA.[/caption]

The switch between the two pathways is the substantia nigra pars compacta, which projects to the striatum and releases the neurotransmitter dopamine. Dopamine receptors are either excitatory (D1-type receptors) or inhibitory (D2-type receptors). The direct pathway is activated by dopamine, and the indirect pathway is inhibited by dopamine. When the substantia nigra pars compacta is firing, it signals to the basal nuclei that the body is in an active state, and movement will be more likely. When the substantia nigra pars compacta is silent, the body is in a passive state, and movement is inhibited. To illustrate this situation, while a student is sitting listening to a lecture, the substantia nigra pars compacta would be silent and the student less likely to get up and walk around. Likewise, while the professor is lecturing, and walking around at the front of the classroom, the professor’s substantia nigra pars compacta would be active, in keeping with his or her activity level.

The Diencephalon

The diencephalon is the one region of the adult brain that retains its name from embryologic development. The etymology of the word diencephalon translates to “through brain.” It is the connection between the cerebrum and the rest of the nervous system, with one exception. The rest of the brain, the spinal cord, and the PNS all send information to the cerebrum through the diencephalon. Output from the cerebrum passes through the diencephalon. The single exception is the system associated with olfaction, or the sense of smell, which connects directly with the cerebrum. In the earliest vertebrate species, the cerebrum was not much more than olfactory bulbs that received peripheral information about the chemical environment (to call it smell in these organisms is imprecise because they lived in the ocean). The diencephalon is deep beneath the cerebrum and constitutes the walls of the third ventricle. The diencephalon can be described as any region of the brain with “thalamus” in its name. The two major regions of the diencephalon are the thalamus itself and the hypothalamus (Figure 6). There are other structures, such as the epithalamus, which contains the pineal gland, or the subthalamus, which includes the subthalamic nucleus that is part of the basal nuclei.

Thalamus

The thalamus is a collection of nuclei that relay information between the cerebral cortex and the periphery, spinal cord, or brain stem. All sensory information, except for the sense of smell, passes through the thalamus before processing by the cortex. Axons from the peripheral sensory organs, or intermediate nuclei, synapse in the thalamus, and thalamic neurons project directly to the cerebrum. It is a requisite synapse in any sensory pathway, except for olfaction. The thalamus does not just pass the information on, it also processes that information. For example, the portion of the thalamus that receives visual information will influence what visual stimuli are important, or what receives attention.

The cerebrum also sends information down to the thalamus, which usually communicates motor commands. This involves interactions with the cerebellum and other nuclei in the brain stem. The cerebrum interacts with the basal nuclei, which involves connections with the thalamus. The primary output of the basal nuclei is to the thalamus, which relays that output to the cerebral cortex. The cortex also sends information to the thalamus that will then influence the effects of the basal nuclei.

Hypothalamus

Inferior and slightly anterior to the thalamus is the hypothalamus, the other major region of the diencephalon. The hypothalamus is a collection of nuclei that are largely involved in regulating homeostasis. The hypothalamus is the executive region in charge of the autonomic nervous system and the endocrine system through its regulation of the anterior pituitary gland. Other parts of the hypothalamus are involved in memory and emotion as part of the limbic system.

[caption id="" align="aligncenter" width="450"] Figure 6. The Diencephalon. The diencephalon is composed primarily of the thalamus and hypothalamus, which together define the walls of the third ventricle. The thalami are two elongated, ovoid structures on either side of the midline that make contact in the middle. The hypothalamus is inferior and anterior to the thalamus, culminating in a sharp angle to which the pituitary gland is attached.[/caption]

Brain Stem

The midbrain and hindbrain (composed of the pons and the medulla) are collectively referred to as the brain stem (Figure 7). The structure emerges from the ventral surface of the forebrain as a tapering cone that connects the brain to the spinal cord. Attached to the brain stem, but considered a separate region of the adult brain, is the cerebellum. The midbrain coordinates sensory representations of the visual, auditory, and somatosensory perceptual spaces. The pons is the main connection with the cerebellum. The pons and the medulla regulate several crucial functions, including the cardiovascular and respiratory systems and rates.

The cranial nerves connect through the brain stem and provide the brain with the sensory input and motor output associated with the head and neck, including most of the special senses. The major ascending and descending pathways between the spinal cord and brain, specifically the cerebrum, pass through the brain stem.

[caption id="" align="aligncenter" width="450"] Figure 7. The Brain Stem. The brain stem comprises three regions: the midbrain, the pons, and the medulla.[/caption]

Midbrain

One of the original regions of the embryonic brain, the midbrain is a small region between the thalamus and pons. It is separated into the tectum and tegmentum, from the Latin words for roof and floor, respectively. The cerebral aqueduct passes through the center of the midbrain, such that these regions are the roof and floor of that canal.

The tectum is composed of four bumps known as the colliculi (singular = colliculus), which means “little hill” in Latin. The inferior colliculus is the inferior pair of these enlargements and is part of the auditory brain stem pathway. Neurons of the inferior colliculus project to the thalamus, which then sends auditory information to the cerebrum for the conscious perception of sound. The superior colliculus is the superior pair and combines sensory information about visual space, auditory space, and somatosensory space. Activity in the superior colliculus is related to orienting the eyes to a sound or touch stimulus. If you are walking along the sidewalk on campus and you hear chirping, the superior colliculus coordinates that information with your awareness of the visual location of the tree right above you. That is the correlation of auditory and visual maps. If you suddenly feel something wet fall on your head, your superior colliculus integrates that with the auditory and visual maps and you know that the chirping bird just relieved itself on you. You want to look up to see the culprit, but do not.

The tegmentum is continuous with the gray matter of the rest of the brain stem. Throughout the midbrain, pons, and medulla, the tegmentum contains the nuclei that receive and send information through the cranial nerves, as well as regions that regulate important functions such as those of the cardiovascular and respiratory systems.

Pons

The word pons comes from the Latin word for bridge. It is visible on the anterior surface of the brain stem as the thick bundle of white matter attached to the cerebellum. The pons is the main connection between the cerebellum and the brain stem. The bridge-like white matter is only the anterior surface of the pons; the gray matter beneath that is a continuation of the tegmentum from the midbrain. Gray matter in the tegmentum region of the pons contains neurons receiving descending input from the forebrain that is sent to the cerebellum.

Medulla oblongata

The medulla oblongata is the region known as the myelencephalon in the embryonic brain. The initial portion of the name, “myel,” refers to the significant white matter found in this region—especially on its exterior, which is continuous with the white matter of the spinal cord. The tegmentum of the midbrain and pons continues into the medulla because this gray matter is responsible for processing cranial nerve information. A diffuse region of gray matter throughout the brain stem, known as the reticular formation, is related to sleep and wakefulness, such as general brain activity and attention.

The Cerebellum

The cerebellum, as the name suggests, is the “little brain.” It is covered in gyri and sulci like the cerebrum, and looks like a miniature version of that part of the brain (Figure 8). The cerebellum is largely responsible for comparing information from the cerebrum with sensory feedback from the periphery through the spinal cord. It accounts for approximately 10 percent of the mass of the brain.

[caption id="" align="aligncenter" width="420"] Figure 8. The Cerebellum. The cerebellum is situated on the posterior surface of the brain stem. Descending input from the cerebellum enters through the large white matter structure of the pons. Ascending input from the periphery and spinal cord enters through the fibers of the inferior olive. Output goes to the midbrain, which sends a descending signal to the spinal cord.[/caption]

Descending fibers from the cerebrum have branches that connect to neurons in the pons. Those neurons project into the cerebellum, providing a copy of motor commands sent to the spinal cord. Sensory information from the periphery, which enters through spinal or cranial nerves, is copied to a nucleus in the medulla known as the inferior olive. Fibers from this nucleus enter the cerebellum and are compared with the descending commands from the cerebrum. If the primary motor cortex of the frontal lobe sends a command down to the spinal cord to initiate walking, a copy of that instruction is sent to the cerebellum. Sensory feedback from the muscles and joints, proprioceptive information about the movements of walking, and sensations of balance are sent to the cerebellum through the inferior olive and the cerebellum compares them. If walking is not coordinated, perhaps because the ground is uneven or a strong wind is blowing, then the cerebellum sends out a corrective command to compensate for the difference between the original cortical command and the sensory feedback. The output of the cerebellum is into the midbrain, which then sends a descending input to the spinal cord to correct the messages going to skeletal muscles.

The Spinal Cord

The description of the CNS is concentrated on the structures of the brain, but the spinal cord is another major organ of the system. Whereas the brain develops out of expansions of the neural tube into primary and then secondary vesicles, the spinal cord maintains the tube structure and is only specialized into certain regions. As the spinal cord continues to develop in the newborn, anatomical features mark its surface. The anterior midline is marked by the anterior median fissure, and the posterior midline is marked by the posterior median sulcus. Axons enter the posterior side through the dorsal (posterior) nerve root, which marks the posterolateral sulcus on either side. The axons emerging from the anterior side do so through the ventral (anterior) nerve root. Note that it is common to see the terms dorsal (dorsal = “back”) and ventral (ventral = “belly”) used interchangeably with posterior and anterior, particularly in reference to nerves and the structures of the spinal cord. You should learn to be comfortable with both.

On the whole, the posterior regions are responsible for sensory functions and the anterior regions are associated with motor functions. This comes from the initial development of the spinal cord, which is divided into the basal plate and the alar plate. The basal plate is closest to the ventral midline of the neural tube, which will become the anterior face of the spinal cord and gives rise to motor neurons. The alar plate is on the dorsal side of the neural tube and gives rise to neurons that will receive sensory input from the periphery.

The length of the spinal cord is divided into regions that correspond to the regions of the vertebral column. The name of a spinal cord region corresponds to the level at which spinal nerves pass through the intervertebral foramina. Immediately adjacent to the brain stem is the cervical region, followed by the thoracic, then the lumbar, and finally the sacral region. The spinal cord is not the full length of the vertebral column because the spinal cord does not grow significantly longer after the first or second year, but the skeleton continues to grow. The nerves that emerge from the spinal cord pass through the intervertebral formina at the respective levels. As the vertebral column grows, these nerves grow with it and result in a long bundle of nerves that resembles a horse’s tail and is named the cauda equina. The sacral spinal cord is at the level of the upper lumbar vertebral bones. The spinal nerves extend from their various levels to the proper level of the vertebral column.

Gray Horns

In cross-section, the gray matter of the spinal cord has the appearance of an ink-blot test, with the spread of the gray matter on one side replicated on the other—a shape reminiscent of a bulbous capital “H.” As shown in Figure 9, the gray matter is subdivided into regions that are referred to as horns. The posterior horn is responsible for sensory processing. The anterior horn sends out motor signals to the skeletal muscles. The lateral horn, which is only found in the thoracic, upper lumbar, and sacral regions, is the central component of the sympathetic division of the autonomic nervous system.

Some of the largest neurons of the spinal cord are the multipolar motor neurons in the anterior horn. The fibers that cause contraction of skeletal muscles are the axons of these neurons. The motor neuron that causes contraction of the big toe, for example, is located in the sacral spinal cord. The axon that has to reach all the way to the belly of that muscle may be a meter in length. The neuronal cell body that maintains that long fiber must be quite large, possibly several hundred micrometers in diameter, making it one of the largest cells in the body.

[caption id="" align="aligncenter" width="380"] Figure 9. Cross-section of Spinal Cord. The cross-section of a thoracic spinal cord segment shows the posterior, anterior, and lateral horns of gray matter, as well as the posterior, anterior, and lateral columns of white matter. LM × 40. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

White Columns

Just as the gray matter is separated into horns, the white matter of the spinal cord is separated into columns. Ascending tracts of nervous system fibers in these columns carry sensory information up to the brain, whereas descending tracts carry motor commands from the brain. Looking at the spinal cord longitudinally, the columns extend along its length as continuous bands of white matter. Between the two posterior horns of gray matter are the posterior columns. Between the two anterior horns, and bounded by the axons of motor neurons emerging from that gray matter area, are the anterior columns. The white matter on either side of the spinal cord, between the posterior horn and the axons of the anterior horn neurons, are the lateral columns. The posterior columns are composed of axons of ascending tracts. The anterior and lateral columns are composed of many different groups of axons of both ascending and descending tracts—the latter carrying motor commands down from the brain to the spinal cord to control output to the periphery.

[caption id="attachment_3000" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of the central nervous system![/caption]

13.3 Circulation and the Central Nervous System

barkerj1 — Wed, 06 Sep 2017 01:19:27 +0000

Learning Objectives

By the end of this section, you will be able to:

The CNS is crucial to the operation of the body, and any compromise in the brain and spinal cord can lead to severe difficulties. The CNS has a privileged blood supply, as suggested by the blood-brain barrier. The function of the tissue in the CNS is crucial to the survival of the organism, so the contents of the blood cannot simply pass into the central nervous tissue. To protect this region from the toxins and pathogens that may be traveling through the blood stream, there is strict control over what can move out of the general systems and into the brain and spinal cord. Because of this privilege, the CNS needs specialized structures for the maintenance of circulation. This begins with a unique arrangement of blood vessels carrying fresh blood into the CNS. Beyond the supply of blood, the CNS filters that blood into cerebrospinal fluid (CSF), which is then circulated through the cavities of the brain and spinal cord called ventricles.

Blood Supply to the Brain

A lack of oxygen to the CNS can be devastating, and the cardiovascular system has specific regulatory reflexes to ensure that the blood supply is not interrupted. There are multiple routes for blood to get into the CNS, with specializations to protect that blood supply and to maximize the ability of the brain to get an uninterrupted perfusion.

Arterial Supply

The major artery carrying recently oxygenated blood away from the heart is the aorta. The very first branches off the aorta supply the heart with nutrients and oxygen. The next branches give rise to the common carotid arteries, which further branch into the internal carotid arteries. The external carotid arteries supply blood to the tissues on the surface of the cranium. The bases of the common carotids contain stretch receptors that immediately respond to the drop in blood pressure upon standing. The orthostatic reflex is a reaction to this change in body position, so that blood pressure is maintained against the increasing effect of gravity (orthostatic means “standing up”). Heart rate increases—a reflex of the sympathetic division of the autonomic nervous system—and this raises blood pressure.

The internal carotid artery enters the cranium through the carotid canal in the temporal bone. A second set of vessels that supply the CNS are the vertebral arteries, which are protected as they pass through the neck region by the transverse foramina of the cervical vertebrae. The vertebral arteries enter the cranium through the foramen magnum of the occipital bone. Branches off the left and right vertebral arteries merge into the anterior spinal artery supplying the anterior aspect of the spinal cord, found along the anterior median fissure. The two vertebral arteries then merge into the basilar artery, which gives rise to branches to the brain stem and cerebellum. The left and right internal carotid arteries and branches of the basilar artery all become the circle of Willis, a confluence of arteries that can maintain perfusion of the brain even if narrowing or a blockage limits flow through one part (Figure 1).

[caption id="" align="aligncenter" width="320"] Figure 1. Circle of Willis. The blood supply to the brain enters through the internal carotid arteries and the vertebral arteries, eventually giving rise to the circle of Willis.[/caption]

Venous Return

After passing through the CNS, blood returns to the circulation through a series of dural sinuses and veins (Figure 2). The superior sagittal sinus runs in the groove of the longitudinal fissure, where it absorbs CSF from the meninges. The superior sagittal sinus drains to the confluence of sinuses, along with the occipital sinuses and straight sinus, to then drain into the transverse sinuses. The transverse sinuses connect to the sigmoid sinuses, which then connect to the jugular veins. From there, the blood continues toward the heart to be pumped to the lungs for reoxygenation.

[caption id="" align="aligncenter" width="550"] Figure 2. Dural Sinuses and Veins. Blood drains from the brain through a series of sinuses that connect to the jugular veins.[/caption]

Protective Coverings of the Brain and Spinal Cord

The outer surface of the CNS is covered by a series of membranes composed of connective tissue called the meninges, which protect the brain. The dura mater is a thick fibrous layer and a strong protective sheath over the entire brain and spinal cord. It is anchored to the inner surface of the cranium and vertebral cavity. The arachnoid mater is a membrane of thin fibrous tissue that forms a loose sac around the CNS. Beneath the arachnoid is a thin, filamentous mesh called the arachnoid trabeculae, which looks like a spider web, giving this layer its name. Directly adjacent to the surface of the CNS is the pia mater, a thin fibrous membrane that follows the convolutions of gyri and sulci in the cerebral cortex and fits into other grooves and indentations (Figure 3).

[caption id="" align="aligncenter" width="500"] Figure 3. Meningeal Layers of Superior Sagittal Sinus. The layers of the meninges in the longitudinal fissure of the superior sagittal sinus are shown, with the dura mater adjacent to the inner surface of the cranium, the pia mater adjacent to the surface of the brain, and the arachnoid and subarachnoid space between them. An arachnoid villus is shown emerging into the dural sinus to allow CSF to filter back into the blood for drainage.[/caption]

Dura Mater

Like a thick cap covering the brain, the dura mater is a tough outer covering. The name comes from the Latin for “tough mother” to represent its physically protective role. It encloses the entire CNS and the major blood vessels that enter the cranium and vertebral cavity. It is directly attached to the inner surface of the bones of the cranium and to the very end of the vertebral cavity.

There are infoldings of the dura that fit into large crevasses of the brain. Two infoldings go through the midline separations of the cerebrum and cerebellum; one forms a shelf-like tent between the occipital lobes of the cerebrum and the cerebellum, and the other surrounds the pituitary gland. The dura also surrounds and supports the venous sinuses.

Arachnoid Mater

The middle layer of the meninges is the arachnoid, named for the spider-web–like trabeculae between it and the pia mater. The arachnoid defines a sac-like enclosure around the CNS. The trabeculae are found in the subarachnoid space, which is filled with circulating CSF. The arachnoid emerges into the dural sinuses as the arachnoid granulations, where the CSF is filtered back into the blood for drainage from the nervous system.

The subarachnoid space is filled with circulating CSF, which also provides a liquid cushion to the brain and spinal cord. Similar to clinical blood work, a sample of CSF can be withdrawn to find chemical evidence of neuropathology or metabolic traces of the biochemical functions of nervous tissue.

Pia Mater

The outer surface of the CNS is covered in the thin fibrous membrane of the pia mater. It is thought to have a continuous layer of cells providing a fluid-impermeable membrane. The name pia mater comes from the Latin for “tender mother,” suggesting the thin membrane is a gentle covering for the brain. The pia extends into every convolution of the CNS, lining the inside of the sulci in the cerebral and cerebellar cortices. At the end of the spinal cord, a thin filament extends from the inferior end of CNS at the upper lumbar region of the vertebral column to the sacral end of the vertebral column. Because the spinal cord does not extend through the lower lumbar region of the vertebral column, a needle can be inserted through the dura and arachnoid layers to withdraw CSF. This procedure is called a lumbar puncture and avoids the risk of damaging the central tissue of the spinal cord. Blood vessels that are nourishing the central nervous tissue are between the pia mater and the nervous tissue.

Disorders of the…

Meninges Meningitis is an inflammation of the meninges, the three layers of fibrous membrane that surround the CNS. Meningitis can be caused by infection by bacteria or viruses. The particular pathogens are not special to meningitis; it is just an inflammation of that specific set of tissues from what might be a broader infection. Bacterial meningitis can be caused by Streptococcus, Staphylococcus, or the tuberculosis pathogen, among many others. Viral meningitis is usually the result of common enteroviruses (such as those that cause intestinal disorders), but may be the result of the herpes virus or West Nile virus. Bacterial meningitis tends to be more severe. The symptoms associated with meningitis can be fever, chills, nausea, vomiting, light sensitivity, soreness of the neck, or severe headache. More important are the neurological symptoms, such as changes in mental state (confusion, memory deficits, and other dementia-type symptoms). A serious risk of meningitis can be damage to peripheral structures because of the nerves that pass through the meninges. Hearing loss is a common result of meningitis. The primary test for meningitis is a lumbar puncture. A needle inserted into the lumbar region of the spinal column through the dura mater and arachnoid membrane into the subarachnoid space can be used to withdraw the fluid for chemical testing. Fatality occurs in 5 to 40 percent of children and 20 to 50 percent of adults with bacterial meningitis. Treatment of bacterial meningitis is through antibiotics, but viral meningitis cannot be treated with antibiotics because viruses do not respond to that type of drug. Fortunately, the viral forms are milder.

The Ventricular System

Cerebrospinal fluid (CSF) circulates throughout and around the CNS. In other tissues, water and small molecules are filtered through capillaries as the major contributor to the interstitial fluid. In the brain, CSF is produced in special structures to perfuse through the nervous tissue of the CNS and is continuous with the interstitial fluid. Specifically, CSF circulates to remove metabolic wastes from the interstitial fluids of nervous tissues and return them to the blood stream. The ventricles are the open spaces within the brain where CSF circulates. In some of these spaces, CSF is produced by filtering of the blood that is performed by a specialized membrane known as a choroid plexus. The CSF circulates through all of the ventricles to eventually emerge into the subarachnoid space where it will be reabsorbed into the blood.

The Ventricles

There are four ventricles within the brain, all of which developed from the original hollow space within the neural tube, the central canal. The first two are named the lateral ventricles and are deep within the cerebrum. These ventricles are connected to the third ventricle by two openings called the interventricular foramina. The third ventricle is the space between the left and right sides of the diencephalon, which opens into the cerebral aqueduct that passes through the midbrain. The aqueduct opens into the fourth ventricle, which is the space between the cerebellum and the pons and upper medulla (Figure 4).

[caption id="" align="aligncenter" width="550"] Figure 4. Cerebrospinal Fluid Circulation. The choroid plexus in the four ventricles produce CSF, which is circulated through the ventricular system and then enters the subarachnoid space through the median and lateral apertures. The CSF is then reabsorbed into the blood at the arachnoid granulations, where the arachnoid membrane emerges into the dural sinuses.[/caption]

As the telencephalon enlarges and grows into the cranial cavity, it is limited by the space within the skull. The telencephalon is the most anterior region of what was the neural tube, but cannot grow past the limit of the frontal bone of the skull. Because the cerebrum fits into this space, it takes on a C-shaped formation, through the frontal, parietal, occipital, and finally temporal regions. The space within the telencephalon is stretched into this same C-shape. The two ventricles are in the left and right sides, and were at one time referred to as the first and second ventricles. The interventricular foramina connect the frontal region of the lateral ventricles with the third ventricle.

The third ventricle is the space bounded by the medial walls of the hypothalamus and thalamus. The two thalami touch in the center in most brains as the massa intermedia, which is surrounded by the third ventricle. The cerebral aqueduct opens just inferior to the epithalamus and passes through the midbrain. The tectum and tegmentum of the midbrain are the roof and floor of the cerebral aqueduct, respectively. The aqueduct opens up into the fourth ventricle. The floor of the fourth ventricle is the dorsal surface of the pons and upper medulla (that gray matter making a continuation of the tegmentum of the midbrain). The fourth ventricle then narrows into the central canal of the spinal cord.

The ventricular system opens up to the subarachnoid space from the fourth ventricle. The single median aperture and the pair of lateral apertures connect to the subarachnoid space so that CSF can flow through the ventricles and around the outside of the CNS. Cerebrospinal fluid is produced within the ventricles by a type of specialized membrane called a choroid plexus. Ependymal cells (one of the types of glial cells described in the introduction to the nervous system) surround blood capillaries and filter the blood to make CSF. The fluid is a clear solution with a limited amount of the constituents of blood. It is essentially water, small molecules, and electrolytes. Oxygen and carbon dioxide are dissolved into the CSF, as they are in blood, and can diffuse between the fluid and the nervous tissue.

Cerebrospinal Fluid Circulation

The choroid plexuses are found in all four ventricles. Observed in dissection, they appear as soft, fuzzy structures that may still be pink, depending on how well the circulatory system is cleared in preparation of the tissue. The CSF is produced from components extracted from the blood, so its flow out of the ventricles is tied to the pulse of cardiovascular circulation.

From the lateral ventricles, the CSF flows into the third ventricle, where more CSF is produced, and then through the cerebral aqueduct into the fourth ventricle where even more CSF is produced. A very small amount of CSF is filtered at any one of the plexuses, for a total of about 500 milliliters daily, but it is continuously made and pulses through the ventricular system, keeping the fluid moving. From the fourth ventricle, CSF can continue down the central canal of the spinal cord, but this is essentially a cul-de-sac, so more of the fluid leaves the ventricular system and moves into the subarachnoid space through the median and lateral apertures.

Within the subarachnoid space, the CSF flows around all of the CNS, providing two important functions. As with elsewhere in its circulation, the CSF picks up metabolic wastes from the nervous tissue and moves it out of the CNS. It also acts as a liquid cushion for the brain and spinal cord. By surrounding the entire system in the subarachnoid space, it provides a thin buffer around the organs within the strong, protective dura mater. The arachnoid granulations are outpocketings of the arachnoid membrane into the dural sinuses so that CSF can be reabsorbed into the blood, along with the metabolic wastes. From the dural sinuses, blood drains out of the head and neck through the jugular veins, along with the rest of the circulation for blood, to be reoxygenated by the lungs and wastes to be filtered out by the kidneys (Table 2).

Components of CSF Circulation (Table 2)
	Lateral ventricles	Third ventricle	Cerebral aqueduct	Fourth ventricle	Central canal	Subarachnoid space
Location in CNS	Cerebrum	Diencephalon	Midbrain	Between pons/upper medulla and cerebellum	Spinal cord	External to entire CNS
Blood vessel structure	Choroid plexus	Choroid plexus	None	Choroid plexus	None	Arachnoid granulations

13.4 The Peripheral Nervous System

barkerj1 — Wed, 06 Sep 2017 01:19:27 +0000

Learning Objectives

By the end of this section, you will be able to:

Name the nerve responsible for carrying nervous impulses from the following sensory receptors to the brain:
- Olfactory receptors
- Photoreceptors
- Auditory hair cells

The PNS is not as contained as the CNS because it is defined as everything that is not the CNS. Some peripheral structures are incorporated into the other organs of the body. In describing the anatomy of the PNS, it is necessary to describe the common structures, the nerves and the ganglia, as they are found in various parts of the body. Many of the neural structures that are incorporated into other organs are features of the digestive system; these structures are known as the enteric nervous system and are a special subset of the PNS.

Ganglia

A ganglion is a group of neuron cell bodies in the periphery. Ganglia can be categorized, for the most part, as either sensory ganglia or autonomic ganglia, referring to their primary functions. The most common type of sensory ganglion is a dorsal (posterior) root ganglion. These ganglia are the cell bodies of neurons with axons that are sensory endings in the periphery, such as in the skin, and that extend into the CNS through the dorsal nerve root. The ganglion is an enlargement of the nerve root. Under microscopic inspection, it can be seen to include the cell bodies of the neurons, as well as bundles of fibers that are the posterior nerve root (Figure 1). The cells of the dorsal root ganglion are unipolar cells, classifying them by shape. Also, the small round nuclei of satellite cells can be seen surrounding—as if they were orbiting—the neuron cell bodies.

[caption id="" align="aligncenter" width="580"] Figure 1. Dorsal Root Ganglion. The cell bodies of sensory neurons, which are unipolar neurons by shape, are seen in this photomicrograph. Also, the fibrous region is composed of the axons of these neurons that are passing through the ganglion to be part of the dorsal nerve root (tissue source: canine). LM × 40. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

[caption id="" align="aligncenter" width="580"] Figure 2. Spinal Cord and Root Ganglion. The slide includes both a cross-section of the lumbar spinal cord and a section of the dorsal root ganglion (see also Figure 1) (tissue source: canine). LM × 1600. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Another type of sensory ganglion is a cranial nerve ganglion. This is analogous to the dorsal root ganglion, except that it is associated with a cranial nerve instead of a spinal nerve. The roots of cranial nerves are within the cranium, whereas the ganglia are outside the skull. For example, the trigeminal ganglion is superficial to the temporal bone whereas its associated nerve is attached to the mid-pons region of the brain stem. The neurons of cranial nerve ganglia are also unipolar in shape with associated satellite cells.

The other major category of ganglia are those of the autonomic nervous system, which is divided into the sympathetic and parasympathetic nervous systems. The sympathetic chain ganglia constitute a row of ganglia along the vertebral column that receive central input from the lateral horn of the thoracic and upper lumbar spinal cord. Superior to the chain ganglia are three paravertebral ganglia in the cervical region. Three other autonomic ganglia that are related to the sympathetic chain are the prevertebral ganglia, which are located outside of the chain but have similar functions. They are referred to as prevertebral because they are anterior to the vertebral column. The neurons of these autonomic ganglia are multipolar in shape, with dendrites radiating out around the cell body where synapses from the spinal cord neurons are made. The neurons of the chain, paravertebral, and prevertebral ganglia then project to organs in the head and neck, thoracic, abdominal, and pelvic cavities to regulate the sympathetic aspect of homeostatic mechanisms.

Another group of autonomic ganglia are the terminal ganglia that receive input from cranial nerves or sacral spinal nerves and are responsible for regulating the parasympathetic aspect of homeostatic mechanisms. These two sets of ganglia, sympathetic and parasympathetic, often project to the same organs—one input from the chain ganglia and one input from a terminal ganglion—to regulate the overall function of an organ. For example, the heart receives two inputs such as these; one increases heart rate, and the other decreases it. The terminal ganglia that receive input from cranial nerves are found in the head and neck, as well as the thoracic and upper abdominal cavities, whereas the terminal ganglia that receive sacral input are in the lower abdominal and pelvic cavities.

Terminal ganglia below the head and neck are often incorporated into the wall of the target organ as a plexus. A plexus, in a general sense, is a network of fibers or vessels. This can apply to nervous tissue (as in this instance) or structures containing blood vessels (such as a choroid plexus). For example, the enteric plexus is the extensive network of axons and neurons in the wall of the small and large intestines. The enteric plexus is actually part of the enteric nervous system, along with the gastric plexuses and the esophageal plexus. Though the enteric nervous system receives input originating from central neurons of the autonomic nervous system, it does not require CNS input to function. In fact, it operates independently to regulate the digestive system.

Nerves

Bundles of axons in the PNS are referred to as nerves. These structures in the periphery are different than the central counterpart, called a tract. Nerves are composed of more than just nervous tissue. They have connective tissues invested in their structure, as well as blood vessels supplying the tissues with nourishment. The outer surface of a nerve is a surrounding layer of fibrous connective tissue called the epineurium. Within the nerve, axons are further bundled into fascicles, which are each surrounded by their own layer of fibrous connective tissue called perineurium. Finally, individual axons are surrounded by loose connective tissue called the endoneurium (Figure 3). These three layers are similar to the connective tissue sheaths for muscles. Nerves are associated with the region of the CNS to which they are connected, either as cranial nerves connected to the brain or spinal nerves connected to the spinal cord.

[caption id="" align="aligncenter" width="480"] Figure 3. Nerve Structure. The structure of a nerve is organized by the layers of connective tissue on the outside, around each fascicle, and surrounding the individual nerve fibers (tissue source: simian). LM × 40. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

[caption id="" align="aligncenter" width="580"] Figure 4. Close-Up of Nerve Trunk. Zoom in on this slide of a nerve trunk to examine the endoneurium, perineurium, and epineurium in greater detail (tissue source: simian). LM × 1600. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Cranial Nerves

The nerves attached to the brain are the cranial nerves, which are primarily responsible for the sensory and motor functions of the head and neck (one of these nerves targets organs in the thoracic and abdominal cavities as part of the parasympathetic nervous system). There are twelve cranial nerves, which are designated CNI through CNXII for “Cranial Nerve,” using Roman numerals for 1 through 12. They can be classified as sensory nerves, motor nerves, or a combination of both, meaning that the axons in these nerves originate out of sensory ganglia external to the cranium or motor nuclei within the brain stem. Sensory axons enter the brain to synapse in a nucleus. Motor axons connect to skeletal muscles of the head or neck. Three of the nerves are solely composed of sensory fibers; five are strictly motor; and the remaining four are mixed nerves.

Learning the cranial nerves is a tradition in anatomy courses, and students have always used mnemonic devices to remember the nerve names. A traditional mnemonic is the rhyming couplet, “On Old Olympus’ Towering Tops/A Finn And German Viewed Some Hops,” in which the initial letter of each word corresponds to the initial letter in the name of each nerve. The names of the nerves have changed over the years to reflect current usage and more accurate naming. An exercise to help learn this sort of information is to generate a mnemonic using words that have personal significance. The names of the cranial nerves are listed in Table 3 along with a brief description of their function, their source (sensory ganglion or motor nucleus), and their target (sensory nucleus or skeletal muscle). They are listed here with a brief explanation of each nerve (Figure 5).

The olfactory nerve and optic nerve are responsible for the sense of smell and vision, respectively. The oculomotor nerve is responsible for eye movements by controlling four of the extraocular muscles. It is also responsible for lifting the upper eyelid when the eyes point up, and for pupillary constriction. The trochlear nerve and the abducens nerve are both responsible for eye movement, but do so by controlling different extraocular muscles. The trigeminal nerve is responsible for cutaneous sensations of the face and controlling the muscles of mastication. The facial nerve is responsible for the muscles involved in facial expressions, as well as part of the sense of taste and the production of saliva. The vestibulocochlear nerve is responsible for the senses of hearing and balance. The glossopharyngeal nerve is responsible for controlling muscles in the oral cavity and upper throat, as well as part of the sense of taste and the production of saliva. The vagus nerve is responsible for contributing to homeostatic control of the organs of the thoracic and upper abdominal cavities. The spinal accessory nerve is responsible for controlling the muscles of the neck, along with cervical spinal nerves. The hypoglossal nerve is responsible for controlling the muscles of the lower throat and tongue.

[caption id="" align="aligncenter" width="480"] Figure 5. The Cranial Nerves. The anatomical arrangement of the roots of the cranial nerves observed from an inferior view of the brain.[/caption] Three of the cranial nerves also contain autonomic fibers, and a fourth is almost purely a component of the autonomic system. The oculomotor, facial, and glossopharyngeal nerves contain fibers that contact autonomic ganglia. The oculomotor fibers initiate pupillary constriction, whereas the facial and glossopharyngeal fibers both initiate salivation. The vagus nerve primarily targets autonomic ganglia in the thoracic and upper abdominal cavities.

Another important aspect of the cranial nerves that lends itself to a mnemonic is the functional role each nerve plays. The nerves fall into one of three basic groups. They are sensory, motor, or both (see Table 3). The sentence, “Some Say Marry Money But My Brother Says Brains Beauty Matter More,” corresponds to the basic function of each nerve. The first, second, and eighth nerves are purely sensory: the olfactory (CNI), optic (CNII), and vestibulocochlear (CNVIII) nerves. The three eye-movement nerves are all motor: the oculomotor (CNIII), trochlear (CNIV), and abducens (CNVI). The spinal accessory (CNXI) and hypoglossal (CNXII) nerves are also strictly motor. The remainder of the nerves contain both sensory and motor fibers. They are the trigeminal (CNV), facial (CNVII), glossopharyngeal (CNIX), and vagus (CNX) nerves. The nerves that convey both are often related to each other. The trigeminal and facial nerves both concern the face; one concerns the sensations and the other concerns the muscle movements. The facial and glossopharyngeal nerves are both responsible for conveying gustatory, or taste, sensations as well as controlling salivary glands. The vagus nerve is involved in visceral responses to taste, namely the gag reflex. This is not an exhaustive list of what these combination nerves do, but there is a thread of relation between them.

Cranial Nerves (Table 3)
Mnemonic	#	Name	Function (S/M/B)	Central connection (nuclei)	Peripheral connection (ganglion or muscle)
On	I	Olfactory	Smell (S)	Olfactory bulb	Olfactory epithelium
Old	II	Optic	Vision (S)	Hypothalamus/thalamus/midbrain	Retina (retinal ganglion cells)
Olympus’	III	Oculomotor	Eye movements (M)	Oculomotor nucleus	Extraocular muscles (other 4), levator palpebrae superioris, ciliary ganglion (autonomic)
Towering	IV	Trochlear	Eye movements (M)	Trochlear nucleus	Superior oblique muscle
Tops	V	Trigeminal	Sensory/motor – face (B)	Trigeminal nuclei in the midbrain, pons, and medulla	Trigeminal
A	VI	Abducens	Eye movements (M)	Abducens nucleus	Lateral rectus muscle
Finn	VII	Facial	Motor – face, Taste (B)	Facial nucleus, solitary nucleus, superior salivatory nucleus	Facial muscles, Geniculate ganglion, Pterygopalatine ganglion (autonomic)
And	VIII	Auditory (Vestibulocochlear)	Hearing/balance (S)	Cochlear nucleus, Vestibular nucleus/cerebellum	Spiral ganglion (hearing), Vestibular ganglion (balance)
German	IX	Glossopharyngeal	Motor – throat Taste (B)	Solitary nucleus, inferior salivatory nucleus, nucleus ambiguus	Pharyngeal muscles, Geniculate ganglion, Otic ganglion (autonomic)
Viewed	X	Vagus	Motor/sensory – viscera (autonomic) (B)	Medulla	Terminal ganglia serving thoracic and upper abdominal organs (heart and small intestines)
Some	XI	Spinal Accessory	Motor – head and neck (M)	Spinal accessory nucleus	Neck muscles
Hops	XII	Hypoglossal	Motor – lower throat (M)	Hypoglossal nucleus	Muscles of the larynx and lower pharynx

Spinal Nerves

The nerves connected to the spinal cord are the spinal nerves. The arrangement of these nerves is much more regular than that of the cranial nerves. All of the spinal nerves are combined sensory and motor axons that separate into two nerve roots. The sensory axons enter the spinal cord as the dorsal nerve root. The motor fibers, both somatic and autonomic, emerge as the ventral nerve root. The dorsal root ganglion for each nerve is an enlargement of the spinal nerve.

There are 31 spinal nerves, named for the level of the spinal cord at which each one emerges. There are eight pairs of cervical nerves designated C1 to C8, twelve thoracic nerves designated T1 to T12, five pairs of lumbar nerves designated L1 to L5, five pairs of sacral nerves designated S1 to S5, and one pair of coccygeal nerves. The nerves are numbered from the superior to inferior positions, and each emerges from the vertebral column through the intervertebral foramen at its level. The first nerve, C1, emerges between the first cervical vertebra and the occipital bone. The second nerve, C2, emerges between the first and second cervical vertebrae. The same occurs for C3 to C7, but C8 emerges between the seventh cervical vertebra and the first thoracic vertebra. For the thoracic and lumbar nerves, each one emerges between the vertebra that has the same designation and the next vertebra in the column. The sacral nerves emerge from the sacral foramina along the length of that unique vertebra.

Spinal nerves extend outward from the vertebral column to enervate the periphery. The nerves in the periphery are not straight continuations of the spinal nerves, but rather the reorganization of the axons in those nerves to follow different courses. Axons from different spinal nerves will come together into a systemic nerve. This occurs at four places along the length of the vertebral column, each identified as a nerve plexus, whereas the other spinal nerves directly correspond to nerves at their respective levels. In this instance, the word plexus is used to describe networks of nerve fibers with no associated cell bodies.

Of the four nerve plexuses, two are found at the cervical level, one at the lumbar level, and one at the sacral level (Figure 6). The cervical plexus is composed of axons from spinal nerves C1 through C5 and branches into nerves in the posterior neck and head, as well as the phrenic nerve, which connects to the diaphragm at the base of the thoracic cavity. The other plexus from the cervical level is the brachial plexus. Spinal nerves C4 through T1 reorganize through this plexus to give rise to the nerves of the arms, as the name brachial suggests. A large nerve from this plexus is the radial nerve from which the axillary nerve branches to go to the armpit region. The radial nerve continues through the arm and is paralleled by the ulnar nerve and the median nerve. The lumbar plexus arises from all the lumbar spinal nerves and gives rise to nerves enervating the pelvic region and the anterior leg. The femoral nerve is one of the major nerves from this plexus, which gives rise to the saphenous nerve as a branch that extends through the anterior lower leg. The sacral plexus comes from the lower lumbar nerves L4 and L5 and the sacral nerves S1 to S4. The most significant systemic nerve to come from this plexus is the sciatic nerve, which is a combination of the tibial nerve and the fibular nerve. The sciatic nerve extends across the hip joint and is most commonly associated with the condition sciatica, which is the result of compression or irritation of the nerve or any of the spinal nerves giving rise to it.

These plexuses are described as arising from spinal nerves and giving rise to certain systemic nerves, but they contain fibers that serve sensory functions or fibers that serve motor functions. This means that some fibers extend from cutaneous or other peripheral sensory surfaces and send action potentials into the CNS. Those are axons of sensory neurons in the dorsal root ganglia that enter the spinal cord through the dorsal nerve root. Other fibers are the axons of motor neurons of the anterior horn of the spinal cord, which emerge in the ventral nerve root and send action potentials to cause skeletal muscles to contract in their target regions. For example, the radial nerve contains fibers of cutaneous sensation in the arm, as well as motor fibers that move muscles in the arm.

Spinal nerves of the thoracic region, T2 through T11, are not part of the plexuses but rather emerge and give rise to the intercostal nerves found between the ribs, which articulate with the vertebrae surrounding the spinal nerve.

[caption id="" align="aligncenter" width="440"] Figure 6. Nerve Plexuses of the Body. There are four main nerve plexuses in the human body. The cervical plexus supplies nerves to the posterior head and neck, as well as to the diaphragm. The brachial plexus supplies nerves to the arm. The lumbar plexus supplies nerves to the anterior leg. The sacral plexus supplies nerves to the posterior leg.[/caption]

14.1 Sensory Perception

barkerj1 — Wed, 06 Sep 2017 01:19:30 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the five main categories of sense receptors that respond to particular types of stimuli
Describe the structure of cutaneous sensors and proprioceptors
For the sense of small (olfaction), describe:
- The location of olfactory receptors
- The structure of olfactory receptors
- The pathway of olfactory impulses from olfactory receptors to the cerebrum
- Describe why the sense of smell usually decreases with age
For the sense of taste (gustation), describe:
- The location of gustatory receptors
- The structure of gustatory receptors
- The five primary tases
For the sense of sight (vision):
- Identify the following components of the human eye on a model or diagram, and describe the locations and functions of each:
  - Sclera, cornea, choroid, conjuctiva
  - Iris, pupil, ciliary body
  - Lens, suspensory ligament
  - Aqueous humor, vitreous humor
  - Retina, macula lutea, fovea, optic disc, optic nerve
- Describe the formation of an image on the retina by explaining:
  - Refraction of light rays
  - Accommodation of the lens
  - Constriction of the pupil
  - Convergence of the eyes
- Specify the two types of photoreceptors in the retina, and describe their distribution and their functions
- Describe the pathway of the nervous impulses from the photoreceptors of the retina to the brain
- Describe the location, structure, and functions of the lacrimal apparatus
- Describe the following visual disorders, and explain the physiological cause of each:
  - Glaucoma
  - Myopia and hyperopia
  - Astigmatism
  - Cataract
For the senses of hearing (audition) and balance (equilibrium):
- Describe the structure and functions of the external ear
- Describe the structure and functions of the middle ear, including the five openings and the auditory ossicles
- Describe how a throat infection can lead to the infection of the middle ear
- Describe the following components of the inner ear:
  - Bony labyrinth and membranous labyrinth
  - Semicircular canals and vestibule (utricle and saccule)
  - Cochlea
- Describe the cochlear as seen in:
  - Longitudinal section
  - Cross section
- Describe the physiology of hearing
- Describe the physiology of static balance (linear acceleration)
- Describe the physiology of dynamic balance (rotation)
- Describe two anatomical reasons for deafness
- Specify three common causes of tinnitus

A major role of sensory receptors is to help us learn about the environment around us, or about the state of our internal environment. Stimuli from varying sources, and of different types, are received and changed into the electrochemical signals of the nervous system. This occurs when a stimulus changes the cell membrane potential of a sensory neuron. The stimulus causes the sensory cell to produce an action potential that is relayed into the central nervous system (CNS), where it is integrated with other sensory information—or sometimes higher cognitive functions—to become a conscious perception of that stimulus. The central integration may then lead to a motor response.

Describing sensory function with the term sensation or perception is a deliberate distinction. Sensation is the activation of sensory receptor cells at the level of the stimulus. Perception is the central processing of sensory stimuli into a meaningful pattern. Perception is dependent on sensation, but not all sensations are perceived. Receptors are the cells or structures that detect sensations. A receptor cell is changed directly by a stimulus. A transmembrane protein receptor is a protein in the cell membrane that mediates a physiological change in a neuron, most often through the opening of ion channels or changes in the cell signaling processes. Transmembrane receptors are activated by chemicals called ligands. For example, a molecule in food can serve as a ligand for taste receptors. Other transmembrane proteins, which are not accurately called receptors, are sensitive to mechanical or thermal changes. Physical changes in these proteins increase ion flow across the membrane, and can generate an action potential or a graded potential in the sensory neurons.

Sensory Receptors

Stimuli in the environment activate specialized receptor cells in the peripheral nervous system. Different types of stimuli are sensed by different types of receptor cells. Receptor cells can be classified into types on the basis of three different criteria: cell type, position, and function. Receptors can be classified structurally on the basis of cell type and their position in relation to stimuli they sense. They can also be classified functionally on the basis of the transduction of stimuli, or how the mechanical stimulus, light, or chemical changed the cell membrane potential.

Structural Receptor Types

The cells that interpret information about the environment can be either (1) a neuron that has a free nerve ending, with dendrites embedded in tissue that would receive a sensation; (2) a neuron that has an encapsulated ending in which the sensory nerve endings are encapsulated in connective tissue that enhances their sensitivity; or (3) a specialized receptor cell, which has distinct structural components that interpret a specific type of stimulus (Figure 1). The pain and temperature receptors in the dermis of the skin are examples of neurons that have free nerve endings. Also located in the dermis of the skin are lamellated corpuscles, neurons with encapsulated nerve endings that respond to pressure and touch. The cells in the retina that respond to light stimuli are an example of a specialized receptor, a photoreceptor.

[caption id="" align="aligncenter" width="490"] Figure 1. Receptor Classification by Cell Type. Receptor cell types can be classified on the basis of their structure. Sensory neurons can have either (a) free nerve endings or (b) encapsulated endings. Photoreceptors in the eyes, such as rod cells, are examples of (c) specialized receptor cells. These cells release neurotransmitters onto a bipolar cell, which then synapses with the optic nerve neurons.[/caption]

Another way that receptors can be classified is based on the location of the stimuli to which they respond. An exteroceptor is a receptor that is located near a stimulus in the external environment, such as the somatosensory receptors that are located in the skin. An interoceptor is one that interprets stimuli from internal organs and tissues, such as the receptors that sense the increase in blood pressure in the aorta or carotid sinus. Finally, a proprioceptor is a receptor located near a moving part of the body, such as a muscle, that interprets the positions of the tissues as they move.

Functional Receptor Types

A third classification of receptors is by how the receptor transduces stimuli into membrane potential changes. Stimuli are of three general types. Some stimuli are ions and macromolecules that affect transmembrane receptor proteins when these chemicals diffuse across the cell membrane. Some stimuli are physical variations in the environment that affect receptor cell membrane potentials. Other stimuli include the electromagnetic radiation from visible light. For humans, the only electromagnetic energy that is perceived by our eyes is visible light. Some other organisms have receptors that humans lack, such as the heat sensors of snakes, the ultraviolet light sensors of bees, or magnetic receptors in migratory birds.

Receptor cells can be further categorized on the basis of the type of stimuli they transduce. Chemical stimuli can be interpreted by a chemoreceptor that detects chemical stimuli that arise from the external environment, such as the compounds that determine an object’s taste or smell, or from the internal environment to monitor physiologically important parameters or the presence of damage. Osmoreceptors for example respond to solute concentrations of body fluids. The sensation of pain is primarily the result of the presence of chemicals released as a result of tissue damage or other intense stimuli through nociceptors.

Physical stimuli such as pressure and vibration, as well as the sensation of sound and body position (balance), are interpreted through mechanoreceptors. A physical stimulus that has its own type of receptor is temperature, which is sensed through thermoreceptors that are sensitive to temperatures either above (warmth/heat) or below (coolness/cold) normal body temperature. Finally, highly specialized receptor cells called photoreceptors are used to detect light. They are found in the retina of the eye.

Sensory Modalities

Ask anyone what the senses are, and they are likely to list the five major senses—taste, smell, touch, hearing, and sight. However, these are not all of the senses. The most obvious omission from this list is balance. Also, what is referred to simply as touch can be further subdivided into pressure, vibration, stretch, and hair-follicle position, on the basis of the type of mechanoreceptors that perceive these touch sensations. Other overlooked senses include temperature perception by thermoreceptors and pain perception by nociceptors.

Within the realm of physiology, senses can be classified as either general or specific. A general sense is one that is distributed throughout the body and has receptor cells within the structures of other organs. Mechanoreceptors in the skin, muscles, or the walls of blood vessels are examples of this type. General senses often contribute to the sense of touch, as described above, or to proprioception (body movement) and kinesthesia (body movement), or to a visceral sense, which is most important to autonomic functions. A special sense is one that has a specific organ devoted to it, namely the eye, inner ear, tongue, or nose.

Each of the senses is referred to as a sensory modality. Modality refers to the way that information is encoded, which is similar to the idea of transduction. The main sensory modalities can be described on the basis of how each is transduced. The chemical senses are taste and smell. The general sense that is usually referred to as touch includes chemical sensation in the form of nociception, or pain. Pressure, vibration, muscle stretch, and the movement of hair by an external stimulus, are all sensed by mechanoreceptors. Hearing and balance are also sensed by mechanoreceptors. Finally, vision involves the activation of photoreceptors.

Listing all the different sensory modalities, which can number as many as 17, involves separating the five major senses into more specific categories, or submodalities, of the larger sense. An individual sensory modality represents the sensation of a specific type of stimulus. For example, the general sense of touch, which is known as somatosensation, can be separated into light pressure, deep pressure, vibration, itch, pain, temperature, or hair movement.

Somatosensation (Touch)

Somatosensation is considered a general sense, as opposed to the special senses discussed in this section. Somatosensation is the group of sensory modalities that are associated with touch, proprioception, and interoception. These modalities include pressure, vibration, light touch, tickle, itch, temperature, pain, and kinesthesia. This means that its receptors are not associated with a specialized organ, but are instead spread throughout the body in a variety of organs. Many of the somatosensory receptors are located in the skin and so are referred to as cutaneous receptors, but receptors are also found in muscles, tendons, joint capsules, ligaments, and in the walls of visceral organs.

Two types of somatosensory signals that are transduced by free nerve endings are pain and temperature. These two modalities use thermoreceptors and nociceptors to transduce temperature and pain stimuli, respectively. Temperature receptors are stimulated when local temperatures differ from body temperature. Some thermoreceptors are sensitive to just cold and others to just heat. Nociception is the sensation of potentially damaging stimuli. Mechanical, chemical, or thermal stimuli beyond a set threshold will elicit painful sensations. Stressed or damaged tissues release chemicals that activate receptor proteins in the nociceptors. For example, the sensation of heat associated with spicy foods involves capsaicin, the active molecule in hot peppers. Capsaicin molecules bind to a transmembrane ion channel in nociceptors that is sensitive to temperatures above 37°C. The dynamics of capsaicin binding with this transmembrane ion channel is unusual in that the molecule remains bound for a long time. Because of this, it will decrease the ability of other stimuli to elicit pain sensations through the activated nociceptor. For this reason, capsaicin can be used as a topical analgesic, such as in products such as Icy Hot™.

If you drag your finger across a textured surface, the skin of your finger will vibrate. Such low frequency vibrations are sensed by mechanoreceptors called Merkel cells, also known as type I cutaneous mechanoreceptors. Merkel cells are located in the stratum basale of the epidermis. Deep pressure and vibration is transduced by lamellated (Pacinian) corpuscles, which are receptors with encapsulated endings found deep in the dermis, or subcutaneous tissue. Light touch is transduced by the encapsulated endings known as tactile (Meissner) corpuscles. Follicles are also wrapped in a plexus of nerve endings known as the hair follicle plexus. These nerve endings detect the movement of hair at the surface of the skin, such as when an insect may be walking along the skin. Stretching of the skin is transduced by stretch receptors known as bulbous corpuscles. Bulbous corpuscles are also known as Ruffini corpuscles, or type II cutaneous mechanoreceptors.

Other somatosensory receptors are found in the joints and muscles. Stretch receptors monitor the stretching of tendons, muscles, and the components of joints. For example, have you ever stretched your muscles before or after exercise and noticed that you can only stretch so far before your muscles spasm back to a less stretched state? This spasm is a reflex that is initiated by stretch receptors to avoid muscle tearing. Such stretch receptors can also prevent over-contraction of a muscle. In skeletal muscle tissue, these stretch receptors are called muscle spindles. Golgi tendon organs similarly transduce the stretch levels of tendons. Bulbous corpuscles are also present in joint capsules, where they measure stretch in the components of the skeletal system within the joint. The types of nerve endings, their locations, and the stimuli they transduce are presented in Table 1.

*No corresponding eponymous name.
Mechanoreceptors of Somatosensation (Table 1)
Name	Historical (eponymous) name	Location(s)	Stimuli
Free nerve endings	*	Dermis, cornea, tongue, joint capsules, visceral organs	Pain, temperature, mechanical deformation
Mechanoreceptors	Merkel’s discs	Epidermal–dermal junction, mucosal membranes	Low frequency vibration (5–15 Hz)
Bulbous corpuscle	Ruffini’s corpuscle	Dermis, joint capsules	Stretch
Tactile corpuscle	Meissner’s corpuscle	Papillary dermis, especially in the fingertips and lips	Light touch, vibrations below 50 Hz
Lamellated corpuscle	Pacinian corpuscle	Deep dermis, subcutaneous tissue	Deep pressure, high-frequency vibration (around 250 Hz)
Hair follicle plexus	*	Wrapped around hair follicles in the dermis	Movement of hair
Muscle spindle	*	In line with skeletal muscle fibers	Muscle contraction and stretch
Tendon stretch organ	Golgi tendon organ	In line with tendons	Stretch of tendons

Gustation (Taste)

Only a few recognized submodalities exist within the sense of taste, or gustation. Until recently, only four tastes were recognized: sweet, salty, sour, and bitter. Research at the turn of the 20th century led to recognition of the fifth taste, umami, during the mid-1980s. Umami is a Japanese word that means “delicious taste,” and is often translated to mean savory. Very recent research has suggested that there may also be a sixth taste for fats, or lipids.

Gustation is the special sense associated with the tongue. The surface of the tongue, along with the rest of the oral cavity, is lined by a stratified squamous epithelium. Raised bumps called papillae (singular = papilla) contain the structures for gustatory transduction. There are four types of papillae, based on their appearance (Figure 2): circumvallate, foliate, filiform, and fungiform. Within the structure of the papillae are taste buds that contain specialized gustatory receptor cells for the transduction of taste stimuli. These receptor cells are sensitive to the chemicals contained within foods that are ingested, and they release neurotransmitters based on the amount of the chemical in the food. Neurotransmitters from the gustatory cells can activate sensory neurons in the facial, glossopharyngeal, and vagus cranial nerves.

[caption id="" align="aligncenter" width="525"] Figure 2. The Tongue. The tongue is covered with small bumps, called papillae, which contain taste buds that are sensitive to chemicals in ingested food or drink. Different types of papillae are found in different regions of the tongue. The taste buds contain specialized gustatory receptor cells that respond to chemical stimuli dissolved in the saliva. These receptor cells activate sensory neurons that are part of the facial and glossopharyngeal nerves. LM × 1600. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Salty taste is simply the perception of sodium ions (Na⁺) in the saliva. When you eat something salty, the salt crystals dissociate into the component ions Na⁺ and Cl^–, which dissolve into the saliva in your mouth. The Na⁺ concentration becomes high outside the gustatory cells, creating a strong concentration gradient that drives the diffusion of the ion into the cells. The entry of Na⁺ into these cells results in the depolarization of the cell membrane and the generation of a receptor potential.

Sour taste is the perception of H⁺ concentration. Just as with sodium ions in salty flavors, these hydrogen ions enter the cell and trigger depolarization. Sour flavors are, essentially, the perception of acids in our food. Increasing hydrogen ion concentrations in the saliva (lowering saliva pH) triggers progressively stronger graded potentials in the gustatory cells. For example, orange juice—which contains citric acid—will taste sour because it has a pH value of approximately 3. Of course, it is often sweetened so that the sour taste is masked.

The first two tastes (salty and sour) are triggered by the cations Na⁺ and H⁺. The other tastes result from food molecules binding to a G protein–coupled receptor. A G protein signal transduction system ultimately leads to depolarization of the gustatory cell. The sweet taste is the sensitivity of gustatory cells to the presence of glucose dissolved in the saliva. Other monosaccharides such as fructose, or artificial sweeteners such as aspartame (NutraSweet™), saccharine, or sucralose (Splenda™) also activate the sweet receptors. The affinity for each of these molecules varies, and some will taste sweeter than glucose because they bind to the G protein–coupled receptor differently.

Bitter taste is similar to sweet in that food molecules bind to G protein–coupled receptors. However, there are a number of different ways in which this can happen because there are a large diversity of bitter-tasting molecules. Some bitter molecules depolarize gustatory cells, whereas others hyperpolarize gustatory cells. Likewise, some bitter molecules increase G protein activation within the gustatory cells, whereas other bitter molecules decrease G protein activation. The specific response depends on which molecule is binding to the receptor.

One major group of bitter-tasting molecules are alkaloids. Alkaloids are nitrogen containing molecules that are commonly found in bitter-tasting plant products, such as coffee, hops (in beer), tannins (in wine), tea, and aspirin. By containing toxic alkaloids, the plant is less susceptible to microbe infection and less attractive to herbivores.

Therefore, the function of bitter taste may primarily be related to stimulating the gag reflex to avoid ingesting poisons. Because of this, many bitter foods that are normally ingested are often combined with a sweet component to make them more palatable (cream and sugar in coffee, for example). The highest concentration of bitter receptors appear to be in the posterior tongue, where a gag reflex could still spit out poisonous food.

The taste known as umami is often referred to as the savory taste. Like sweet and bitter, it is based on the activation of G protein–coupled receptors by a specific molecule. The molecule that activates this receptor is the amino acid L-glutamate. Therefore, the umami flavor is often perceived while eating protein-rich foods. Not surprisingly, dishes that contain meat are often described as savory.

Once the gustatory cells are activated by the taste molecules, they release neurotransmitters onto the dendrites of sensory neurons. These neurons are part of the facial and glossopharyngeal cranial nerves, as well as a component within the vagus nerve dedicated to the gag reflex. The facial nerve connects to taste buds in the anterior third of the tongue. The glossopharyngeal nerve connects to taste buds in the posterior two thirds of the tongue. The vagus nerve connects to taste buds in the extreme posterior of the tongue, verging on the pharynx, which are more sensitive to noxious stimuli such as bitterness.

Olfaction (Smell)

Like taste, the sense of smell, or olfaction, is also responsive to chemical stimuli. The olfactory receptor neurons are located in a small region within the superior nasal cavity (Figure 3). This region is referred to as the olfactory epithelium and contains bipolar sensory neurons. Each olfactory sensory neuron has dendrites that extend from the apical surface of the epithelium into the mucus lining the cavity. As airborne molecules are inhaled through the nose, they pass over the olfactory epithelial region and dissolve into the mucus. These odorant molecules bind to proteins that keep them dissolved in the mucus and help transport them to the olfactory dendrites. The odorant–protein complex binds to a receptor protein within the cell membrane of an olfactory dendrite. These receptors are G protein–coupled, and will produce a graded membrane potential in the olfactory neurons.

The axon of an olfactory neuron extends from the basal surface of the epithelium, through an olfactory foramen in the cribriform plate of the ethmoid bone, and into the brain. The group of axons called the olfactory tract connect to the olfactory bulb on the ventral surface of the frontal lobe. From there, the axons split to travel to several brain regions. Some travel to the cerebrum, specifically to the primary olfactory cortex that is located in the inferior and medial areas of the temporal lobe. Others project to structures within the limbic system and hypothalamus, where smells become associated with long-term memory and emotional responses. This is how certain smells trigger emotional memories, such as the smell of food associated with one’s birthplace. Smell is the one sensory modality that does not synapse in the thalamus before connecting to the cerebral cortex. This intimate connection between the olfactory system and the cerebral cortex is one reason why smell can be a potent trigger of memories and emotion.

The nasal epithelium, including the olfactory cells, can be harmed by airborne toxic chemicals. Therefore, the olfactory neurons are regularly replaced within the nasal epithelium, after which the axons of the new neurons must find their appropriate connections in the olfactory bulb. These new axons grow along the axons that are already in place in the cranial nerve.

[caption id="" align="aligncenter" width="500"] Figure 3. The Olfactory System. (a) The olfactory system begins in the peripheral structures of the nasal cavity. (b) The olfactory receptor neurons are within the olfactory epithelium. (c) Axons of the olfactory receptor neurons project through the cribriform plate of the ethmoid bone and synapse with the neurons of the olfactory bulb (tissue source: simian). LM × 812. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

[caption id="attachment_3002" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of taste and smell![/caption]

Audition (Hearing)

Hearing, or audition, is the transduction of sound waves into a neural signal that is made possible by the structures of the ear (Figure 4). The large, fleshy structure on the lateral aspect of the head is known as the auricle. Some sources will also refer to this structure as the pinna, though that term is more appropriate for a structure that can be moved, such as the external ear of a cat. The C-shaped curves of the auricle direct sound waves toward the auditory canal. The canal enters the skull through the external auditory meatus of the temporal bone. At the end of the auditory canal is the tympanic membrane, or ear drum, which vibrates after it is struck by sound waves. The auricle, ear canal, and tympanic membrane are often referred to as the external ear. The middle ear consists of a space spanned by three small bones called the ossicles. The three ossicles are the malleus, incus, and stapes, which are Latin names that roughly translate to hammer, anvil, and stirrup. The malleus is attached to the tympanic membrane and articulates with the incus. The incus, in turn, articulates with the stapes. The stapes is then attached to the inner ear, where the sound waves will be transduced into a neural signal. The outer and middle ear are responsible for directing sound waves towards the inner ear; interference with this conduction of sound waves through the outer and middle ear can cause conductive deafness if the sound waves fail to reach the inner ear.

The middle ear is connected to the pharynx through the Eustachian tube, which helps equilibrate air pressure across the tympanic membrane. The tube is normally closed but will pop open when the muscles of the pharynx contract during swallowing or yawning. The middle ear is also connected to the mastoid antrum, a space which in turn leads to the mastoid cells, air spaces in the mastoid process.

[caption id="" align="aligncenter" width="425"] Figure 4. Structures of the Ear. The external ear contains the auricle, ear canal, and tympanic membrane. The middle ear contains the ossicles and is connected to the pharynx by the Eustachian tube. The inner ear contains the cochlea and vestibule, which are responsible for audition and equilibrium, respectively.[/caption]

The inner ear is often described as a bony labyrinth, as it is composed of a series of canals embedded within the temporal bone. It has two separate regions, the cochlea and the vestibule, which are responsible for hearing and balance, respectively. The neural signals from these two regions are relayed to the brain stem through separate fiber bundles. However, these two distinct bundles travel together from the inner ear to the brain stem as the vestibulocochlear nerve. Sound is transduced into neural signals within the cochlear region of the inner ear, which contains the sensory neurons of the spiral ganglia. These ganglia are located within the spiral-shaped cochlea of the inner ear. The cochlea is attached to the stapes through the oval window. Interference in the mechanisms that are responsible for transducing sound pressure waves to neural signals, or in the passage of information along the cochlear portion of the vestibulocochlear nerve, can result in sensorineural deafness, where a sound wave may reach the inner ear but not ultimately be perceived.

The oval window is located at the beginning of a fluid-filled (perilymph-filled) tube within the cochlea called the scala vestibuli. The scala vestibuli extends from the oval window, travelling above the cochlear duct (scala media), which is the central cavity of the cochlea that contains the sound-transducing neurons. At the uppermost tip of the cochlea, the scala vestibuli curves over the top of the cochlear duct. The perilymph-filled tube, now called the scala tympani, returns to the base of the cochlea, this time travelling under the cochlear duct. The scala tympani ends at the round window, which is covered by a membrane that contains the fluid within the scala. As vibrations of the ossicles travel through the oval window, the fluid of the scala vestibuli and scala tympani moves in a wave-like motion. The frequency of the fluid waves match the frequencies of the sound waves (Figure 5). The membrane covering the round window will bulge out or pucker in with the movement of the fluid within the scala tympani.

[caption id="" align="aligncenter" width="520"] Figure 5. Transmission of Sound Waves to Cochlea. A sound wave causes the tympanic membrane to vibrate. This vibration is amplified as it moves across the malleus, incus, and stapes. The amplified vibration is picked up by the oval window causing pressure waves in the fluid of the scala vestibuli and scala tympani. The complexity of the pressure waves is determined by the changes in amplitude and frequency of the sound waves entering the ear.[/caption]

A cross-sectional view of the cochlea shows that the scala vestibuli and scala tympani run along both sides of the cochlear duct (Figure 6). The cochlear duct contains several organs of Corti, which tranduce the wave motion of the two scala into neural signals. The organs of Corti lie on top of the basilar membrane, which is the side of the cochlear duct located between the organs of Corti and the scala tympani. As the fluid waves move through the scala vestibuli and scala tympani, the basilar membrane moves at a specific spot, depending on the frequency of the waves. Higher frequency waves move the region of the basilar membrane that is close to the base of the cochlea. Lower frequency waves move the region of the basilar membrane that is near the tip of the cochlea.

[caption id="" align="aligncenter" width="480"] Figure 6. Cross Section of the Cochlea. The three major spaces within the cochlea are highlighted. The scala tympani and scala vestibuli lie on either side of the cochlear duct. The organ of Corti, containing the mechanoreceptor hair cells, is adjacent to the scala tympani, where it sits atop the basilar membrane.[/caption]

The organs of Corti contain hair cells, which are named for the hair-like stereocilia extending from the cell’s apical surfaces (Figure 7). The stereocilia are an array of microvilli-like structures arranged from tallest to shortest. Protein fibers tether adjacent hairs together within each array, such that the array will bend in response to movements of the basilar membrane. The stereocilia extend up from the hair cells to the overlying tectorial membrane, which is attached medially to the organ of Corti. When the pressure waves from the scala move the basilar membrane, the tectorial membrane slides across the stereocilia. This bends the stereocilia either toward or away from the tallest member of each array. When the stereocilia bend toward the tallest member of their array, tension in the protein tethers opens ion channels in the hair cell membrane. This will depolarize the hair cell membrane, triggering nerve impulses that travel down the afferent nerve fibers attached to the hair cells. When the stereocilia bend toward the shortest member of their array, the tension on the tethers slackens and the ion channels close. When no sound is present, and the stereocilia are standing straight, a small amount of tension still exists on the tethers, keeping the membrane potential of the hair cell slightly depolarized.

The fluid in the scala vestibuli, helicotrema, and scale tympani is perilymph, a fluid similar in composition to cerebrospinal fluid. In contrast, the fluid in the cochlear duct is endolymph, which contains a relatively high concentration of potassium ions (K⁺). The depolarization that occurs when stereocilia bend is largely the result of these potassium ions rushing into the hair cells from the surrounding endolymph.

[caption id="" align="aligncenter" width="500"] Figure 7. Hair Cell. The hair cell is a mechanoreceptor with an array of stereocilia emerging from its apical surface. The stereocilia are tethered together by proteins that open ion channels when the array is bent toward the tallest member of their array, and closed when the array is bent toward the shortest member of their array.[/caption]

As stated above, a given region of the basilar membrane will only move if the incoming sound is at a specific frequency. Because the tectorial membrane only moves where the basilar membrane moves, the hair cells in this region will also only respond to sounds of this specific frequency. Therefore, as the frequency of a sound changes, different hair cells are activated all along the basilar membrane. The cochlea encodes auditory stimuli for frequencies between 20 and 20,000 Hz, which is the range of sound that human ears can detect. The unit of Hertz measures the frequency of sound waves in terms of cycles produced per second. Frequencies as low as 20 Hz are detected by hair cells at the apex, or tip, of the cochlea. Frequencies in the higher ranges of 20 KHz are encoded by hair cells at the base of the cochlea, close to the round and oval windows (Figure 9). Most auditory stimuli contain a mixture of sounds at a variety of frequencies and intensities (represented by the amplitude of the sound wave). The hair cells along the length of the cochlear duct, which are each sensitive to a particular frequency, allow the cochlea to separate auditory stimuli by frequency, just as a prism separates visible light into its component colors.

[caption id="" align="aligncenter" width="500"] Figure 9. Frequency Coding in the Cochlea. The standing sound wave generated in the cochlea by the movement of the oval window deflects the basilar membrane on the basis of the frequency of sound. Therefore, hair cells at the base of the cochlea are activated only by high frequencies, whereas those at the apex of the cochlea are activated only by low frequencies.[/caption]

Disruptions to Hearing

Impairment in the ability to hear can be classified as either conductive deafness or neural deafness. Conductive deafness (or transmission deafness) is caused by any interference with the transmission of sound waves. It can be corrected by using a hearing aid that allows sound waves to be conducted towards the inner ear. Conductive deafness is usually caused by middle ear inflammation (otitis media) or otosclerosis. It may also be caused by too much impacted, hardened wax in the ear canal, or by perforation of the tympanic membrane. Neural deafness (perceptive deafness), on the other hand, is the result of a difficulty perceiving sound. It is usually due to a disease in the organ of Corti or the vestibulocochlear nerve, and cannot be corrected with a hearing aid. Another type of hearing disorder is tinnitus, which refers to a ringing sensation in the ear in the absence of auditory stimuli. It may appear as a precursor to either of the types of deafness described above. Common causes include wax buildup, a perforated tympanic membrane, degeneration of the vestibulocochlear nerve or auditory cortex, inflammation of the middle or inner ear, or certain drugs (e.g. aspirin, streptomycin).

Equilibrium (Balance)

Along with audition, the inner ear is responsible for encoding information about equilibrium, the sense of balance. A similar mechanoreceptor—a hair cell with stereocilia—senses head position, head movement, and whether our bodies are in motion. These cells are located within the vestibule of the inner ear. Head position (statis equilibrium) is sensed by the utricle and saccule, whereas head movement (dynamic equilibrium) is sensed by the semicircular canals. The neural signals generated in the vestibular ganglion are transmitted through the vestibulocochlear nerve to the brain stem and cerebellum.

The utricle and saccule are both largely composed of macula tissue (plural = maculae). The macula is composed of hair cells surrounded by support cells. The stereocilia of the hair cells extend into a viscous gel called the otolithic membrane (Figure 10). On top of the otolithic membrane is a layer of calcium carbonate crystals, called otoliths. The otoliths essentially make the otolithic membrane top-heavy. The otolithic membrane moves separately from the macula in response to head movements. Tilting the head causes the otolithic membrane to slide over the macula in the direction of gravity. The moving otolithic membrane, in turn, bends the sterocilia, causing some hair cells to depolarize as others hyperpolarize. The exact position of the head is interpreted by the brain based on the pattern of hair-cell depolarization.

[caption id="" align="aligncenter" width="520"] Figure 10. Linear Acceleration Coding by Maculae. The maculae are specialized for sensing linear acceleration, such as when gravity acts on the tilting head, or if the head starts moving in a straight line. The difference in inertia between the hair cell stereocilia and the otolithic membrane in which they are embedded leads to a shearing force that causes the stereocilia to bend in the direction of that linear acceleration.[/caption]

The semicircular canals are three ring-like extensions of the vestibule. One is oriented in the horizontal plane, whereas the other two are oriented in the vertical plane. The anterior and posterior vertical canals are oriented at approximately 45 degrees relative to the sagittal plane (Figure 11). The base of each semicircular canal, where it meets with the vestibule, connects to an enlarged region known as the ampulla. The ampulla contains the hair cells that respond to rotational movement, such as turning the head while saying “no.” The stereocilia of these hair cells extend into the cupula, a membrane that attaches to the top of the ampulla. As the head rotates in a plane parallel to the semicircular canal, the fluid lags, deflecting the cupula in the direction opposite to the head movement. The semicircular canals contain several ampullae, with some oriented horizontally and others oriented vertically. By comparing the relative movements of both the horizontal and vertical ampullae, the vestibular system can detect the direction of most head movements within three-dimensional (3-D) space.

[caption id="" align="aligncenter" width="520"] Figure 11. Rotational Coding by Semicircular Canals. Rotational movement of the head is encoded by the hair cells in the base of the semicircular canals. As one of the canals moves in an arc with the head, the internal fluid moves in the opposite direction, causing the cupula and stereocilia to bend. The movement of two canals within a plane results in information about the direction in which the head is moving, and activation of all six canals can give a very precise indication of head movement in three dimensions.[/caption] [caption id="attachment_3002" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of hearing and balance![/caption]

Vision

Vision is the special sense of sight that is based on the transduction of light stimuli received through the eyes. The eyes are located within either orbit in the skull. The bony orbits surround the eyeballs, protecting them and anchoring the soft tissues of the eye (Figure 12). The eyelids, with lashes at their leading edges, help to protect the eye from abrasions by blocking particles that may land on the surface of the eye. The inner surface of each lid is a thin membrane known as the palpebral conjunctiva. The conjunctiva extends over the white areas of the eye (the sclera), connecting the eyelids to the eyeball. Tears are produced by the lacrimal gland, located beneath the lateral edges of the nose. Tears produced by this gland flow through the lacrimal duct to the medial corner of the eye, where the tears flow over the conjunctiva, washing away foreign particles.

[caption id="" align="aligncenter" width="430"] Figure 12. The Eye in the Orbit. The eye is located within the orbit and surrounded by soft tissues that protect and support its function. The orbit is surrounded by cranial bones of the skull.[/caption]

Movement of the eye within the orbit is accomplished by the contraction of six extraocular muscles that originate from the bones of the orbit and insert into the surface of the eyeball (Figure 13). Four of the muscles are arranged at the cardinal points around the eye and are named for those locations. They are the superior rectus, medial rectus, inferior rectus, and lateral rectus. When each of these muscles contract, the eye to moves toward the contracting muscle. For example, when the superior rectus contracts, the eye rotates to look up. The superior oblique originates at the posterior orbit, near the origin of the four rectus muscles. However, the tendon of the oblique muscles threads through a pulley-like piece of cartilage known as the trochlea. The tendon inserts obliquely into the superior surface of the eye. The angle of the tendon through the trochlea means that contraction of the superior oblique rotates the eye medially. The inferior oblique muscle originates from the floor of the orbit and inserts into the inferolateral surface of the eye. When it contracts, it laterally rotates the eye, in opposition to the superior oblique. Rotation of the eye by the two oblique muscles is necessary because the eye is not perfectly aligned on the sagittal plane. When the eye looks up or down, the eye must also rotate slightly to compensate for the superior rectus pulling at approximately a 20-degree angle, rather than straight up. The same is true for the inferior rectus, which is compensated by contraction of the inferior oblique. A seventh muscle in the orbit is the levator palpebrae superioris, which is responsible for elevating and retracting the upper eyelid, a movement that usually occurs in concert with elevation of the eye by the superior rectus (see Figure 12).

The extraocular muscles are innervated by three cranial nerves. The lateral rectus, which causes abduction of the eye, is innervated by the abducens nerve. The superior oblique is innervated by the trochlear nerve. All of the other muscles are innervated by the oculomotor nerve, as is the levator palpebrae superioris. The motor nuclei of these cranial nerves connect to the brain stem, which coordinates eye movements.

[caption id="" align="aligncenter" width="520"] Figure 13. Extraocular Muscles. The extraocular muscles move the eye within the orbit.[/caption]

The eye itself is a hollow sphere composed of three layers of tissue. The outermost layer is the fibrous tunic, which includes the white sclera and clear cornea. The sclera accounts for five sixths of the surface of the eye, most of which is not visible, though humans are unique compared with many other species in having so much of the “white of the eye” visible (Figure 14). The transparent cornea covers the anterior tip of the eye and allows light to enter the eye. The middle layer of the eye is the vascular tunic, which is mostly composed of the choroid, ciliary body, and iris. The choroid is a layer of highly vascularized connective tissue that provides a blood supply to the eyeball. The choroid is posterior to the ciliary body, a muscular structure that is attached to the lens by zonule fibers (suspensory ligaments). These two structures bend the lens, allowing it to focus light on the back of the eye.

Overlaying the ciliary body, and visible in the anterior eye, is the iris—the colored part of the eye. The iris is composed of two smooth muscles - the circular sphincter pupillae and the radial dilator pupillae that open and close the pupil, which is the hole at the center of the eye that allows light to enter. The sphincter pupillae contracts in response to parasympathetic nervous system activation, contracting the pupil, and the dilator pupillae contracts in response to sympathetic nervous system activation, dilating the pupil. The iris generally constricts the pupil in response to bright light and dilates the pupil in response to dim light, to regulate the amount of light reaching the innermost layer of the eye. This innermost layer is the neural tunic, or retina, which contains the nervous tissue responsible for photoreception. The eye is also divided into two cavities: the anterior cavity and the posterior cavity. The anterior cavity is the space between the cornea and lens, including the iris and ciliary body. It is filled with a watery fluid called the aqueous humor. The posterior cavity is the space behind the lens that extends to the posterior side of the interior eyeball, where the retina is located. The posterior cavity is filled with a more viscous fluid called the vitreous humor.

The retina is composed of several layers and contains specialized cells for the initial processing of visual stimuli. The photoreceptors (rods and cones) change their membrane potential when stimulated by light energy. The change in membrane potential alters the amount of neurotransmitter that the photoreceptor cells release onto bipolar cells in the outer synaptic layer. It is the bipolar cell in the retina that connects a photoreceptor to a retinal ganglion cell (RGC) in the inner synaptic layer. There, amacrine cells additionally contribute to retinal processing before an action potential is produced by the RGC. The axons of RGCs, which lie at the innermost layer of the retina, collect at the optic disc and leave the eye as the optic nerve (see Figure 14). Because these axons pass through the retina, there are no photoreceptors at the very back of the eye, where the optic nerve begins. This creates a “blind spot” in the retina, and a corresponding blind spot in our visual field.

[caption id="" align="aligncenter" width="520"] Figure 14. Structure of the Eye. The sphere of the eye can be divided into anterior and posterior chambers. The wall of the eye is composed of three layers: the fibrous tunic, vascular tunic, and neural tunic. Within the neural tunic is the retina, with three layers of cells and two synaptic layers in between. The center of the retina has a small indentation known as the fovea.[/caption]

Note that the photoreceptors in the retina (rods and cones) are located behind the axons, RGCs, bipolar cells, and retinal blood vessels. A significant amount of light is absorbed by these structures before the light reaches the photoreceptor cells. However, at the exact center of the retina is a small area known as the fovea. At the fovea, the retina lacks the supporting cells and blood vessels, and only contains photoreceptors. Therefore, visual acuity, or the sharpness of vision, is greatest at the fovea. This is because the fovea is where the least amount of incoming light is absorbed by other retinal structures (see Figure 14). As one moves in either direction from this central point of the retina, visual acuity drops significantly. In addition, each photoreceptor cell of the fovea is connected to a single RGC. Therefore, this RGC does not have to integrate inputs from multiple photoreceptors, which reduces the accuracy of visual transduction. Toward the edges of the retina, several photoreceptors converge on RGCs (through the bipolar cells) up to a ratio of 50 to 1. The difference in visual acuity between the fovea and peripheral retina is easily evidenced by looking directly at a word in the middle of this paragraph. The visual stimulus in the middle of the field of view falls on the fovea and is in the sharpest focus. Without moving your eyes off that word, notice that words at the beginning or end of the paragraph are not in focus. The images in your peripheral vision are focused by the peripheral retina, and have vague, blurry edges and words that are not as clearly identified. As a result, a large part of the neural function of the eyes is concerned with moving the eyes and head so that important visual stimuli are centered on the fovea. Finally, there is a high concentration of cones (rather than rods) in the fovea, which allow the detection of different colours as described below.

Light falling on the retina causes chemical changes to pigment molecules in the photoreceptors, ultimately leading to a change in the activity of the RGCs. Photoreceptor cells have two parts, the inner segment and the outer segment (Figure 15). The inner segment contains the nucleus and other common organelles of a cell, whereas the outer segment is a specialized region in which photoreception takes place. There are two types of photoreceptors—rods and cones—which differ in the shape of their outer segment. The rod-shaped outer segments of the rod photoreceptor contain a stack of membrane-bound discs that contain the photosensitive pigment rhodopsin. The cone-shaped outer segments of the cone photoreceptor contain their photosensitive pigments in infoldings of the cell membrane. There are three cone photopigments, called opsins, which are each sensitive to a particular wavelength of light. The wavelength of visible light determines its color. The pigments in human eyes are specialized in perceiving three different primary colors: red, green, and blue.

[caption id="" align="aligncenter" width="450"] Figure 15. Photoreceptor. (a) All photoreceptors have inner segments containing the nucleus and other important organelles and outer segments with membrane arrays containing the photosensitive opsin molecules. Rod outer segments are long columnar shapes with stacks of membrane-bound discs that contain the rhodopsin pigment. Cone outer segments are short, tapered shapes with folds of membrane in place of the discs in the rods. (b) Tissue of the retina shows a dense layer of nuclei of the rods and cones. LM × 800. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

At the molecular level, visual stimuli cause changes in the photopigment molecule that lead to changes in membrane potential of the photoreceptor cell. A single unit of light is called a photon, which is described in physics as a packet of energy with properties of both a particle and a wave. The energy of a photon is represented by its wavelength, with each wavelength of visible light corresponding to a particular color. Visible light is electromagnetic radiation with a wavelength between 380 and 720 nm. Wavelengths of electromagnetic radiation longer than 720 nm fall into the infrared range, whereas wavelengths shorter than 380 nm fall into the ultraviolet range. Light with a wavelength of 380 nm is blue whereas light with a wavelength of 720 nm is dark red. All other colors fall between red and blue at various points along the wavelength scale.

Opsin pigments are actually transmembrane proteins that contain a cofactor known as retinal. Retinal is a hydrocarbon molecule related to vitamin A. When a photon hits retinal, the long hydrocarbon chain of the molecule is biochemically altered. Specifically, photons cause some of the double-bonded carbons within the chain to switch from a cis to a trans conformation. This process is called photoisomerization. Before interacting with a photon, retinal’s flexible double-bonded carbons are in the cis conformation. This molecule is referred to as 11-cis-retinal. A photon interacting with the molecule causes the flexible double-bonded carbons to change to the trans- conformation, forming all-trans-retinal, which has a straight hydrocarbon chain (Figure 16).

The shape change of retinal in the photoreceptors initiates visual transduction in the retina. Activation of retinal and the opsin proteins result in activation of a G protein. The G protein changes the membrane potential of the photoreceptor cell, which then releases less neurotransmitter into the outer synaptic layer of the retina. Until the retinal molecule is changed back to the 11-cis-retinal shape, the opsin cannot respond to light energy, which is called bleaching. When a large group of photopigments is bleached, the retina will send information as if opposing visual information is being perceived. After a bright flash of light, afterimages are usually seen in negative. The photoisomerization is reversed by a series of enzymatic changes so that the retinal responds to more light energy.

[caption id="" align="aligncenter" width="520"] Figure 16. Retinal Isomers. The retinal molecule has two isomers, (a) one before a photon interacts with it and (b) one that is altered through photoisomerization.[/caption]

The opsins are sensitive to limited wavelengths of light. Rhodopsin, the photopigment in rods, is most sensitive to light at a wavelength of 498 nm. The three color opsins have peak sensitivities of 564 nm, 534 nm, and 420 nm corresponding roughly to the primary colors of red, green, and blue (Figure 17). The absorbance of rhodopsin in the rods is much more sensitive than in the cone opsins; specifically, rods are sensitive to vision in low light conditions, and cones are sensitive to brighter conditions. In normal sunlight, rhodopsin will be constantly bleached while the cones are active. In a darkened room, there is not enough light to activate cone opsins, and vision is entirely dependent on rods. Rods are so sensitive to light that a single photon can result in an action potential from a rod’s corresponding RGC.

The three types of cone opsins, being sensitive to different wavelengths of light, provide us with color vision. By comparing the activity of the three different cones, the brain can extract color information from visual stimuli. For example, a bright blue light that has a wavelength of approximately 450 nm would activate the “red” cones minimally, the “green” cones marginally, and the “blue” cones predominantly. The relative activation of the three different cones is calculated by the brain, which perceives the color as blue. However, cones cannot react to low-intensity light, and rods do not sense the color of light. Therefore, our low-light vision is—in essence—in grayscale. In other words, in a dark room, everything appears as a shade of gray. If you think that you can see colors in the dark, it is most likely because your brain knows what color something is and is relying on that memory.

[caption id="" align="aligncenter" width="420"] Figure 17. Comparison of Color Sensitivity of Photopigments. Comparing the peak sensitivity and absorbance spectra of the four photopigments suggests that they are most sensitive to particular wavelengths.[/caption]

Focussing Light on the Retina

To see an object in sharp focus and in colour, the light rays from that object must travel to the fovea of the retina. This is largely accomplished through a combination of contraction or relaxation of the appropriate extraocular muscles and accommodation of the lens.

The extraocular muscles allow for greater or lesser convergence of the eyeballs, so both eyeballs can be directed at the same point in space. When looking at a distant object, both eyes are pointed roughly parallel to each other. Since the eyeballs are a fixed distance from each other in the skull, when focussing on a nearby object, the eyes must rotate medially by contraction of the medial rectus muscle to direct both eyes towards the object being viewed. The closer the object, the greater the degree of convergence required. [caption id="attachment_1139" align="alignleft" width="208"] Figure 18. Accommodation of the lens. For distant vision, the lens is flat to reduce refraction to a minimum (top image). If the lens were to bulge as shown in the middle image, it would cause too much refraction, changing the direction of the incoming light rays too much, so they would focus in front of the retina and could not be focussed. For viewing nearby objects, however, the light rays need to be refracted more than rays coming from distant objects; a bulging lens allows focussing on nearby objects (bottom image). Although there is extensive refraction by the cornea, this refraction is constant and so is not shown in these images.[/caption] When light rays pass from one medium (e.g., air) to another (e.g., water), they tend to bend, or "refract". This refraction of light allows light rays entering the eye to be pulled closer together to meet at the fovea. The cornea is responsible for the majority of refraction occurring as light rays enter the eyeball, but the cornea itself is not adjustable so this refraction is constant and cannot be used to focus on objects at different distances. However, additional refraction occurs as the light passes through the lens, and the shape and thickness of the lens can be modified to control the degree of refraction (Figure 18). This change in shape of the lens to produce more or less refraction of incoming light rays is known as accommodation, and is accomplished by contraction or relaxation of the circular ciliary muscle to which the suspensory ligaments are attached. When the ciliary muscle contracts, it allows the suspensory ligaments to loosen and allows the lens to bulge. When the ciliary muscle relaxes, it pulls the suspensory ligaments taut, pulling the lens flat. There are physical limits to how far the lens can flatten or bulge, setting a maximum and minimum amount by which light rays can be refracted to land on the retina. If the retina is further or closer to the lens than normal, the lens may not be able to adjust enough to focus on objects at particular distances. If the retina is too far from the lens, as in myopia, then flattening the lens enough to focus on a distant object becomes impossible, although focussing on near objects is still possible. If the retina is too close to the lens, as in hyperopia, then the lens cannot bulge enough to focus on a near object, although focussing on distant objects is possible. In addition to their role regulating total amount of light striking the retina, the pupillary muscles also participate in allowing focussed vision by limiting the amount of light hitting the edges of the lens specifically. When viewing a distant object, the lens is relatively flat, so there is relatively equivalent changes in light direction at the edges relative to the centre. However, when viewing a nearby object the lens bulges and light entering near the edges could result in a distorted or blurry image as a result of spherical aberration. Constricting the pupil by contracting the sphincter pupillae muscle and relaxing the dilator pupillae muscle covers the edge of the lens with the iris, eliminating this distortion. When viewing a distant object the sphincter pupillae muscle tends to relax and the dilator pupillae contracts, dilating the pupil.

Disorders of the Eye

Myopia and hyperopia (discussed above) both result from the inability of the lens to refract light rays so they focus on the retina. These conditions can be corrected by the use of lenses that refract incoming light in the appropriate direction to compensate. Similarly, if the cornea or lens is not smoothly curved, light rays striking different regions will be refracted differently, preventing proper focussing and resulting in blurry vision as a result of astigmatism, which again can be corrected with the use of corrective lenses or by laser surgery to reshape the affected structure. Visual problems can also result from improper light transmission. If for example the normally-transparent proteins in the lens, called crystallins, clump together then a cataract develops. In such cases, the light cannot be transmitted cleanly through the lens and clouded vision results. Finally, vision problems may also arise from a problem transmitting information about light, rather than necessarily the light itself. The condition called glaucoma arises when the drainage of aqueous humor is blocked, and pressure in the eye builds up. This pressure can compress the retina and optic nerve, initially resulting in a slow reduction in visual ability leading to blurred vision, but ultimately killing the retinal cells and resulting in blindness.

[caption id="attachment_3004" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of vision![/caption]

Sensory Nerves

Once any sensory cell transduces a stimulus into a nerve impulse, that impulse has to travel along axons to reach the CNS. In many of the special senses, the axons leaving the sensory receptors have a topographical arrangement, meaning that the location of the sensory receptor relates to the location of the axon in the nerve. For example, in the retina, axons from RGCs in the fovea are located at the center of the optic nerve, where they are surrounded by axons from the more peripheral RGCs.

Spinal Nerves

Generally, spinal nerves contain afferent axons from sensory receptors in the periphery, such as from the skin, mixed with efferent axons travelling to the muscles or other effector organs. As the spinal nerve nears the spinal cord, it splits into dorsal and ventral roots. The dorsal root contains only the axons of sensory neurons, whereas the ventral roots contain only the axons of the motor neurons. Some of the branches will synapse with local neurons in the dorsal root ganglion, posterior (dorsal) horn, or even the anterior (ventral) horn, at the level of the spinal cord where they enter. Other branches will travel a short distance up or down the spine to interact with neurons at other levels of the spinal cord. A branch may also turn into the posterior (dorsal) column of the white matter to connect with the brain. For the sake of convenience, we will use the terms ventral and dorsal in reference to structures within the spinal cord that are part of these pathways. This will help to underscore the relationships between the different components. Typically, spinal nerve systems that connect to the brain are contralateral, in that the right side of the body is connected to the left side of the brain and the left side of the body to the right side of the brain.

Cranial Nerves

Cranial nerves convey specific sensory information from the head and neck directly to the brain. For sensations below the neck, the right side of the body is connected to the left side of the brain and the left side of the body to the right side of the brain. Whereas spinal information is contralateral, cranial nerve systems are mostly ipsilateral, meaning that a cranial nerve on the right side of the head is connected to the right side of the brain. Some cranial nerves contain only sensory axons, such as the olfactory, optic, and vestibulocochlear nerves. Other cranial nerves contain both sensory and motor axons, including the trigeminal, facial, glossopharyngeal, and vagus nerves (however, the vagus nerve is not associated with the somatic nervous system). The general senses of somatosensation for the face travel through the trigeminal system.

14.2 Central Processing

barkerj1 — Wed, 06 Sep 2017 01:19:31 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the pathway of the nervous impulses from the photoreceptors of the retina through the brain
Explain why the left side of the brain interprets images from the right side of an object

Sensory Pathways

Specific regions of the CNS coordinate different somatic processes using sensory inputs and motor outputs of peripheral nerves. A simple case is a reflex caused by a synapse between a dorsal sensory neuron axon and a motor neuron in the ventral horn. More complex arrangements are possible to integrate peripheral sensory information with higher processes. The important regions of the CNS that play a role in somatic processes can be separated into the spinal cord brain stem, diencephalon, cerebral cortex, and subcortical structures.

Spinal Cord and Brain Stem

A sensory pathway that carries peripheral sensations to the brain is referred to as an ascending pathway, or ascending tract. The various sensory modalities each follow specific pathways through the CNS. Tactile and other somatosensory stimuli activate receptors in the skin, muscles, tendons, and joints throughout the entire body. However, the somatosensory pathways are divided into two separate systems on the basis of the location of the receptor neurons. Somatosensory stimuli from below the neck pass along the sensory pathways of the spinal cord, whereas somatosensory stimuli from the head and neck travel through the cranial nerves—specifically, the trigeminal system.

The dorsal column system (sometimes referred to as the dorsal column–medial lemniscus) and the spinothalamic tract are two major pathways that bring sensory information to the brain (Figure 1). The sensory pathways in each of these systems are composed of three successive neurons.

The dorsal column system begins with the axon of a dorsal root ganglion neuron entering the dorsal root and joining the dorsal column white matter in the spinal cord. As axons of this pathway enter the dorsal column, they take on a positional arrangement so that axons from lower levels of the body position themselves medially, whereas axons from upper levels of the body position themselves laterally. The dorsal column is separated into two component tracts, the fasciculus gracilis that contains axons from the legs and lower body, and the fasciculus cuneatus that contains axons from the upper body and arms.

The axons in the dorsal column terminate in the nuclei of the medulla, where each synapses with the second neuron in their respective pathway. The nucleus gracilis is the target of fibers in the fasciculus gracilis, whereas the nucleus cuneatus is the target of fibers in the fasciculus cuneatus. The second neuron in the system projects from one of the two nuclei and then decussates, or crosses the midline of the medulla. These axons then continue to ascend the brain stem as a bundle called the medial lemniscus. These axons terminate in the thalamus, where each synapses with the third neuron in their respective pathway. The third neuron in the system projects its axons to the postcentral gyrus of the cerebral cortex, where somatosensory stimuli are initially processed and the conscious perception of the stimulus occurs.

The spinothalamic tract also begins with neurons in a dorsal root ganglion. These neurons extend their axons to the dorsal horn, where they synapse with the second neuron in their respective pathway. The name “spinothalamic” comes from this second neuron, which has its cell body in the spinal cord gray matter and connects to the thalamus. Axons from these second neurons then decussate within the spinal cord and ascend to the brain and enter the thalamus, where each synapses with the third neuron in its respective pathway. The neurons in the thalamus then project their axons to the spinothalamic tract, which synapses in the postcentral gyrus of the cerebral cortex.

These two systems are similar in that they both begin with dorsal root ganglion cells, as with most general sensory information. The dorsal column system is primarily responsible for touch sensations and proprioception, whereas the spinothalamic tract pathway is primarily responsible for pain and temperature sensations. Another similarity is that the second neurons in both of these pathways are contralateral, because they project across the midline to the other side of the brain or spinal cord. In the dorsal column system, this decussation takes place in the brain stem; in the spinothalamic pathway, it takes place in the spinal cord at the same spinal cord level at which the information entered. The third neurons in the two pathways are essentially the same. In both, the second neuron synapses in the thalamus, and the thalamic neuron projects to the somatosensory cortex.

[caption id="" align="aligncenter" width="530"] Figure 1. Ascending Sensory Pathways of the Spinal Cord. The dorsal column system and spinothalamic tract are the major ascending pathways that connect the periphery with the brain.[/caption]

The trigeminal pathway carries somatosensory information from the face, head, mouth, and nasal cavity. As with the previously discussed nerve tracts, the sensory pathways of the trigeminal pathway each involve three successive neurons. First, axons from the trigeminal ganglion enter the brain stem at the level of the pons. These axons project to one of three locations. The spinal trigeminal nucleus of the medulla receives information similar to that carried by spinothalamic tract, such as pain and temperature sensations. Other axons go to either the chief sensory nucleus in the pons or the mesencephalic nuclei in the midbrain. These nuclei receive information like that carried by the dorsal column system, such as touch, pressure, vibration, and proprioception. Axons from the second neuron decussate and ascend to the thalamus along the trigeminothalamic tract. In the thalamus, each axon synapses with the third neuron in its respective pathway. Axons from the third neuron then project from the thalamus to the primary somatosensory cortex of the cerebrum.

The sensory pathway for gustation travels along the facial and glossopharyngeal cranial nerves, which synapse with neurons of the solitary nucleus in the brain stem. Axons from the solitary nucleus then project to the ventral posterior nucleus of the thalamus. Finally, axons from the ventral posterior nucleus project to the gustatory cortex of the cerebral cortex, where taste is processed and consciously perceived.

The sensory pathway for audition travels along the vestibulocochlear nerve, which synapses with neurons in the cochlear nuclei of the superior medulla. Within the brain stem, input from either ear is combined to extract location information from the auditory stimuli. Whereas the initial auditory stimuli received at the cochlea strictly represent the frequency—or pitch—of the stimuli, the locations of sounds can be determined by comparing information arriving at both ears.

Sound localization is a feature of central processing in the auditory nuclei of the brain stem. Sound localization is achieved by the brain calculating the interaural time difference and the interaural intensity difference. A sound originating from a specific location will arrive at each ear at different times, unless the sound is directly in front of the listener. If the sound source is slightly to the left of the listener, the sound will arrive at the left ear microseconds before it arrives at the right ear (Figure 2). This time difference is an example of an interaural time difference. Also, the sound will be slightly louder in the left ear than in the right ear because some of the sound waves reaching the opposite ear are blocked by the head. This is an example of an interaural intensity difference.

[caption id="" align="aligncenter" width="290"] Figure 2. Auditory Brain Stem Mechanisms of Sound Localization. Localizing sound in the horizontal plane is achieved by processing in the medullary nuclei of the auditory system. Connections between neurons on either side are able to compare very slight differences in sound stimuli that arrive at either ear and represent interaural time and intensity differences.[/caption]

Auditory processing continues on to a nucleus in the midbrain called the inferior colliculus. Axons from the inferior colliculus project to two locations, the thalamus and the superior colliculus. The medial geniculate nucleus of the thalamus receives the auditory information and then projects that information to the auditory cortex in the temporal lobe of the cerebral cortex. The superior colliculus receives input from the visual and somatosensory systems, as well as the ears, to initiate stimulation of the muscles that turn the head and neck toward the auditory stimulus.

Balance is coordinated through the vestibular system, the nerves of which are composed of axons from the vestibular ganglion that carries information from the utricle, saccule, and semicircular canals. The system contributes to controlling head and neck movements in response to vestibular signals. An important function of the vestibular system is coordinating eye and head movements to maintain visual attention. Most of the axons terminate in the vestibular nuclei of the medulla. Some axons project from the vestibular ganglion directly to the cerebellum, with no intervening synapse in the vestibular nuclei. The cerebellum is primarily responsible for initiating movements on the basis of equilibrium information.

Neurons in the vestibular nuclei project their axons to targets in the brain stem. One target is the reticular formation, which influences respiratory and cardiovascular functions in relation to body movements. A second target of the axons of neurons in the vestibular nuclei is the spinal cord, which initiates the spinal reflexes involved with posture and balance. To assist the visual system, fibers of the vestibular nuclei project to the oculomotor, trochlear, and abducens nuclei to influence signals sent along the cranial nerves. These connections constitute the pathway of the vestibulo-ocular reflex (VOR), which compensates for head and body movement by stabilizing images on the retina (Figure 3). Finally, the vestibular nuclei project to the thalamus to join the proprioceptive pathway of the dorsal column system, allowing conscious perception of equilibrium.

[caption id="" align="aligncenter" width="480"] Figure 3. Vestibulo-ocular Reflex. Connections between the vestibular system and the cranial nerves controlling eye movement keep the eyes centered on a visual stimulus, even though the head is moving. During head movement, the eye muscles move the eyes in the opposite direction as the head movement, keeping the visual stimulus centered in the field of view.[/caption]

The connections of the optic nerve are more complicated than those of other cranial nerves. Instead of the connections being between each eye and the brain, visual information is segregated between the left and right sides of the visual field. In addition, some of the information from one side of the visual field projects to the opposite side of the brain. Within each eye, the axons projecting from the medial side of the retina decussate at the optic chiasm. For example, the axons from the medial retina of the left eye cross over to the right side of the brain at the optic chiasm. However, within each eye, the axons projecting from the lateral side of the retina do not decussate. For example, the axons from the lateral retina of the right eye project back to the right side of the brain. Therefore the left field of view of each eye is processed on the right side of the brain, whereas the right field of view of each eye is processed on the left side of the brain (Figure 4).

[caption id="" align="aligncenter" width="395"] Figure 4. Segregation of Visual Field Information at the Optic Chiasm. Contralateral visual field information from the lateral retina projects to the ipsilateral brain, whereas ipsilateral visual field information has to decussate at the optic chiasm to reach the opposite side of the brain.[/caption]

A unique clinical presentation that relates to this anatomic arrangement is the loss of lateral peripheral vision, known as bilateral hemianopia. This is different from “tunnel vision” because the superior and inferior peripheral fields are not lost. Visual field deficits can be disturbing for a patient, but in this case, the cause is not within the visual system itself. A growth of the pituitary gland presses against the optic chiasm and interferes with signal transmission. However, the axons projecting to the same side of the brain are unaffected. Therefore, the patient loses the outermost areas of their field of vision and cannot see objects to their right and left.

Extending from the optic chiasm, the axons of the visual system are referred to as the optic tract instead of the optic nerve. The optic tract has three major targets, two in the diencephalon and one in the midbrain. The connection between the eyes and diencephalon is demonstrated during development, in which the neural tissue of the retina differentiates from that of the diencephalon by the growth of the secondary vesicles. The connections of the retina into the CNS are a holdover from this developmental association. The majority of the connections of the optic tract are to the thalamus—specifically, the lateral geniculate nucleus. Axons from this nucleus then project to the visual cortex of the cerebrum, located in the occipital lobe. Another target of the optic tract is the superior colliculus.

In addition, a very small number of RGC axons project from the optic chiasm to the suprachiasmatic nucleus of the hypothalamus. These RGCs are photosensitive, in that they respond to the presence or absence of light. Unlike the photoreceptors, however, these photosensitive RGCs cannot be used to perceive images. By simply responding to the absence or presence of light, these RGCs can send information about day length. The perceived proportion of sunlight to darkness establishes the circadian rhythm of our bodies, allowing certain physiological events to occur at approximately the same time every day.

Diencephalon

The diencephalon is beneath the cerebrum and includes the thalamus and hypothalamus. In the somatic nervous system, the thalamus is an important relay for communication between the cerebrum and the rest of the nervous system. The hypothalamus has both somatic and autonomic functions. In addition, the hypothalamus communicates with the limbic system, which controls emotions and memory functions.

Sensory input to the thalamus comes from most of the special senses and ascending somatosensory tracts. Each sensory system is relayed through a particular nucleus in the thalamus. The thalamus is a required transfer point for most sensory tracts that reach the cerebral cortex, where conscious sensory perception begins. The one exception to this rule is the olfactory system. The olfactory tract axons from the olfactory bulb project directly to the cerebral cortex, along with the limbic system and hypothalamus.

The thalamus is a collection of several nuclei that can be categorized into three anatomical groups. White matter running through the thalamus defines the three major regions of the thalamus, which are an anterior nucleus, a medial nucleus, and a lateral group of nuclei. The anterior nucleus serves as a relay between the hypothalamus and the emotion and memory-producing limbic system. The medial nuclei serve as a relay for information from the limbic system and basal ganglia to the cerebral cortex. This allows memory creation during learning, but also determines alertness. The special and somatic senses connect to the lateral nuclei, where their information is relayed to the appropriate sensory cortex of the cerebrum.

Cortical Processing

As described earlier, many of the sensory axons are positioned in the same way as their corresponding receptor cells in the body. This allows identification of the position of a stimulus on the basis of which receptor cells are sending information. The cerebral cortex also maintains this sensory topography in the particular areas of the cortex that correspond to the position of the receptor cells. The somatosensory cortex provides an example in which, in essence, the locations of the somatosensory receptors in the body are mapped onto the somatosensory cortex. This mapping is often depicted using a sensory homunculus (Figure 5).

The term homunculus comes from the Latin word for “little man” and refers to a map of the human body that is laid across a portion of the cerebral cortex. In the somatosensory cortex, the external genitals, feet, and lower legs are represented on the medial face of the gyrus within the longitudinal fissure. As the gyrus curves out of the fissure and along the surface of the parietal lobe, the body map continues through the thighs, hips, trunk, shoulders, arms, and hands. The head and face are just lateral to the fingers as the gyrus approaches the lateral sulcus. The representation of the body in this topographical map is medial to lateral from the lower to upper body. It is a continuation of the topographical arrangement seen in the dorsal column system, where axons from the lower body are carried in the fasciculus gracilis, whereas axons from the upper body are carried in the fasciculus cuneatus. As the dorsal column system continues into the medial lemniscus, these relationships are maintained. Also, the head and neck axons running from the trigeminal nuclei to the thalamus run adjacent to the upper body fibers. The connections through the thalamus maintain topography such that the anatomic information is preserved. Note that this correspondence does not result in a perfectly miniature scale version of the body, but rather exaggerates the more sensitive areas of the body, such as the fingers and lower face. Less sensitive areas of the body, such as the shoulders and back, are mapped to smaller areas on the cortex.

[caption id="" align="aligncenter" width="380"] Figure 5. The Sensory Homunculus. A cartoon representation of the sensory homunculus arranged adjacent to the cortical region in which the processing takes place.[/caption]

Likewise, the topographic relationship between the retina and the visual cortex is maintained throughout the visual pathway. The visual field is projected onto the two retinae, as described above, with sorting at the optic chiasm. The right peripheral visual field falls on the medial portion of the right retina and the lateral portion of the left retina. The right medial retina then projects across the midline through the optic chiasm. This results in the right visual field being processed in the left visual cortex. Likewise, the left visual field is processed in the right visual cortex (see Figure 4). Though the chiasm is helping to sort right and left visual information, superior and inferior visual information is maintained topographically in the visual pathway. Light from the superior visual field falls on the inferior retina, and light from the inferior visual field falls on the superior retina. This topography is maintained such that the superior region of the visual cortex processes the inferior visual field and vice versa. Therefore, the visual field information is inverted and reversed as it enters the visual cortex—up is down, and left is right. However, the cortex processes the visual information such that the final conscious perception of the visual field is correct. The topographic relationship is evident in that information from the foveal region of the retina is processed in the center of the primary visual cortex. Information from the peripheral regions of the retina are correspondingly processed toward the edges of the visual cortex. Similar to the exaggerations in the sensory homunculus of the somatosensory cortex, the foveal-processing area of the visual cortex is disproportionately larger than the areas processing peripheral vision.

In an experiment performed in the 1960s, subjects wore prism glasses so that the visual field was inverted before reaching the eye. On the first day of the experiment, subjects would duck when walking up to a table, thinking it was suspended from the ceiling. However, after a few days of acclimation, the subjects behaved as if everything were represented correctly. Therefore, the visual cortex is somewhat flexible in adapting to the information it receives from our eyes (Figure 6).

[caption id="" align="aligncenter" width="380"] Figure 6. Topographic Mapping of the Retina onto the Visual Cortex. The visual field projects onto the retina through the lenses and falls on the retinae as an inverted, reversed image. The topography of this image is maintained as the visual information travels through the visual pathway to the cortex.[/caption]

The cortex has been described as having specific regions that are responsible for processing specific information; there is the visual cortex, somatosensory cortex, gustatory cortex, etc. However, our experience of these senses is not divided. Instead, we experience what can be referred to as a seamless percept. Our perceptions of the various sensory modalities—though distinct in their content—are integrated by the brain so that we experience the world as a continuous whole.

In the cerebral cortex, sensory processing begins at the primary sensory cortex, then proceeds to an association area, and finally, into a multimodal integration area. For example, the visual pathway projects from the retinae through the thalamus to the primary visual cortex in the occipital lobe. This area is primarily in the medial wall within the longitudinal fissure. Here, visual stimuli begin to be recognized as basic shapes. Edges of objects are recognized and built into more complex shapes. Also, inputs from both eyes are compared to extract depth information. Because of the overlapping field of view between the two eyes, the brain can begin to estimate the distance of stimuli based on binocular depth cues.

[caption id="" align="aligncenter" width="120"] Watch this video to learn more about how the brain perceives 3-D motion.[/caption]

Depth Perception, 3-D Movies, and Optical Illusions The visual field is projected onto the retinal surface, where photoreceptors transduce light energy into neural signals for the brain to interpret. The retina is a two-dimensional surface, so it does not encode three-dimensional information. However, we can perceive depth. How is that accomplished?

Two ways in which we can extract depth information from the two-dimensional retinal signal are based on monocular cues and binocular cues, respectively. Monocular depth cues are those that are the result of information within the two-dimensional visual field. One object that overlaps another object has to be in front. Relative size differences are also a cue. For example, if a basketball appears larger than the basket, then the basket must be further away. On the basis of experience, we can estimate how far away the basket is. Binocular depth cues compare information represented in the two retinae because they do not see the visual field exactly the same.

The centers of the two eyes are separated by a small distance, which is approximately 6 to 6.5 cm in most people. Because of this offset, visual stimuli do not fall on exactly the same spot on both retinae unless we are fixated directly on them and they fall on the fovea of each retina. All other objects in the visual field, either closer or farther away than the fixated object, will fall on different spots on the retina. When vision is fixed on an object in space, closer objects will fall on the lateral retina of each eye, and more distant objects will fall on the medial retina of either eye (Figure 7). This is easily observed by holding a finger up in front of your face as you look at a more distant object. You will see two images of your finger that represent the two disparate images that are falling on either retina.

These depth cues, both monocular and binocular, can be exploited to make the brain think there are three dimensions in two-dimensional information. This is the basis of 3-D movies. The projected image on the screen is two dimensional, but it has disparate information embedded in it. The 3-D glasses that are available at the theater filter the information so that only one eye sees one version of what is on the screen, and the other eye sees the other version. If you take the glasses off, the image on the screen will have varying amounts of blur because both eyes are seeing both layers of information, and the third dimension will not be evident. Some optical illusions can take advantage of depth cues as well, though those are more often using monocular cues to fool the brain into seeing different parts of the scene as being at different depths.

[caption id="" align="aligncenter" width="380"] Figure 7. Retinal Disparity. Because of the interocular distance, which results in objects of different distances falling on different spots of the two retinae, the brain can extract depth perception from the two-dimensional information of the visual field.[/caption]

There are two main regions that surround the primary cortex that are usually referred to as areas V2 and V3 (the primary visual cortex is area V1). These surrounding areas are the visual association cortex. The visual association regions develop more complex visual perceptions by adding color and motion information. The information processed in these areas is then sent to regions of the temporal and parietal lobes. Visual processing has two separate streams of processing: one into the temporal lobe and one into the parietal lobe. These are the ventral and dorsal streams, respectively (Figure 8). The ventral stream identifies visual stimuli and their significance. Because the ventral stream uses temporal lobe structures, it begins to interact with the non-visual cortex and may be important in visual stimuli becoming part of memories. The dorsal stream locates objects in space and helps in guiding movements of the body in response to visual inputs. The dorsal stream enters the parietal lobe, where it interacts with somatosensory cortical areas that are important for our perception of the body and its movements. The dorsal stream can then influence frontal lobe activity where motor functions originate.

[caption id="" align="aligncenter" width="475"] Figure 8. Ventral and Dorsal Visual Streams. From the primary visual cortex in the occipital lobe, visual processing continues in two streams—one into the temporal lobe and one into the parietal lobe.[/caption]

14.3 Motor Responses

barkerj1 — Wed, 06 Sep 2017 01:19:32 +0000

Learning Objectives

By the end of this section, you will be able to:

Provide several examples of reflex arcs

The defining characteristic of the somatic nervous system is that it controls skeletal muscles. Somatic senses inform the nervous system about the external environment, but the response to that is through voluntary muscle movement. The term “voluntary” suggests that there is a conscious decision to make a movement. However, some aspects of the somatic system use voluntary muscles without conscious control. One example is the ability of our breathing to switch to unconscious control while we are focused on another task. However, the muscles that are responsible for the basic process of breathing are also utilized for speech, which is entirely voluntary.

Cortical Responses

Let’s start with sensory stimuli that have been registered through receptor cells and the information relayed to the CNS along ascending pathways. In the cerebral cortex, the initial processing of sensory perception progresses to associative processing and then integration in multimodal areas of cortex. These levels of processing can lead to the incorporation of sensory perceptions into memory, but more importantly, they lead to a response. The completion of cortical processing through the primary, associative, and integrative sensory areas initiates a similar progression of motor processing, usually in different cortical areas.

Whereas the sensory cortical areas are located in the occipital, temporal, and parietal lobes, motor functions are largely controlled by the frontal lobe. The most anterior regions of the frontal lobe—the prefrontal areas—are important for executive functions, which are those cognitive functions that lead to goal-directed behaviors. These higher cognitive processes include working memory, which has been called a “mental scratch pad,” that can help organize and represent information that is not in the immediate environment. The prefrontal lobe is responsible for aspects of attention, such as inhibiting distracting thoughts and actions so that a person can focus on a goal and direct behavior toward achieving that goal.

The functions of the prefrontal cortex are integral to the personality of an individual, because it is largely responsible for what a person intends to do and how they accomplish those plans. A famous case of damage to the prefrontal cortex is that of Phineas Gage, dating back to 1848. He was a railroad worker who had a metal spike impale his prefrontal cortex (Figure 1). He survived the accident, but according to second-hand accounts, his personality changed drastically. Friends described him as no longer acting like himself. Whereas he was a hardworking, amiable man before the accident, he turned into an irritable, temperamental, and lazy man after the accident. Many of the accounts of his change may have been inflated in the retelling, and some behavior was likely attributable to alcohol used as a pain medication. However, the accounts suggest that some aspects of his personality did change. Also, there is new evidence that though his life changed dramatically, he was able to become a functioning stagecoach driver, suggesting that the brain has the ability to recover even from major trauma such as this.

Phineas Gage

The victim of an accident while working on a railroad in 1848, Phineas Gage had a large iron rod impaled through the prefrontal cortex of his frontal lobe. After the accident, his personality appeared to change, but he eventually learned to cope with the trauma and lived as a coach driver even after such a traumatic event. (credit b: John M. Harlow, MD)

[caption id="" align="aligncenter" width="300"] Figure 1. Phineas Gage. The victim of an accident while working on a railroad in 1848, Phineas Gage had a large iron rod impaled through the prefrontal cortex of his frontal lobe. After the accident, his personality appeared to change, but he eventually learned to cope with the trauma and lived as a coach driver even after such a traumatic event. (credit b: John M. Harlow, MD)[/caption]

Secondary Motor Cortices

In generating motor responses, the executive functions of the prefrontal cortex will need to initiate actual movements. One way to define the prefrontal area is any region of the frontal lobe that does not elicit movement when electrically stimulated. These are primarily in the anterior part of the frontal lobe. The regions of the frontal lobe that remain are the regions of the cortex that produce movement. The prefrontal areas project into the secondary motor cortices, which include the premotor cortex and the supplemental motor area.

Two important regions that assist in planning and coordinating movements are located adjacent to the primary motor cortex. The premotor cortex is more lateral, whereas the supplemental motor area is more medial and superior. The premotor area aids in controlling movements of the core muscles to maintain posture during movement, whereas the supplemental motor area is hypothesized to be responsible for planning and coordinating movement. The supplemental motor area also manages sequential movements that are based on prior experience (that is, learned movements). Neurons in these areas are most active leading up to the initiation of movement. For example, these areas might prepare the body for the movements necessary to drive a car in anticipation of a traffic light changing.

Adjacent to these two regions are two specialized motor planning centers. The frontal eye fields are responsible for moving the eyes in response to visual stimuli. There are direct connections between the frontal eye fields and the superior colliculus. Also, anterior to the premotor cortex and primary motor cortex is Broca’s area. This area is responsible for controlling movements of the structures of speech production. The area is named after a French surgeon and anatomist who studied patients who could not produce speech. They did not have impairments to understanding speech, only to producing speech sounds, suggesting a damaged or underdeveloped Broca’s area.

Primary Motor Cortex

The primary motor cortex is located in the precentral gyrus of the frontal lobe. A neurosurgeon, Walter Penfield, described much of the basic understanding of the primary motor cortex by electrically stimulating the surface of the cerebrum. Penfield would probe the surface of the cortex while the patient was only under local anesthesia so that he could observe responses to the stimulation. This led to the belief that the precentral gyrus directly stimulated muscle movement. We now know that the primary motor cortex receives input from several areas that aid in planning movement, and its principle output stimulates spinal cord neurons to stimulate skeletal muscle contraction.

The primary motor cortex is arranged in a similar fashion to the primary somatosensory cortex, in that it has a topographical map of the body, creating a motor homunculus (see Chapter 14.2 Figure 5). The neurons responsible for musculature in the feet and lower legs are in the medial wall of the precentral gyrus, with the thighs, trunk, and shoulder at the crest of the longitudinal fissure. The hand and face are in the lateral face of the gyrus. Also, the relative space allotted for the different regions is exaggerated in muscles that have greater enervation. The greatest amount of cortical space is given to muscles that perform fine, agile movements, such as the muscles of the fingers and the lower face. The “power muscles” that perform coarser movements, such as the buttock and back muscles, occupy much less space on the motor cortex.

Descending Pathways

The motor output from the cortex descends into the brain stem and to the spinal cord to control the musculature through motor neurons. Neurons located in the primary motor cortex, named Betz cells, are large cortical neurons that synapse with lower motor neurons in the spinal cord or the brain stem. The two descending pathways travelled by the axons of Betz cells are the corticospinal tract and the corticobulbar tract. Both tracts are named for their origin in the cortex and their targets—either the spinal cord or the brain stem (the term “bulbar” refers to the brain stem as the bulb, or enlargement, at the top of the spinal cord).

These two descending pathways are responsible for the conscious or voluntary movements of skeletal muscles. Any motor command from the primary motor cortex is sent down the axons of the Betz cells to activate upper motor neurons in either the cranial motor nuclei or in the ventral horn of the spinal cord. The axons of the corticobulbar tract are ipsilateral, meaning they project from the cortex to the motor nucleus on the same side of the nervous system. Conversely, the axons of the corticospinal tract are largely contralateral, meaning that they cross the midline of the brain stem or spinal cord and synapse on the opposite side of the body. Therefore, the right motor cortex of the cerebrum controls muscles on the left side of the body, and vice versa.

The corticospinal tract descends from the cortex through the deep white matter of the cerebrum. It then passes between the caudate nucleus and putamen of the basal nuclei as a bundle called the internal capsule. The tract then passes through the midbrain as the cerebral peduncles, after which it burrows through the pons. Upon entering the medulla, the tracts make up the large white matter tract referred to as the pyramids (Figure 2). The defining landmark of the medullary-spinal border is the pyramidal decussation, which is where most of the fibers in the corticospinal tract cross over to the opposite side of the brain. At this point, the tract separates into two parts, which have control over different domains of the musculature.

[caption id="" align="aligncenter" width="325"] Figure 2. Corticospinal Tract. The major descending tract that controls skeletal muscle movements is the corticospinal tract. It is composed of two neurons, the upper motor neuron and the lower motor neuron. The upper motor neuron has its cell body in the primary motor cortex of the frontal lobe and synapses on the lower motor neuron, which is in the ventral horn of the spinal cord and projects to the skeletal muscle in the periphery.[/caption]

Appendicular Control

The lateral corticospinal tract is composed of the fibers that cross the midline at the pyramidal decussation (see Figure 2). The axons cross over from the anterior position of the pyramids in the medulla to the lateral column of the spinal cord. These axons are responsible for controlling appendicular muscles.

This influence over the appendicular muscles means that the lateral corticospinal tract is responsible for moving the muscles of the arms and legs. The ventral horn in both the lower cervical spinal cord and the lumbar spinal cord both have wider ventral horns, representing the greater number of muscles controlled by these motor neurons. The cervical enlargement is particularly large because there is greater control over the fine musculature of the upper limbs, particularly of the fingers. The lumbar enlargement is not as significant in appearance because there is less fine motor control of the lower limbs.

Axial Control

The anterior corticospinal tract is responsible for controlling the muscles of the body trunk (see Figure 2). These axons do not decussate in the medulla. Instead, they remain in an anterior position as they descend the brain stem and enter the spinal cord. These axons then travel to the spinal cord level at which they synapse with a lower motor neuron. Upon reaching the appropriate level, the axons decussate, entering the ventral horn on the opposite side of the spinal cord from which they entered. In the ventral horn, these axons synapse with their corresponding lower motor neurons. The lower motor neurons are located in the medial regions of the ventral horn, because they control the axial muscles of the trunk.

Because movements of the body trunk involve both sides of the body, the anterior corticospinal tract is not entirely contralateral. Some collateral branches of the tract will project into the ipsilateral ventral horn to control synergistic muscles on that side of the body, or to inhibit antagonistic muscles through interneurons within the ventral horn. Through the influence of both sides of the body, the anterior corticospinal tract can coordinate postural muscles in broad movements of the body. These coordinating axons in the anterior corticospinal tract are often considered bilateral, as they are both ipsilateral and contralateral.

Extrapyramidal Controls

Other descending connections between the brain and the spinal cord are called the extrapyramidal system. The name comes from the fact that this system is outside the corticospinal pathway, which includes the pyramids in the medulla. A few pathways originating from the brain stem contribute to this system.

The tectospinal tract projects from the midbrain to the spinal cord and is important for postural movements that are driven by the superior colliculus. The name of the tract comes from an alternate name for the superior colliculus, which is the tectum. The reticulospinal tract connects the reticular system, a diffuse region of gray matter in the brain stem, with the spinal cord. This tract influences trunk and proximal limb muscles related to posture and locomotion. The reticulospinal tract also contributes to muscle tone and influences autonomic functions. The vestibulospinal tract connects the brain stem nuclei of the vestibular system with the spinal cord. This allows posture, movement, and balance to be modulated on the basis of equilibrium information provided by the vestibular system.

The pathways of the extrapyramidal system are influenced by subcortical structures. For example, connections between the secondary motor cortices and the extrapyramidal system modulate spine and cranium movements. The basal nuclei, which are important for regulating movement initiated by the CNS, influence the extrapyramidal system as well as its thalamic feedback to the motor cortex.

The conscious movement of our muscles is more complicated than simply sending a single command from the precentral gyrus down to the proper motor neurons. During the movement of any body part, our muscles relay information back to the brain, and the brain is constantly sending “revised” instructions back to the muscles. The cerebellum is important in contributing to the motor system because it compares cerebral motor commands with proprioceptive feedback. The corticospinal fibers that project to the ventral horn of the spinal cord have branches that also synapse in the pons, which project to the cerebellum. Also, the proprioceptive sensations of the dorsal column system have a collateral projection to the medulla that projects to the cerebellum. These two streams of information are compared in the cerebellar cortex. Conflicts between the motor commands sent by the cerebrum and body position information provided by the proprioceptors cause the cerebellum to stimulate the red nucleus of the midbrain. The red nucleus then sends corrective commands to the spinal cord along the rubrospinal tract. The name of this tract comes from the word for red that is seen in the English word “ruby.”

A good example of how the cerebellum corrects cerebral motor commands can be illustrated by walking in water. An original motor command from the cerebrum to walk will result in a highly coordinated set of learned movements. However, in water, the body cannot actually perform a typical walking movement as instructed. The cerebellum can alter the motor command, stimulating the leg muscles to take larger steps to overcome the water resistance. The cerebellum can make the necessary changes through the rubrospinal tract. Modulating the basic command to walk also relies on spinal reflexes, but the cerebellum is responsible for calculating the appropriate response. When the cerebellum does not work properly, coordination and balance are severely affected. The most dramatic example of this is during the overconsumption of alcohol. Alcohol inhibits the ability of the cerebellum to interpret proprioceptive feedback, making it more difficult to coordinate body movements, such as walking a straight line, or guide the movement of the hand to touch the tip of the nose.

Ventral Horn Output

The somatic nervous system provides output strictly to skeletal muscles. The lower motor neurons, which are responsible for the contraction of these muscles, are found in the ventral horn of the spinal cord. These large, multipolar neurons have a corona of dendrites surrounding the cell body and an axon that extends out of the ventral horn. This axon travels through the ventral nerve root to join the emerging spinal nerve. The axon is relatively long because it needs to reach muscles in the periphery of the body. The diameters of cell bodies may be on the order of hundreds of micrometers to support the long axon; some axons are a meter in length, such as the lumbar motor neurons that innervate muscles in the first digits of the feet.

The axons will also branch to innervate multiple muscle fibers. Together, the motor neuron and all the muscle fibers that it controls make up a motor unit. Motor units vary in size. Some may contain up to 1000 muscle fibers, such as in the quadriceps, or they may only have 10 fibers, such as in an extraocular muscle. The number of muscle fibers that are part of a motor unit corresponds to the precision of control of that muscle. Also, muscles that have finer motor control have more motor units connecting to them, and this requires a larger topographical field in the primary motor cortex.

Motor neuron axons connect to muscle fibers at a neuromuscular junction. This is a specialized synaptic structure at which multiple axon terminals synapse with the muscle fiber sarcolemma. The synaptic end bulbs of the motor neurons secrete acetylcholine, which binds to receptors on the sarcolemma. The binding of acetylcholine opens ligand-gated ion channels, increasing the movement of cations across the sarcolemma. This depolarizes the sarcolemma, initiating muscle contraction. Whereas other synapses result in graded potentials that must reach a threshold in the postsynaptic target, activity at the neuromuscular junction reliably leads to muscle fiber contraction with every nerve impulse received from a motor neuron. However, the strength of contraction and the number of fibers that contract can be affected by the frequency of the motor neuron impulses.

Reflexes

This chapter began by introducing reflexes as an example of the basic elements of the somatic nervous system. Simple somatic reflexes do not include the higher centers discussed for conscious or voluntary aspects of movement. Reflexes can be spinal or cranial, depending on the nerves and central components that are involved. The example described at the beginning of the chapter involved heat and pain sensations from a hot stove causing withdrawal of the arm through a connection in the spinal cord that leads to contraction of the biceps brachii. The description of this withdrawal reflex was simplified, for the sake of the introduction, to emphasize the parts of the somatic nervous system. But to consider reflexes fully, more attention needs to be given to this example.

As you withdraw your hand from the stove, you do not want to slow that reflex down. As the biceps brachii contracts, the antagonistic triceps brachii needs to relax. Because the neuromuscular junction is strictly excitatory, the biceps will contract when the motor nerve is active. Skeletal muscles do not actively relax. Instead the motor neuron needs to “quiet down,” or be inhibited. In the hot-stove withdrawal reflex, this occurs through an interneuron in the spinal cord. The interneuron’s cell body is located in the dorsal horn of the spinal cord. The interneuron receives a synapse from the axon of the sensory neuron that detects that the hand is being burned. In response to this stimulation from the sensory neuron, the interneuron then inhibits the motor neuron that controls the triceps brachii. This is done by releasing a neurotransmitter or other signal that hyperpolarizes the motor neuron connected to the triceps brachii, making it less likely to initiate an action potential. With this motor neuron being inhibited, the triceps brachii relaxes. Without the antagonistic contraction, withdrawal from the hot stove is faster and keeps further tissue damage from occurring.

Another example of a withdrawal reflex occurs when you step on a painful stimulus, like a tack or a sharp rock. The nociceptors that are activated by the painful stimulus activate the motor neurons responsible for contraction of the tibialis anterior muscle. This causes dorsiflexion of the foot. An inhibitory interneuron, activated by a collateral branch of the nociceptor fiber, will inhibit the motor neurons of the gastrocnemius and soleus muscles to cancel plantar flexion. An important difference in this reflex is that plantar flexion is most likely in progress as the foot is pressing down onto the tack. Contraction of the tibialis anterior is not the most important aspect of the reflex, as continuation of plantar flexion will result in further damage from stepping onto the tack.

Another type of reflex is a stretch reflex. In this reflex, when a skeletal muscle is stretched, a muscle spindle receptor is activated. The axon from this receptor structure will cause direct contraction of the muscle. A collateral of the muscle spindle fiber will also inhibit the motor neuron of the antagonist muscles. The reflex helps to maintain muscles at a constant length. A common example of this reflex is the knee jerk that is elicited by a rubber hammer struck against the patellar ligament in a physical exam.

A specialized reflex to protect the surface of the eye is the corneal reflex, or the eye blink reflex. When the cornea is stimulated by a tactile stimulus, or even by bright light in a related reflex, blinking is initiated. The sensory component travels through the trigeminal nerve, which carries somatosensory information from the face, or through the optic nerve, if the stimulus is bright light. The motor response travels through the facial nerve and innervates the orbicularis oculi on the same side. This reflex is commonly tested during a physical exam using an air puff or a gentle touch of a cotton-tipped applicator.

[caption id="attachment_3007" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about reflexes and the peripheral nervous system![/caption]

15.1 Divisions of the Autonomic Nervous System

barkerj1 — Wed, 06 Sep 2017 01:19:32 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the function of the autonomic nervous system
Compare the specific functions of the parasympathetic and sympathetic divisions of the autonomic nervous system

The nervous system can be divided into two functional parts: the somatic nervous system and the autonomic nervous system. The major differences between the two systems are evident in the responses that each produces. The somatic nervous system causes contraction of skeletal muscles. The autonomic nervous system controls cardiac and smooth muscle, as well as glandular tissue. The somatic nervous system is associated with voluntary responses (though many can happen without conscious awareness, like breathing), and the autonomic nervous system is associated with involuntary responses, such as those related to homeostasis.

The autonomic nervous system regulates many of the internal organs through a balance of two aspects, or divisions. In addition to the endocrine system, the autonomic nervous system is instrumental in homeostatic mechanisms in the body. The two divisions of the autonomic nervous system are the sympathetic division and the parasympathetic division. The sympathetic system is associated with the fight-or-flight response, and parasympathetic activity is referred to by the epithet of rest and digest. Homeostasis is the balance between the two systems. At each target effector, dual innervation determines activity. For example, the heart receives connections from both the sympathetic and parasympathetic divisions. One causes heart rate to increase, whereas the other causes heart rate to decrease.

Sympathetic Division of the Autonomic Nervous System

To respond to a threat—to fight or to run away—the sympathetic system causes divergent effects as many different effector organs are activated together for a common purpose. More oxygen needs to be inhaled and delivered to skeletal muscle. The respiratory, cardiovascular, and musculoskeletal systems are all activated together. Additionally, sweating keeps the excess heat that comes from muscle contraction from causing the body to overheat. The digestive system shuts down so that blood is not absorbing nutrients when it should be delivering oxygen to skeletal muscles. To coordinate all these responses, the connections in the sympathetic system diverge from a limited region of the central nervous system (CNS) to a wide array of ganglia that project to the many effector organs simultaneously. The complex set of structures that compose the output of the sympathetic system make it possible for these disparate effectors to come together in a coordinated, systemic change.

The sympathetic division of the autonomic nervous system influences the various organ systems of the body through connections emerging from the thoracic and upper lumbar spinal cord. It is referred to as the thoracolumbar system to reflect this anatomical basis. A central neuron in the lateral horn of any of these spinal regions projects to ganglia adjacent to the vertebral column through the ventral spinal roots. The majority of ganglia of the sympathetic system belong to a network of sympathetic chain ganglia that runs alongside the vertebral column. The ganglia appear as a series of clusters of neurons linked by axonal bridges. There are typically 23 ganglia in the chain on either side of the spinal column. Three correspond to the cervical region, 12 are in the thoracic region, four are in the lumbar region, and four correspond to the sacral region. The cervical and sacral levels are not connected to the spinal cord directly through the spinal roots, but through ascending or descending connections through the bridges within the chain.

A diagram that shows the connections of the sympathetic system is somewhat like a circuit diagram that shows the electrical connections between different receptacles and devices. In Figure 1, the “circuits” of the sympathetic system are intentionally simplified.

[caption id="" align="aligncenter" width="520"] Figure 1. Connections of Sympathetic Division of the Autonomic Nervous System. Neurons from the lateral horn of the spinal cord (preganglionic nerve fibers - solid lines)) project to the chain ganglia on either side of the vertebral column or to collateral (prevertebral) ganglia that are anterior to the vertebral column in the abdominal cavity. Axons from these ganglionic neurons (postganglionic nerve fibers - dotted lines) then project to target effectors throughout the body.[/caption]

To continue with the analogy of the circuit diagram, there are three different types of “junctions” that operate within the sympathetic system (Figure 2). The first type is most direct: the sympathetic nerve projects to the chain ganglion at the same level as the target effector (the organ, tissue, or gland to be innervated). An example of this type is spinal nerve T1 that synapses with the T1 chain ganglion to innervate the trachea. The fibers of this branch are called white rami communicantes (singular = ramus communicans); they are myelinated and therefore referred to as white (see Figure 2a). The axon from the central neuron (the preganglionic fiber shown as a solid line) synapses with the ganglionic neuron (with the postganglionic fiber shown as a dashed line). This neuron then projects to a target effector—in this case, the trachea—via gray rami communicantes, which are unmyelinated axons.

In some cases, the target effectors are located superior or inferior to the spinal segment at which the preganglionic fiber emerges. With respect to the “wiring” involved, the synapse with the ganglionic neuron occurs at chain ganglia superior or inferior to the location of the central neuron. An example of this is spinal nerve T1 that innervates the eye. The spinal nerve tracks up through the chain until it reaches the superior cervical ganglion, where it synapses with the postganglionic neuron (see Figure 2b). The cervical ganglia are referred to as paravertebral ganglia, given their location adjacent to prevertebral ganglia in the sympathetic chain.

Not all axons from the central neurons terminate in the chain ganglia. Additional branches from the ventral nerve root continue through the chain and on to one of the collateral ganglia as the greater splanchnic nerve or lesser splanchnic nerve. For example, the greater splanchnic nerve at the level of T5 synapses with a collateral ganglion outside the chain before making the connection to the postganglionic nerves that innervate the stomach (see Figure 2c).

Collateral ganglia, also called prevertebral ganglia, are situated anterior to the vertebral column and receive inputs from splanchnic nerves as well as central sympathetic neurons. They are associated with controlling organs in the abdominal cavity, and are also considered part of the enteric nervous system. The three collateral ganglia are the celiac ganglion, the superior mesenteric ganglion, and the inferior mesenteric ganglion (see Figure 1). The word celiac is derived from the Latin word “coelom,” which refers to a body cavity (in this case, the abdominal cavity), and the word mesenteric refers to the digestive system.

[caption id="" align="aligncenter" width="520"] Figure 2. Sympathetic Connections and Chain Ganglia. The axon from a central sympathetic neuron in the spinal cord can project to the periphery in a number of different ways. (a) The fiber can project out to the ganglion at the same level and synapse on a ganglionic neuron. (b) A branch can project to more superior or inferior ganglion in the chain. (c) A branch can project through the white ramus communicans, but not terminate on a ganglionic neuron in the chain. Instead, it projects through one of the splanchnic nerves to a collateral ganglion or the adrenal medulla (not pictured).[/caption] An axon from the central neuron that projects to a sympathetic ganglion is referred to as a preganglionic fiber or neuron, and represents the output from the CNS to the ganglion. Because the sympathetic ganglia are adjacent to the vertebral column, preganglionic sympathetic fibers are relatively short, and they are myelinated. A postganglionic fiber—the axon from a ganglionic neuron that projects to the target effector—represents the output of a ganglion that directly influences the organ. Compared with the preganglionic fibers, postganglionic sympathetic fibers are long because of the relatively greater distance from the ganglion to the target effector. These fibers are unmyelinated. (Note that the term “postganglionic neuron” may be used to describe the projection from a ganglion to the target. The problem with that usage is that the cell body is in the ganglion, and only the fiber is postganglionic. Typically, the term neuron applies to the entire cell.)

One type of preganglionic sympathetic fiber does not terminate in a ganglion. These are the axons from central sympathetic neurons that project to the adrenal medulla, the interior portion of the adrenal gland. These axons are still referred to as preganglionic fibers, but the target is not a ganglion. The adrenal medulla releases signaling molecules into the bloodstream, rather than using axons to communicate with target structures. The cells in the adrenal medulla that are contacted by the preganglionic fibers are called chromaffin cells. These cells are neurosecretory cells that develop from the neural crest along with the sympathetic ganglia, reinforcing the idea that the gland is, functionally, a sympathetic ganglion.

The projections of the sympathetic division of the autonomic nervous system diverge widely, resulting in a broad influence of the system throughout the body. As a response to a threat, the sympathetic system would increase heart rate and breathing rate and cause blood flow to the skeletal muscle to increase and blood flow to the digestive system to decrease. Sweat gland secretion should also increase as part of an integrated response. All of those physiological changes are going to be required to occur together to run away from the hunting lioness, or the modern equivalent. This divergence is seen in the branching patterns of preganglionic sympathetic neurons—a single preganglionic sympathetic neuron may have 10–20 targets. An axon that leaves a central neuron of the lateral horn in the thoracolumbar spinal cord will pass through the white ramus communicans and enter the sympathetic chain, where it will branch toward a variety of targets. At the level of the spinal cord at which the preganglionic sympathetic fiber exits the spinal cord, a branch will synapse on a neuron in the adjacent chain ganglion. Some branches will extend up or down to a different level of the chain ganglia. Other branches will pass through the chain ganglia and project through one of the splanchnic nerves to a collateral ganglion. Finally, some branches may project through the splanchnic nerves to the adrenal medulla. All of these branches mean that one preganglionic neuron can influence different regions of the sympathetic system very broadly, by acting on widely distributed organs.

Parasympathetic Division of the Autonomic Nervous System

The parasympathetic division of the autonomic nervous system is named because its central neurons are located on either side of the thoracolumbar region of the spinal cord (para- = “beside” or “near”). The parasympathetic system can also be referred to as the craniosacral system (or outflow) because the preganglionic neurons are located in nuclei of the brain stem and the lateral horn of the sacral spinal cord.

The connections, or “circuits,” of the parasympathetic division are similar to the general layout of the sympathetic division with a few specific differences (Figure 3). The preganglionic fibers from the cranial region travel in cranial nerves, whereas preganglionic fibers from the sacral region travel in spinal nerves. The targets of these fibers are terminal ganglia, which are located near—or even within—the target effector. These ganglia are often referred to as intramural ganglia when they are found within the walls of the target organ. The postganglionic fiber projects from the terminal ganglia a short distance to the target effector, or to the specific target tissue within the organ. Comparing the relative lengths of axons in the parasympathetic system, the preganglionic fibers are long and the postganglionic fibers are short because the ganglia are close to—and sometimes within—the target effectors.

The cranial component of the parasympathetic system is based in particular nuclei of the brain stem. In the midbrain, the Edinger–Westphal nucleus is part of the oculomotor complex, and axons from those neurons travel with the fibers in the oculomotor nerve (cranial nerve III) that innervate the extraocular muscles. The preganglionic parasympathetic fibers within cranial nerve III terminate in the ciliary ganglion, which is located in the posterior orbit. The postganglionic parasympathetic fibers then project to the smooth muscle of the iris to control pupillary size. In the upper medulla, the salivatory nuclei contain neurons with axons that project through the facial and glossopharyngeal nerves to ganglia that control salivary glands. Tear production is influenced by parasympathetic fibers in the facial nerve, which activate a ganglion, and ultimately the lacrimal (tear) gland. Neurons in the dorsal nucleus of the vagus nerve and the nucleus ambiguus project through the vagus nerve (cranial nerve X) to the terminal ganglia of the thoracic and abdominal cavities. Parasympathetic preganglionic fibers primarily influence the heart, bronchi, and esophagus in the thoracic cavity and the stomach, liver, pancreas, gall bladder, and small intestine of the abdominal cavity. The postganglionic fibers from the ganglia activated by the vagus nerve are often incorporated into the structure of the organ, such as the mesenteric plexus of the digestive tract organs and the intramural ganglia.

[caption id="" align="aligncenter" width="520"] Figure 3. Connections of Parasympathetic Division of the Autonomic Nervous System. Neurons from brain-stem nuclei, or from the lateral horn of the sacral spinal cord, project to terminal ganglia near or within the various organs of the body. Axons from these ganglionic neurons then project the short distance to those target effectors.[/caption]

Chemical Signaling in the Autonomic Nervous System

Where an autonomic neuron connects with a target, there is a synapse. The electrical signal of the action potential causes the release of a signaling molecule, which will bind to receptor proteins on the target cell. Synapses of the autonomic system are classified as either cholinergic, meaning that acetylcholine (ACh) is released, or adrenergic, meaning that norepinephrine is released. The terms cholinergic and adrenergic refer not only to the signaling molecule that is released but also to the class of receptors that each binds.

The cholinergic system includes two classes of receptor: the nicotinic receptor and the muscarinic receptor. Both receptor types bind to ACh and cause changes in the target cell. The nicotinic receptor is a ligand-gated cation channel and the muscarinic receptor is a G protein–coupled receptor. The receptors are named for, and differentiated by, other molecules that bind to them. Whereas nicotine will bind to the nicotinic receptor, and muscarine will bind to the muscarinic receptor, there is no cross-reactivity between the receptors. The situation is similar to locks and keys. Imagine two locks—one for a classroom and the other for an office—that are opened by two separate keys. The classroom key will not open the office door and the office key will not open the classroom door. This is similar to the specificity of nicotine and muscarine for their receptors. However, a master key can open multiple locks, such as a master key for the Biology Department that opens both the classroom and the office doors. This is similar to ACh that binds to both types of receptors. The molecules that define these receptors are not crucial—they are simply tools for researchers to use in the laboratory. These molecules are exogenous, meaning that they are made outside of the human body, so a researcher can use them without any confounding endogenous results (results caused by the molecules produced in the body).

The adrenergic system also has two types of receptors, named the alpha (α)-adrenergic receptor and beta (β)-adrenergic receptor. Unlike cholinergic receptors, these receptor types are not classified by which drugs can bind to them. All of them are G protein–coupled receptors. There are three types of α-adrenergic receptors, termed α₁, α₂, and α₃, and there are two types of β-adrenergic receptors, termed β₁ and β₂. An additional aspect of the adrenergic system is that there is a second signaling molecule called epinephrine. The chemical difference between norepinephrine and epinephrine is the addition of a methyl group (CH₃) in epinephrine. The prefix “nor-” actually refers to this chemical difference, in which a methyl group is missing.

The term adrenergic should remind you of the word adrenaline, which is associated with the fight-or-flight response described at the beginning of the chapter. Adrenaline and epinephrine are two names for the same molecule. The adrenal gland (in Latin, ad- = “on top of”; renal = “kidney”) secretes adrenaline. The ending “-ine” refers to the chemical being derived, or extracted, from the adrenal gland. A similar construction from Greek instead of Latin results in the word epinephrine (epi- = “above”; nephr- = “kidney”). In scientific usage, epinephrine is preferred in the United States, whereas adrenaline is preferred in Great Britain, because “adrenalin” was once a registered, proprietary drug name in the United States. Though the drug is no longer sold, the convention of referring to this molecule by the two different names persists. Similarly, norepinephrine and noradrenaline are two names for the same molecule.

Having understood the cholinergic and adrenergic systems, their role in the autonomic system is relatively simple to understand. All preganglionic fibers, both sympathetic and parasympathetic, release ACh. All ganglionic neurons—the targets of these preganglionic fibers—have nicotinic receptors in their cell membranes. The nicotinic receptor is a ligand-gated cation channel that results in depolarization of the postsynaptic membrane. The postganglionic parasympathetic fibers also release ACh, but the receptors on their targets are muscarinic receptors, which are G protein–coupled receptors and do not exclusively cause depolarization of the postsynaptic membrane. Postganglionic sympathetic fibers release norepinephrine, except for fibers that project to sweat glands and to blood vessels associated with skeletal muscles, which release ACh (table 1).

Autonomic System Signaling Molecules (Table 1)
	Sympathetic	Parasympathetic
Preganglionic	Acetylcholine → nicotinic receptor	Acetylcholine → nicotinic receptor
Postganglionic	Norepinephrine → α- or β-adrenergic receptors Acetylcholine → muscarinic receptor (associated with sweat glands and the blood vessels associated with skeletal muscles only	Acetylcholine → muscarinic receptor

Signaling molecules can belong to two broad groups. Neurotransmitters are released at synapses, whereas hormones are released into the bloodstream. These are simplistic definitions, but they can help to clarify this point. Acetylcholine can be considered a neurotransmitter because it is released by axons at synapses. The adrenergic system, however, presents a challenge. Postganglionic sympathetic fibers release norepinephrine, which can be considered a neurotransmitter. But the adrenal medulla releases epinephrine and norepinephrine into circulation, so they should be considered hormones.

What are referred to here as synapses may not fit the strictest definition of synapse. Some sources will refer to the connection between a postganglionic fiber and a target effector as neuroeffector junctions; neurotransmitters, as defined above, would be called neuromodulators. The structure of postganglionic connections are not the typical synaptic end bulb that is found at the neuromuscular junction, but rather are chains of swellings along the length of a postganglionic fiber called a varicosity (Figure 4).

[caption id="" align="aligncenter" width="520"] Figure 4. Autonomic Varicosities. The connection between autonomic fibers and target effectors is not the same as the typical synapse, such as the neuromuscular junction. Instead of a synaptic end bulb, a neurotransmitter is released from swellings along the length of a fiber that makes an extended network of connections in the target effector.[/caption]

[caption id="attachment_3009" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of the autonomic nervous system![/caption]

15.2 Autonomic Reflexes and Homeostasis

barkerj1 — Wed, 06 Sep 2017 01:19:34 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the components of a reflex arc
Explain how a reflex arc works

The autonomic nervous system regulates organ systems through circuits that resemble the reflexes described in the somatic nervous system. The main difference between the somatic and autonomic systems is in what target tissues are effectors. Somatic responses are solely based on skeletal muscle contraction. The autonomic system, however, targets cardiac and smooth muscle, as well as glandular tissue. Whereas the basic circuit is a reflex arc, there are differences in the structure of those reflexes for the somatic and autonomic systems.

The Structure of Reflexes

One difference between a somatic reflex, such as the withdrawal reflex, and a visceral reflex, which is an autonomic reflex, is in the efferent branch. The output of a somatic reflex is the lower motor neuron in the ventral horn of the spinal cord that projects directly to a skeletal muscle to cause its contraction. The output of a visceral reflex is a two-step pathway starting with the preganglionic fiber emerging from a lateral horn neuron in the spinal cord, or a cranial nucleus neuron in the brain stem, to a ganglion—followed by the postganglionic fiber projecting to a target effector. The other part of a reflex, the afferent branch, is often the same between the two systems. Sensory neurons receiving input from the periphery—with cell bodies in the sensory ganglia, either of a cranial nerve or a dorsal root ganglion adjacent to the spinal cord—project into the CNS to initiate the reflex (Figure 1). The Latin root “effere” means “to carry.” Adding the prefix “ef-” suggests the meaning “to carry away,” whereas adding the prefix “af-” suggests “to carry toward or inward.”

[caption id="" align="aligncenter" width="500"] Figure 1. Comparison of Somatic and Visceral Reflexes. The afferent inputs to somatic and visceral reflexes are essentially the same, whereas the efferent branches are different. Somatic reflexes, for instance, involve a direct connection from the ventral horn of the spinal cord to the skeletal muscle. Visceral reflexes involve a projection from the central neuron to a ganglion, followed by a second projection from the ganglion to the target effector.[/caption]

Afferent Branch

The afferent branch of a reflex arc does differ between somatic and visceral reflexes in some instances. Many of the inputs to visceral reflexes are from special or somatic senses, but particular senses are associated with the viscera that are not part of the conscious perception of the environment through the somatic nervous system. For example, there is a specific type of mechanoreceptor, called a baroreceptor, in the walls of the aorta and carotid sinuses that senses the stretch of those organs when blood volume or pressure increases. You do not have a conscious perception of having high blood pressure, but that is an important afferent branch of the cardiovascular and, particularly, vasomotor reflexes. The sensory neuron is essentially the same as any other general sensory neuron. The baroreceptor apparatus is part of the ending of a unipolar neuron that has a cell body in a sensory ganglion. The baroreceptors from the carotid arteries have axons in the glossopharyngeal nerve, and those from the aorta have axons in the vagus nerve.

Though visceral senses are not primarily a part of conscious perception, those sensations sometimes make it to conscious awareness. If a visceral sense is strong enough, it will be perceived. The sensory homunculus—the representation of the body in the primary somatosensory cortex—only has a small region allotted for the perception of internal stimuli. If you swallow a large bolus of food, for instance, you will probably feel the lump of that food as it pushes through your esophagus, or even if your stomach is distended after a large meal. If you inhale especially cold air, you can feel it as it enters your larynx and trachea. These sensations are not the same as feeling high blood pressure or blood sugar levels.

When particularly strong visceral sensations rise to the level of conscious perception, the sensations are often felt in unexpected places. For example, strong visceral sensations of the heart will be felt as pain in the left shoulder and left arm. This irregular pattern of projection of conscious perception of visceral sensations is called referred pain. Depending on the organ system affected, the referred pain will project to different areas of the body (Figure 2). The location of referred pain is not random, but a definitive explanation of the mechanism has not been established. The most broadly accepted theory for this phenomenon is that the visceral sensory fibers enter into the same level of the spinal cord as the somatosensory fibers of the referred pain location. By this explanation, the visceral sensory fibers from the mediastinal region, where the heart is located, would enter the spinal cord at the same level as the spinal nerves from the shoulder and arm, so the brain misinterprets the sensations from the mediastinal region as being from the axillary and brachial regions. Projections from the medial and inferior divisions of the cervical ganglia do enter the spinal cord at the middle to lower cervical levels, which is where the somatosensory fibers enter.

[caption id="" align="aligncenter" width="520"] Figure 2. Referred Pain Chart. Conscious perception of visceral sensations map to specific regions of the body, as shown in this chart. Some sensations are felt locally, whereas others are perceived as affecting areas that are quite distant from the involved organ.[/caption]

Efferent Branch

The efferent branch of the visceral reflex arc begins with the projection from the central neuron along the preganglionic fiber. This fiber then makes a synapse on the ganglionic neuron that projects to the target effector.

The effector organs that are the targets of the autonomic system range from the iris and ciliary body of the eye to the urinary bladder and reproductive organs. The thoracolumbar output, through the various sympathetic ganglia, reaches all of these organs. The cranial component of the parasympathetic system projects from the eye to part of the intestines. The sacral component picks up with the majority of the large intestine and the pelvic organs of the urinary and reproductive systems.

Short and Long Reflexes

Somatic reflexes involve sensory neurons that connect sensory receptors to the CNS and motor neurons that project back out to the skeletal muscles. Visceral reflexes that involve the thoracolumbar or craniosacral systems share similar connections. However, there are reflexes that do not need to involve any CNS components. A long reflex has afferent branches that enter the spinal cord or brain and involve the efferent branches, as previously explained. A short reflex is completely peripheral and only involves the local integration of sensory input with motor output (Figure 3).

[caption id="" align="aligncenter" width="520"] Figure 3. Short and Long Reflexes. Sensory input can stimulate either a short or a long reflex. A sensory neuron can project to the CNS or to an autonomic ganglion. The short reflex involves the direct stimulation of a postganglionic fiber by the sensory neuron, whereas the long reflex involves integration in the spinal cord or brain.[/caption]

The difference between short and long reflexes is in the involvement of the CNS. Somatic reflexes always involve the CNS, even in a monosynaptic reflex in which the sensory neuron directly activates the motor neuron. That synapse is in the spinal cord or brain stem, so it has to involve the CNS. However, in the autonomic system there is the possibility that the CNS is not involved. Because the efferent branch of a visceral reflex involves two neurons—the central neuron and the ganglionic neuron—a “short circuit” can be possible. If a sensory neuron projects directly to the ganglionic neuron and causes it to activate the effector target, then the CNS is not involved.

A division of the nervous system that is related to the autonomic nervous system is the enteric nervous system. The word enteric refers to the digestive organs, so this represents the nervous tissue that is part of the digestive system. There are a few myenteric plexuses in which the nervous tissue in the wall of the digestive tract organs can directly influence digestive function. If stretch receptors in the stomach are activated by the filling and distension of the stomach, a short reflex will directly activate the smooth muscle fibers of the stomach wall to increase motility to digest the excessive food in the stomach. No CNS involvement is needed because the stretch receptor is directly activating a neuron in the wall of the stomach that causes the smooth muscle to contract. That neuron, connected to the smooth muscle, is a postganglionic parasympathetic neuron that can be controlled by a fiber found in the vagus nerve.

Balance in Competing Autonomic Reflex Arcs

The autonomic nervous system is important for homeostasis because its two divisions compete at the target effector. The balance of homeostasis is attributable to the competing inputs from the sympathetic and parasympathetic divisions (dual innervation). At the level of the target effector, the signal of which system is sending the message is strictly chemical. A signaling molecule binds to a receptor that causes changes in the target cell, which in turn causes the tissue or organ to respond to the changing conditions of the body.

Competing Neurotransmitters

The postganglionic fibers of the sympathetic and parasympathetic divisions both release neurotransmitters that bind to receptors on their targets. Postganglionic sympathetic fibers release norepinephrine, with a minor exception, whereas postganglionic parasympathetic fibers release ACh. For any given target, the difference in which division of the autonomic nervous system is exerting control is just in what chemical binds to its receptors. The target cells will have adrenergic and muscarinic receptors. If norepinephrine is released, it will bind to the adrenergic receptors present on the target cell, and if ACh is released, it will bind to the muscarinic receptors on the target cell.

In the sympathetic system, there are exceptions to this pattern of dual innervation. The postganglionic sympathetic fibers that contact the blood vessels within skeletal muscle and that contact sweat glands do not release norepinephrine, they release ACh. This does not create any problem because there is no parasympathetic input to the sweat glands. Sweat glands have muscarinic receptors and produce and secrete sweat in response to the presence of ACh.

At most of the other targets of the autonomic system, the effector response is based on which neurotransmitter is released and what receptor is present. For example, regions of the heart that establish heart rate are contacted by postganglionic fibers from both systems. If norepinephrine is released onto those cells, it binds to an adrenergic receptor that causes the cells to depolarize faster, and the heart rate increases. If ACh is released onto those cells, it binds to a muscarinic receptor that causes the cells to hyperpolarize so that they cannot reach threshold as easily, and the heart rate slows. Without this parasympathetic input, the heart would work at a rate of approximately 100 beats per minute (bpm). The sympathetic system speeds that up, as it would during exercise, to 120–140 bpm, for example. The parasympathetic system slows it down to the resting heart rate of 60–80 bpm.

Another example is in the control of pupillary size (Figure 4). The afferent branch responds to light hitting the retina. Photoreceptors are activated, and the signal is transferred to the retinal ganglion cells that send an action potential along the optic nerve into the diencephalon. If light levels are low, the sympathetic system sends a signal out through the upper thoracic spinal cord to the superior cervical ganglion of the sympathetic chain. The postganglionic fiber then projects to the iris, where it releases norepinephrine onto the radial fibers of the iris (a smooth muscle). When those fibers contract, the pupil dilates—increasing the amount of light hitting the retina. If light levels are too high, the parasympathetic system sends a signal out from the Eddinger–Westphal nucleus through the oculomotor nerve. This fiber synapses in the ciliary ganglion in the posterior orbit. The postganglionic fiber then projects to the iris, where it releases ACh onto the circular fibers of the iris—another smooth muscle. When those fibers contract, the pupil constricts to limit the amount of light hitting the retina.

[caption id="" align="aligncenter" width="580"] Figure 4. Autonomic Control of Pupillary Size. Activation of the pupillary reflex comes from the amount of light activating the retinal ganglion cells, as sent along the optic nerve. The output of the sympathetic system projects through the superior cervical ganglion, whereas the parasympathetic system originates out of the midbrain and projects through the oculomotor nerve to the ciliary ganglion, which then projects to the iris. The postganglionic fibers of either division release neurotransmitters onto the smooth muscles of the iris to cause changes in the pupillary size. Norepinephrine results in dilation and ACh results in constriction.[/caption]

In this example, the autonomic system is controlling how much light hits the retina. It is a homeostatic reflex mechanism that keeps the activation of photoreceptors within certain limits. In the context of avoiding a threat like the lioness on the savannah, the sympathetic response for fight or flight will increase pupillary diameter so that more light hits the retina and more visual information is available for running away. Likewise, the parasympathetic response of rest reduces the amount of light reaching the retina, allowing the photoreceptors to cycle through bleaching and be regenerated for further visual perception; this is what the homeostatic process is attempting to maintain.

Autonomic Tone

Organ systems are balanced between the input from the sympathetic and parasympathetic divisions. When something upsets that balance, the homeostatic mechanisms strive to return it to its regular state. For each organ system, there may be more of a sympathetic or parasympathetic tendency to the resting state, which is known as the autonomic tone of the system. For example, the heart rate was described above. Because the resting heart rate is the result of the parasympathetic system slowing the heart down from its intrinsic rate of 100 bpm, the heart can be said to be in parasympathetic tone.

In a similar fashion, another aspect of the cardiovascular system is primarily under sympathetic control. Blood pressure is partially determined by the contraction of smooth muscle in the walls of blood vessels. These tissues have adrenergic receptors that respond to the release of norepinephrine from postganglionic sympathetic fibers by constricting and increasing blood pressure. The hormones released from the adrenal medulla—epinephrine and norepinephrine—will also bind to these receptors. Those hormones travel through the bloodstream where they can easily interact with the receptors in the vessel walls. The parasympathetic system has no significant input to the systemic blood vessels, so the sympathetic system determines their tone.

There are a limited number of blood vessels that respond to sympathetic input in a different fashion. Blood vessels in skeletal muscle, particularly those in the lower limbs, are more likely to dilate. It does not have an overall effect on blood pressure to alter the tone of the vessels, but rather allows for blood flow to increase for those skeletal muscles that will be active in the fight-or-flight response. The blood vessels that have a parasympathetic projection are limited to those in the erectile tissue of the reproductive organs. Acetylcholine released by these postganglionic parasympathetic fibers cause the vessels to dilate, leading to the engorgement of the erectile tissue.

Homeostatic Imbalances

Orthostatic Hypotension Have you ever stood up quickly and felt dizzy for a moment? This is because, for one reason or another, blood is not getting to your brain so it is briefly deprived of oxygen. When you change position from sitting or lying down to standing, your cardiovascular system has to adjust for a new challenge, keeping blood pumping up into the head while gravity is pulling more and more blood down into the legs.

The reason for this is a sympathetic reflex that maintains the output of the heart in response to postural change. When a person stands up, proprioceptors indicate that the body is changing position. A signal goes to the CNS, which then sends a signal to the upper thoracic spinal cord neurons of the sympathetic division. The sympathetic system then causes the heart to beat faster and the blood vessels to constrict. Both changes will make it possible for the cardiovascular system to maintain the rate of blood delivery to the brain. Blood is being pumped superiorly through the internal branch of the carotid arteries into the brain, against the force of gravity. Gravity is not increasing while standing, but blood is more likely to flow down into the legs as they are extended for standing. This sympathetic reflex keeps the brain well oxygenated so that cognitive and other neural processes are not interrupted.

Sometimes this does not work properly. If the sympathetic system cannot increase cardiac output, then blood pressure into the brain will decrease, and a brief neurological loss can be felt. This can be brief, as a slight “wooziness” when standing up too quickly, or a loss of balance and neurological impairment for a period of time. The name for this is orthostatic hypotension, which means that blood pressure goes below the homeostatic set point when standing. It can be the result of standing up faster than the reflex can occur, which may be referred to as a benign “head rush,” or it may be the result of an underlying cause.

There are two basic reasons that orthostatic hypotension can occur. First, blood volume is too low and the sympathetic reflex is not effective. This hypovolemia may be the result of dehydration or medications that affect fluid balance, such as diuretics or vasodilators. Both of these medications are meant to lower blood pressure, which may be necessary in the case of systemic hypertension, and regulation of the medications may alleviate the problem. Sometimes increasing fluid intake or water retention through salt intake can improve the situation.

The second underlying cause of orthostatic hypotension is autonomic failure. There are several disorders that result in compromised sympathetic functions. The disorders range from diabetes to multiple system atrophy (a loss of control over many systems in the body), and addressing the underlying condition can improve the hypotension. For example, with diabetes, peripheral nerve damage can occur, which would affect the postganglionic sympathetic fibers. Getting blood glucose levels under control can improve neurological deficits associated with diabetes.

15.3 Central Control

barkerj1 — Wed, 06 Sep 2017 01:19:34 +0000

Learning Objectives

By the end of this section, you will be able to:

The pupillary light reflex (Figure 1) begins when light hits the retina and causes a signal to travel along the optic nerve. This is visual sensation, because the afferent branch of this reflex is simply sharing the special sense pathway. Bright light hitting the retina leads to the parasympathetic response, through the oculomotor nerve, followed by the postganglionic fiber from the ciliary ganglion, which stimulates the circular fibers of the iris to contract and constrict the pupil. When light hits the retina in one eye, both pupils contract. When that light is removed, both pupils dilate again back to the resting position. When the stimulus is unilateral (presented to only one eye), the response is bilateral (both eyes). The same is not true for somatic reflexes. If you touch a hot radiator, you only pull that arm back, not both. Central control of autonomic reflexes is different than for somatic reflexes. The hypothalamus, along with other CNS locations, controls the autonomic system.

[caption id="" align="aligncenter" width="530"] Figure 1. Pupillary Reflex Pathways. The pupil is under competing autonomic control in response to light levels hitting the retina. The sympathetic system will dilate the pupil when the retina is not receiving enough light, and the parasympathetic system will constrict the pupil when too much light hits the retina.[/caption]

Forebrain Structures

Autonomic control is based on the visceral reflexes, composed of the afferent and efferent branches. These homeostatic mechanisms are based on the balance between the two divisions of the autonomic system, which results in tone for various organs that is based on the predominant input from the sympathetic or parasympathetic systems. Coordinating that balance requires integration that begins with forebrain structures like the hypothalamus and continues into the brain stem and spinal cord.

The Hypothalamus

The hypothalamus is the control center for many homeostatic mechanisms. It regulates both autonomic function and endocrine function. The roles it plays in the pupillary reflexes demonstrates the importance of this control center. The optic nerve projects primarily to the thalamus, which is the necessary relay to the occipital cortex for conscious visual perception. Another projection of the optic nerve, however, goes to the hypothalamus.

The hypothalamus then uses this visual system input to drive the pupillary reflexes. If the retina is activated by high levels of light, the hypothalamus stimulates the parasympathetic response. If the optic nerve message shows that low levels of light are falling on the retina, the hypothalamus activates the sympathetic response. Output from the hypothalamus follows two main tracts, the dorsal longitudinal fasciculus and the medial forebrain bundle (Figure 2). Along these two tracts, the hypothalamus can influence the Eddinger–Westphal nucleus of the oculomotor complex or the lateral horns of the thoracic spinal cord.

[caption id="" align="aligncenter" width="480"] Figure 2. Fiber Tracts of the Central Autonomic System. The hypothalamus is the source of most of the central control of autonomic function. It receives input from cerebral structures and projects to brain stem and spinal cord structures to regulate the balance of sympathetic and parasympathetic input to the organ systems of the body. The main pathways for this are the medial forebrain bundle and the dorsal longitudinal fasciculus.[/caption] These two tracts connect the hypothalamus with the major parasympathetic nuclei in the brain stem and the preganglionic (central) neurons of the thoracolumbar spinal cord. The hypothalamus also receives input from other areas of the forebrain through the medial forebrain bundle. The olfactory cortex, the septal nuclei of the basal forebrain, and the amygdala project into the hypothalamus through the medial forebrain bundle. These forebrain structures inform the hypothalamus about the state of the nervous system and can influence the regulatory processes of homeostasis. A good example of this is found in the amygdala, which is found beneath the cerebral cortex of the temporal lobe and plays a role in our ability to remember and feel emotions.

The Amygdala

The amygdala is a group of nuclei in the medial region of the temporal lobe that is part of the limbic lobe (Figure 3). The limbic lobe includes structures that are involved in emotional responses, as well as structures that contribute to memory function. The limbic lobe has strong connections with the hypothalamus and influences the state of its activity on the basis of emotional state. For example, when you are anxious or scared, the amygdala will send signals to the hypothalamus along the medial forebrain bundle that will stimulate the sympathetic fight-or-flight response. The hypothalamus will also stimulate the release of stress hormones through its control of the endocrine system in response to amygdala input.

[caption id="" align="aligncenter" width="510"] Figure 3. The Limbic Lobe. Structures arranged around the edge of the cerebrum constitute the limbic lobe, which includes the amygdala, hippocampus, and cingulate gyrus, and connects to the hypothalamus.[/caption]

The Medulla

The medulla contains nuclei referred to as the cardiovascular center, which controls the smooth and cardiac muscle of the cardiovascular system through autonomic connections. When the homeostasis of the cardiovascular system shifts, such as when blood pressure changes, the coordination of the autonomic system can be accomplished within this region. Furthermore, when descending inputs from the hypothalamus stimulate this area, the sympathetic system can increase activity in the cardiovascular system, such as in response to anxiety or stress. The preganglionic sympathetic fibers that are responsible for increasing heart rate are referred to as the cardiac accelerator nerves, whereas the preganglionic sympathetic fibers responsible for constricting blood vessels compose the vasomotor nerves.

Several brain stem nuclei are important for the visceral control of major organ systems. One brain stem nucleus involved in cardiovascular function is the solitary nucleus. It receives sensory input about blood pressure and cardiac function from the glossopharyngeal and vagus nerves, and its output will activate sympathetic stimulation of the heart or blood vessels through the upper thoracic lateral horn. Another brain stem nucleus important for visceral control is the dorsal motor nucleus of the vagus nerve, which is the motor nucleus for the parasympathetic functions ascribed to the vagus nerve, including decreasing the heart rate, relaxing bronchial tubes in the lungs, and activating digestive function through the enteric nervous system. The nucleus ambiguus, which is named for its ambiguous histology, also contributes to the parasympathetic output of the vagus nerve and targets muscles in the pharynx and larynx for swallowing and speech, as well as contributing to the parasympathetic tone of the heart along with the dorsal motor nucleus of the vagus.

17.1 An Overview of the Endocrine System

barkerj1 — Wed, 06 Sep 2017 01:19:36 +0000

Learning Objectives

By the end of this section, you will be able to:

Specify several overall functions of hormones
Compare hormonal action with nervous action
Name and specify the locations of the endocrine glands

Communication is a process in which a sender transmits signals to one or more receivers to control and coordinate actions. In the human body, two major organ systems participate in relatively “long distance” communication: the nervous system and the endocrine system. Together, these two systems are primarily responsible for maintaining homeostasis in the body.

Neural and Endocrine Signaling

The nervous system uses two types of intercellular communication—electrical and chemical signaling—either by the direct action of an electrical potential, or in the latter case, through the action of chemical neurotransmitters such as serotonin or norepinephrine. Neurotransmitters act locally and rapidly. When an electrical signal in the form of an action potential arrives at the synaptic terminal, they diffuse across the synaptic cleft (the gap between a sending neuron and a receiving neuron or muscle cell). Once the neurotransmitters interact (bind) with receptors on the receiving (post-synaptic) cell, the receptor stimulation is transduced into a response such as continued electrical signaling or modification of cellular response. The target cell responds within milliseconds of receiving the chemical “message”; this response then ceases very quickly once the neural signaling ends. In this way, neural communication enables body functions that involve quick, brief actions, such as movement, sensation, and cognition.In contrast, the endocrine system uses just one method of communication: chemical signaling. These signals are sent by the endocrine organs, which secrete chemicals—the hormone—into the extracellular fluid. Hormones are transported primarily via the bloodstream throughout the body, where they bind to receptors on target cells, inducing a characteristic response. As a result, endocrine signaling requires more time than neural signaling to prompt a response in target cells, though the precise amount of time varies with different hormones. For example, the hormones released when you are confronted with a dangerous or frightening situation, called the fight-or-flight response, occur by the release of adrenal hormones—epinephrine and norepinephrine—within seconds. In contrast, it may take up to 48 hours for target cells to respond to certain reproductive hormones.

[caption id="" align="aligncenter" width="120"] Visit this link to watch an animation of the events that occur when a hormone binds to a cell membrane receptor.[/caption]

In addition, endocrine signaling is typically less specific than neural signaling. The same hormone may play a role in a variety of different physiological processes depending on the target cells involved. For example, the hormone oxytocin promotes uterine contractions in women in labor. It is also important in breastfeeding, and may be involved in the sexual response and in feelings of emotional attachment in both males and females.

In general, the nervous system involves quick responses to rapid changes in the external environment, and the endocrine system is usually slower acting—taking care of the internal environment of the body, maintaining homeostasis, and controlling reproduction (Table 1). So how does the fight-or-flight response that was mentioned earlier happen so quickly if hormones are usually slower acting? It is because the two systems are connected. It is the fast action of the nervous system in response to the danger in the environment that stimulates the adrenal glands to secrete their hormones. As a result, the nervous system can cause rapid endocrine responses to keep up with sudden changes in both the external and internal environments when necessary.

Endocrine and Nervous Systems (Table 1)
	Endocrine system	Nervous system
Signaling mechanism(s)	Chemical	Chemical/electrical
Primary chemical signal	Hormones	Neurotransmitters
Distance traveled	Long or short	Always short
Response time	Fast or slow	Always fast
Environment targeted	Internal	Internal and external

Structures of the Endocrine System

The endocrine system consists of cells, tissues, and organs that secrete hormones as a primary or secondary function. The endocrine gland is the major player in this system. The primary function of these ductless glands is to secrete their hormones directly into the surrounding fluid. The interstitial fluid and the blood vessels then transport the hormones throughout the body. The endocrine system includes the pituitary, thyroid, parathyroid, adrenal, and pineal glands (Figure 1). Some of these glands have both endocrine and non-endocrine functions. For example, the pancreas contains cells that function in digestion as well as cells that secrete the hormones insulin and glucagon, which regulate blood glucose levels. The hypothalamus, thymus, heart, kidneys, stomach, small intestine, liver, skin, female ovaries, and male testes are other organs that contain cells with endocrine function. Moreover, adipose tissue has long been known to produce hormones, and recent research has revealed that even bone tissue has endocrine functions.

[caption id="" align="aligncenter" width="520"] Figure 1. Endocrine System. Endocrine glands and cells are located throughout the body and play an important role in homeostasis.[/caption]

The ductless endocrine glands are not to be confused with the body’s exocrine system, whose glands release their secretions through ducts. Examples of exocrine glands include the sebaceous and sweat glands of the skin. As just noted, the pancreas also has an exocrine function: most of its cells secrete pancreatic juice through the pancreatic and accessory ducts to the lumen of the small intestine.

Other Types of Chemical Signaling

In endocrine signaling, hormones secreted into the extracellular fluid diffuse into the blood or lymph, and can then travel great distances throughout the body. In contrast, autocrine signaling takes place within the same cell. An autocrine (auto- = “self”) is a chemical that elicits a response in the same cell that secreted it. Interleukin-1, or IL-1, is a signaling molecule that plays an important role in inflammatory response. The cells that secrete IL-1 have receptors on their cell surface that bind these molecules, resulting in autocrine signaling.

Local intercellular communication is the province of the paracrine, also called a paracrine factor, which is a chemical that induces a response in neighboring cells. Although paracrines may enter the bloodstream, their concentration is generally too low to elicit a response from distant tissues. A familiar example to those with asthma is histamine, a paracrine that is released by immune cells in the bronchial tree. Histamine causes the smooth muscle cells of the bronchi to constrict, narrowing the airways. Another example is the neurotransmitters of the nervous system, which act only locally within the synaptic cleft.

[caption id="attachment_3011" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of the endocrine system![/caption]

17.2 Hormones

barkerj1 — Wed, 06 Sep 2017 01:19:37 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe how homeostatic mechanisms operate to maintain body health

Although a given hormone may travel throughout the body in the bloodstream, it will affect the activity only of its target cells; that is, cells with receptors for that particular hormone. Once the hormone binds to the receptor, a chain of events is initiated that leads to the target cell’s response. Hormones play a critical role in the regulation of physiological processes because of the target cell responses they regulate. These responses contribute to human reproduction, growth and development of body tissues, metabolism, fluid, and electrolyte balance, sleep, and many other body functions. The major hormones of the human body and their effects are identified in Table 2.

Endocrine Glands and Their Major Hormones (Table 2)
Endocrine gland	Associated hormones	Chemical class	Effect
Pituitary (anterior)	Growth hormone (GH)	Protein	Promotes growth of body tissues
Pituitary (anterior)	Prolactin (PRL)	Peptide	Promotes milk production
Pituitary (anterior)	Thyroid-stimulating hormone (TSH)	Glycoprotein	Stimulates thyroid hormone release
Pituitary (anterior)	Adrenocorticotropic hormone (ACTH)	Peptide	Stimulates hormone release by adrenal cortex
Pituitary (anterior)	Follicle-stimulating hormone (FSH)	Glycoprotein	Stimulates gamete production
Pituitary (anterior)	Luteinizing hormone (LH)	Glycoprotein	Stimulates androgen production by gonads
Pituitary (posterior)	Antidiuretic hormone (ADH)	Peptide	Stimulates water reabsorption by kidneys
Pituitary (posterior)	Oxytocin	Peptide	Stimulates uterine contractions during childbirth
Thyroid	Thyroxine (T₄), triiodothyronine (T₃)	Amine	Stimulate basal metabolic rate
Thyroid	Calcitonin	Peptide	Reduces blood Ca²⁺ levels
Parathyroid	Parathyroid hormone (PTH)	Peptide	Increases blood Ca²⁺levels
Adrenal (cortex)	Aldosterone	Steroid	Increases blood Na⁺ levels
Adrenal (cortex)	Cortisol, corticosterone, cortisone	Steroid	Increase blood glucose levels
Adrenal (medulla)	Epinephrine, norepinephrine	Amine	Stimulate fight-or-flight response
Pineal	Melatonin	Amine	Regulates sleep cycles
Pancreas	Insulin	Protein	Reduces blood glucose levels
Pancreas	Glucagon	Protein	Increases blood glucose levels
Testes	Testosterone	Steroid	Stimulates development of male secondary sex characteristics and sperm production
Ovaries	Estrogens and progesterone	Steroid	Stimulate development of female secondary sex characteristics and prepare the body for childbirth

Types of Hormones

The hormones of the human body can be divided into two major groups on the basis of their chemical structure. Hormones derived from amino acids include amines, peptides, and proteins. Those derived from lipids include steroids (Figure 1). These chemical groups affect a hormone’s distribution, the type of receptors it binds to, and other aspects of its function.

[caption id="" align="aligncenter" width="550"] Figure 1. Amine, Peptide, Protein, and Steroid Hormone Structure[/caption]

Amine Hormones

Hormones derived from the modification of amino acids are referred to as amine hormones. Typically, the original structure of the amino acid is modified such that a –COOH, or carboxyl, group is removed, whereas the −NH3+−NH3+, or amine, group remains. Amine hormones are synthesized from the amino acids tryptophan or tyrosine. An example of a hormone derived from tryptophan is melatonin, which is secreted by the pineal gland and helps regulate circadian rhythm. Tyrosine derivatives include the metabolism-regulating thyroid hormones, as well as the catecholamines, such as epinephrine, norepinephrine, and dopamine. Epinephrine and norepinephrine are secreted by the adrenal medulla and play a role in the fight-or-flight response, whereas dopamine is secreted by the hypothalamus and inhibits the release of certain anterior pituitary hormones.

Peptide and Protein Hormones

Whereas the amine hormones are derived from a single amino acid, peptide and protein hormones consist of multiple amino acids that link to form an amino acid chain. Peptide hormones consist of short chains of amino acids, whereas protein hormones are longer polypeptides. Both types are synthesized like other body proteins: DNA is transcribed into mRNA, which is translated into an amino acid chain.

Examples of peptide hormones include antidiuretic hormone (ADH), a pituitary hormone important in fluid balance, and atrial-natriuretic peptide, which is produced by the heart and helps to decrease blood pressure. Some examples of protein hormones include growth hormone, which is produced by the pituitary gland, and follicle-stimulating hormone (FSH), which has an attached carbohydrate group and is thus classified as a glycoprotein. FSH helps stimulate the maturation of eggs in the ovaries and sperm in the testes.

Steroid Hormones

The primary hormones derived from lipids are steroids. Steroid hormones are derived from the lipid cholesterol. For example, the reproductive hormones testosterone and the estrogens—which are produced by the gonads (testes and ovaries)—are steroid hormones. The adrenal glands produce the steroid hormone aldosterone, which is involved in osmoregulation, and cortisol, which plays a role in metabolism.

Like cholesterol, steroid hormones are not soluble in water (they are hydrophobic). Because blood is water-based, lipid-derived hormones must travel to their target cell bound to a transport protein. This more complex structure extends the half-life of steroid hormones much longer than that of hormones derived from amino acids. A hormone’s half-life is the time required for half the concentration of the hormone to be degraded. For example, the lipid-derived hormone cortisol has a half-life of approximately 60 to 90 minutes. In contrast, the amino acid–derived hormone epinephrine has a half-life of approximately one minute.

Pathways of Hormone Action

The message a hormone sends is received by a hormone receptor, a protein located either inside the cell or within the cell membrane. The receptor will process the message by initiating other signaling events or cellular mechanisms that result in the target cell’s response. Hormone receptors recognize molecules with specific shapes and side groups, and respond only to those hormones that are recognized. The same type of receptor may be located on cells in different body tissues, and trigger somewhat different responses. Thus, the response triggered by a hormone depends not only on the hormone, but also on the target cell.

Once the target cell receives the hormone signal, it can respond in a variety of ways. The response may include the stimulation of protein synthesis, activation or deactivation of enzymes, alteration in the permeability of the cell membrane, altered rates of mitosis and cell growth, and stimulation of the secretion of products. Moreover, a single hormone may be capable of inducing different responses in a given cell.

Pathways Involving Intracellular Hormone Receptors

Intracellular hormone receptors are located inside the cell. Hormones that bind to this type of receptor must be able to cross the cell membrane. Steroid hormones are derived from cholesterol and therefore can readily diffuse through the lipid bilayer of the cell membrane to reach the intracellular receptor (Figure 2). Thyroid hormones, which contain benzene rings studded with iodine, are also lipid-soluble and can enter the cell.

The location of steroid and thyroid hormone binding differs slightly: a steroid hormone may bind to its receptor within the cytosol or within the nucleus. In either case, this binding generates a hormone-receptor complex that moves toward the chromatin in the cell nucleus and binds to a particular segment of the cell’s DNA. In contrast, thyroid hormones bind to receptors already bound to DNA. For both steroid and thyroid hormones, binding of the hormone-receptor complex with DNA triggers transcription of a target gene to mRNA, which moves to the cytosol and directs protein synthesis by ribosomes.

[caption id="" align="aligncenter" width="480"] Figure 2. Binding of Lipid-Soluble Hormones. A steroid hormone directly initiates the production of proteins within a target cell. Steroid hormones easily diffuse through the cell membrane. The hormone binds to its receptor in the cytosol, forming a receptor–hormone complex. The receptor–hormone complex then enters the nucleus and binds to the target gene on the DNA. Transcription of the gene creates a messenger RNA that is translated into the desired protein within the cytoplasm.[/caption]

Pathways Involving Cell Membrane Hormone Receptors

Hydrophilic, or water-soluble, hormones are unable to diffuse through the lipid bilayer of the cell membrane and must therefore pass on their message to a receptor located at the surface of the cell. Except for thyroid hormones, which are lipid-soluble, all amino acid–derived hormones bind to cell membrane receptors that are located, at least in part, on the extracellular surface of the cell membrane. Therefore, they do not directly affect the transcription of target genes, but instead initiate a signaling cascade that is carried out by a molecule called a second messenger. In this case, the hormone is called a first messenger.

The second messenger used by most hormones is cyclic adenosine monophosphate (cAMP). In the cAMP second messenger system, a water-soluble hormone binds to its receptor in the cell membrane (Step 1 in Figure 3). This receptor is associated with an intracellular component called a G protein, and binding of the hormone activates the G-protein component (Step 2). The activated G protein in turn activates an enzyme called adenylyl cyclase, also known as adenylate cyclase (Step 3), which converts adenosine triphosphate (ATP) to cAMP (Step 4). As the second messenger, cAMP activates a type of enzyme called a protein kinase that is present in the cytosol (Step 5). Activated protein kinases initiate a phosphorylation cascade, in which multiple protein kinases phosphorylate (add a phosphate group to) numerous and various cellular proteins, including other enzymes (Step 6).

[caption id="" align="aligncenter" width="480"] Figure 3. Binding of Water-Soluble Hormones. Water-soluble hormones cannot diffuse through the cell membrane. These hormones must bind to a surface cell-membrane receptor. The receptor then initiates a cell-signaling pathway within the cell involving G proteins, adenylyl cyclase, the secondary messenger cyclic AMP (cAMP), and protein kinases. In the final step, these protein kinases phosphorylate proteins in the cytoplasm. This activates proteins in the cell that carry out the changes specified by the hormone.[/caption]

The phosphorylation of cellular proteins can trigger a wide variety of effects, from nutrient metabolism to the synthesis of different hormones and other products. The effects vary according to the type of target cell, the G proteins and kinases involved, and the phosphorylation of proteins. Examples of hormones that use cAMP as a second messenger include calcitonin, which is important for bone construction and regulating blood calcium levels; glucagon, which plays a role in blood glucose levels; and thyroid-stimulating hormone, which causes the release of T₃ and T₄ from the thyroid gland. Overall, the phosphorylation cascade significantly increases the efficiency, speed, and specificity of the hormonal response, as thousands of signaling events can be initiated simultaneously in response to a very low concentration of hormone in the bloodstream. However, the duration of the hormone signal is short, as cAMP is quickly deactivated by the enzyme phosphodiesterase (PDE), which is located in the cytosol. The action of PDE helps to ensure that a target cell’s response ceases quickly unless new hormones arrive at the cell membrane.

Importantly, there are also G proteins that decrease the levels of cAMP in the cell in response to hormone binding. For example, when growth hormone–inhibiting hormone (GHIH), also known as somatostatin, binds to its receptors in the pituitary gland, the level of cAMP decreases, thereby inhibiting the secretion of human growth hormone.

Not all water-soluble hormones initiate the cAMP second messenger system. One common alternative system uses calcium ions as a second messenger. In this system, G proteins activate the enzyme phospholipase C (PLC), which functions similarly to adenylyl cyclase. Once activated, PLC cleaves a membrane-bound phospholipid into two molecules: diacylglycerol (DAG) and inositol triphosphate (IP₃). Like cAMP, DAG activates protein kinases that initiate a phosphorylation cascade. At the same time, IP₃ causes calcium ions to be released from storage sites within the cytosol, such as from within the smooth endoplasmic reticulum. The calcium ions then act as second messengers in two ways: they can influence enzymatic and other cellular activities directly, or they can bind to calcium-binding proteins, the most common of which is calmodulin. Upon binding calcium, calmodulin is able to modulate protein kinase within the cell. Examples of hormones that use calcium ions as a second messenger system include angiotensin II, which helps regulate blood pressure through vasoconstriction, and growth hormone–releasing hormone (GHRH), which causes the pituitary gland to release growth hormones.

Factors Affecting Target Cell Response

You will recall that target cells must have receptors specific to a given hormone if that hormone is to trigger a response. But several other factors influence the target cell response. For example, the presence of a significant level of a hormone circulating in the bloodstream can cause its target cells to decrease their number of receptors for that hormone. This process is called downregulation, and it allows cells to become less reactive to the excessive hormone levels. When the level of a hormone is chronically reduced, target cells engage in upregulation to increase their number of receptors. This process allows cells to be more sensitive to the hormone that is present. Cells can also alter the sensitivity of the receptors themselves to various hormones. Two or more hormones can interact to affect the response of cells in a variety of ways. The three most common types of interaction are as follows:

The permissive effect, in which the presence of one hormone enables another hormone to act. For example, thyroid hormones have complex permissive relationships with certain reproductive hormones. A dietary deficiency of iodine, a component of thyroid hormones, can therefore affect reproductive system development and functioning.
The synergistic effect, in which two hormones with similar effects produce an amplified response. In some cases, two hormones are required for an adequate response. For example, two different reproductive hormones—FSH from the pituitary gland and estrogens from the ovaries—are required for the maturation of female ova (egg cells).
The antagonistic effect, in which two hormones have opposing effects. A familiar example is the effect of two pancreatic hormones, insulin and glucagon. Insulin increases the liver’s storage of glucose as glycogen, decreasing blood glucose, whereas glucagon stimulates the breakdown of glycogen stores, increasing blood glucose.

Regulation of Hormone Secretion

To prevent abnormal hormone levels and a potential disease state, hormone levels must be tightly controlled. The body maintains this control by balancing hormone production and degradation. Feedback loops govern the initiation and maintenance of most hormone secretion in response to various stimuli.

Role of Feedback Loops

The contribution of feedback loops to homeostasis will only be briefly reviewed here. Positive feedback loops are characterized by the release of additional hormone in response to an original hormone release. The release of oxytocin during childbirth is a positive feedback loop. The initial release of oxytocin begins to signal the uterine muscles to contract, which pushes the fetus toward the cervix, causing it to stretch. This, in turn, signals the pituitary gland to release more oxytocin, causing labor contractions to intensify. The release of oxytocin decreases after the birth of the child.

The more common method of hormone regulation is the negative feedback loop. Negative feedback is characterized by the inhibition of further secretion of a hormone in response to adequate levels of that hormone. This allows blood levels of the hormone to be regulated within a narrow range. An example of a negative feedback loop is the release of glucocorticoid hormones from the adrenal glands, as directed by the hypothalamus and pituitary gland. As glucocorticoid concentrations in the blood rise, the hypothalamus and pituitary gland reduce their signaling to the adrenal glands to prevent additional glucocorticoid secretion (Figure 4).

[caption id="" align="aligncenter" width="520"] Figure 4. Negative Feedback Loop. The release of adrenal glucocorticoids is stimulated by the release of hormones from the hypothalamus and pituitary gland. This signaling is inhibited when glucocorticoid levels become elevated by causing negative signals to the pituitary gland and hypothalamus.[/caption]

Role of Endocrine Gland Stimuli

Reflexes triggered by both chemical and neural stimuli control endocrine activity. These reflexes may be simple, involving only one hormone response, or they may be more complex and involve many hormones, as is the case with the hypothalamic control of various anterior pituitary–controlled hormones.

Humoral stimuli are changes in blood levels of non-hormone chemicals, such as nutrients or ions, which cause the release or inhibition of a hormone to, in turn, maintain homeostasis. For example, osmoreceptors in the hypothalamus detect changes in blood osmolarity (the concentration of solutes in the blood plasma). If blood osmolarity is too high, meaning that the blood is not dilute enough, osmoreceptors signal the hypothalamus to release ADH. The hormone causes the kidneys to reabsorb more water and reduce the volume of urine produced. This reabsorption causes a reduction of the osmolarity of the blood, diluting the blood to the appropriate level. The regulation of blood glucose is another example. High blood glucose levels cause the release of insulin from the pancreas, which increases glucose uptake by cells and liver storage of glucose as glycogen.

An endocrine gland may also secrete a hormone in response to the presence of another hormone produced by a different endocrine gland. Such hormonal stimuli often involve the hypothalamus, which produces releasing and inhibiting hormones that control the secretion of a variety of pituitary hormones.

In addition to these chemical signals, hormones can also be released in response to neural stimuli. A common example of neural stimuli is the activation of the fight-or-flight response by the sympathetic nervous system. When an individual perceives danger, sympathetic neurons signal the adrenal glands to secrete norepinephrine and epinephrine. The two hormones dilate blood vessels, increase the heart and respiratory rate, and suppress the digestive and immune systems. These responses boost the body’s transport of oxygen to the brain and muscles, thereby improving the body’s ability to fight or flee.

17.3 The Pituitary Gland and Hypothalamus

barkerj1 — Wed, 06 Sep 2017 01:19:37 +0000

Learning Objectives

By the end of this section, you will be able to:

Name and specify the functions of the hormones released from the hypothalamus
Name and specify the functions of the hormones released from the posterior pituitary gland
Name and specify the functions of the hormones released from the anterior pituitary gland
Describe the effects of:
- Hyposecretion of growth hormone during childhood
- Hyposecretion of growth hormone during adulthood
- Hypersecretion of growth hormone during childhood
- Hypersecretion of growth hormone during adulthood
- Hyposecretion of antidiuretic hormone

The hypothalamus–pituitary complex can be thought of as the “command center” of the endocrine system. This complex secretes several hormones that directly produce responses in target tissues, as well as hormones that regulate the synthesis and secretion of hormones of other glands. In addition, the hypothalamus–pituitary complex coordinates the messages of the endocrine and nervous systems. In many cases, a stimulus received by the nervous system must pass through the hypothalamus–pituitary complex to be translated into hormones that can initiate a response.

The hypothalamus is a structure of the diencephalon of the brain located anterior and inferior to the thalamus (Figure 1). It has both neural and endocrine functions, producing and secreting many hormones. In addition, the hypothalamus is anatomically and functionally related to the pituitary gland (or hypophysis), a bean-sized organ suspended from it by a stem called the infundibulum (or pituitary stalk). The pituitary gland is cradled within the sellaturcica of the sphenoid bone of the skull. It consists of two lobes that arise from distinct parts of embryonic tissue: the posterior pituitary (neurohypophysis) is neural tissue, whereas the anterior pituitary (also known as the adenohypophysis) is glandular tissue that develops from the primitive digestive tract. The hormones secreted by the posterior and anterior pituitary, and the intermediate zone between the lobes are summarized in Table 3.

[caption id="" align="aligncenter" width="520"] Figure 1. Hypothalamus–Pituitary Complex. The hypothalamus region lies inferior and anterior to the thalamus. It connects to the pituitary gland by the stalk-like infundibulum. The pituitary gland consists of an anterior and posterior lobe, with each lobe secreting different hormones in response to signals from the hypothalamus.[/caption]

Pituitary Hormones (Table 3)
Pituitary lobe	Associated hormones	Chemical class	Effect
Anterior	Growth hormone (GH)	Protein	Promotes growth of body tissues
Anterior	Prolactin (PRL)	Peptide	Promotes milk production from mammary glands
Anterior	Thyroid-stimulating hormone (TSH)	Glycoprotein	Stimulates thyroid hormone release from thyroid
Anterior	Adrenocorticotropic hormone (ACTH)	Peptide	Stimulates hormone release by adrenal cortex
Anterior	Follicle-stimulating hormone (FSH)	Glycoprotein	Stimulates gamete production in gonads
Anterior	Luteinizing hormone (LH)	Glycoprotein	Stimulates androgen production by gonads
Posterior	Antidiuretic hormone (ADH)	Peptide	Stimulates water reabsorption by kidneys
Posterior	Oxytocin	Peptide	Stimulates uterine contractions during childbirth
Intermediate zone	Melanocyte-stimulating hormone	Peptide	Stimulates melanin formation in melanocytes

Posterior Pituitary

The posterior pituitary is actually an extension of the neurons of the paraventricular and supraoptic nuclei of the hypothalamus. The cell bodies of these regions rest in the hypothalamus, but their axons descend as the hypothalamic–hypophyseal tract within the infundibulum, and end in axon terminals that comprise the posterior pituitary (Figure 2).

[caption id="" align="aligncenter" width="520"] Figure 2. Posterior Pituitary. Neurosecretory cells in the hypothalamus release oxytocin (OT) or ADH into the posterior lobe of the pituitary gland. These hormones are stored or released into the blood via the capillary plexus.[/caption]

The posterior pituitary gland does not produce hormones, but rather stores and secretes hormones produced by the hypothalamus. The paraventricular nuclei produce the hormone oxytocin, whereas the supraoptic nuclei produce ADH. These hormones travel along the axons into storage sites in the axon terminals of the posterior pituitary. In response to signals from the same hypothalamic neurons, the hormones are released from the axon terminals into the bloodstream.

Oxytocin

When fetal development is complete, the peptide-derived hormone oxytocin (tocia- = “childbirth”) stimulates uterine contractions and dilation of the cervix. Throughout most of pregnancy, oxytocin hormone receptors are not expressed at high levels in the uterus. Toward the end of pregnancy, the synthesis of oxytocin receptors in the uterus increases, and the smooth muscle cells of the uterus become more sensitive to its effects. Oxytocin is continually released throughout childbirth through a positive feedback mechanism. As noted earlier, oxytocin prompts uterine contractions that push the fetal head toward the cervix. In response, cervical stretching stimulates additional oxytocin to be synthesized by the hypothalamus and released from the pituitary. This increases the intensity and effectiveness of uterine contractions and prompts additional dilation of the cervix. The feedback loop continues until birth.

Although the mother’s high blood levels of oxytocin begin to decrease immediately following birth, oxytocin continues to play a role in maternal and newborn health. First, oxytocin is necessary for the milk ejection reflex (commonly referred to as “let-down”) in breastfeeding women. As the newborn begins suckling, sensory receptors in the nipples transmit signals to the hypothalamus. In response, oxytocin is secreted and released into the bloodstream. Within seconds, cells in the mother’s milk ducts contract, ejecting milk into the infant’s mouth. Secondly, in both males and females, oxytocin is thought to contribute to parent–newborn bonding, known as attachment. Oxytocin is also thought to be involved in feelings of love and closeness, as well as in the sexual response.

Antidiuretic Hormone (ADH)

The solute concentration of the blood, or blood osmolarity, may change in response to the consumption of certain foods and fluids, as well as in response to disease, injury, medications, or other factors. Blood osmolarity is constantly monitored by osmoreceptors—specialized cells within the hypothalamus that are particularly sensitive to the concentration of sodium ions and other solutes.

In response to high blood osmolarity, which can occur during dehydration or following a very salty meal, the osmoreceptors signal the posterior pituitary to release antidiuretic hormone (ADH). The target cells of ADH are located in the tubular cells of the kidneys. Its effect is to increase epithelial permeability to water, allowing increased water reabsorption. The more water reabsorbed from the filtrate, the greater the amount of water that is returned to the blood and the less that is excreted in the urine. A greater concentration of water results in a reduced concentration of solutes. ADH is also known as vasopressin because, in very high concentrations, it causes constriction of blood vessels, which increases blood pressure by increasing peripheral resistance. The release of ADH is controlled by a negative feedback loop. As blood osmolarity decreases, the hypothalamic osmoreceptors sense the change and prompt a corresponding decrease in the secretion of ADH. As a result, less water is reabsorbed from the urine filtrate.

Interestingly, drugs can affect the secretion of ADH. For example, alcohol consumption inhibits the release of ADH, resulting in increased urine production that can eventually lead to dehydration and a hangover. A disease called diabetes insipidus is characterized by chronic underproduction of ADH that causes chronic dehydration. Because little ADH is produced and secreted, not enough water is reabsorbed by the kidneys. Although patients feel thirsty, and increase their fluid consumption, this doesn’t effectively decrease the solute concentration in their blood because ADH levels are not high enough to trigger water reabsorption in the kidneys. Electrolyte imbalances can occur in severe cases of diabetes insipidus.

Anterior Pituitary

The anterior pituitary originates from the digestive tract in the embryo and migrates toward the brain during fetal development. There are three regions: the pars distalis is the most anterior, the pars intermedia is adjacent to the posterior pituitary, and the pars tuberalis is a slender “tube” that wraps the infundibulum. Recall that the posterior pituitary does not synthesize hormones, but merely stores them. In contrast, the anterior pituitary does manufacture hormones. However, the secretion of hormones from the anterior pituitary is regulated by two classes of hormones. These hormones—secreted by the hypothalamus—are the releasing hormones that stimulate the secretion of hormones from the anterior pituitary and the inhibiting hormones that inhibit secretion. Hypothalamic hormones are secreted by neurons, but enter the anterior pituitary through blood vessels (Figure 3). Within the infundibulum is a bridge of capillaries that connects the hypothalamus to the anterior pituitary. This network, called the hypophyseal portal system, allows hypothalamic hormones to be transported to the anterior pituitary without first entering the systemic circulation. The system originates from the superior hypophyseal artery, which branches off the carotid arteries and transports blood to the hypothalamus. The branches of the superior hypophyseal artery form the hypophyseal portal system (see Figure 3). Hypothalamic releasing and inhibiting hormones travel through a primary capillary plexus to the portal veins, which carry them into the anterior pituitary. Hormones produced by the anterior pituitary (in response to releasing hormones) enter a secondary capillary plexus, and from there drain into the circulation.

[caption id="" align="aligncenter" width="520"] Figure 3. Anterior Pituitary. The anterior pituitary manufactures seven hormones. The hypothalamus produces separate hormones that stimulate or inhibit hormone production in the anterior pituitary. Hormones from the hypothalamus reach the anterior pituitary via the hypophyseal portal system.[/caption]

The anterior pituitary produces seven hormones. These are the growth hormone (GH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), beta endorphin, and prolactin. Of the hormones of the anterior pituitary, TSH, ACTH, FSH, and LH are collectively referred to as tropic hormones (trope- = “turning”) because they turn on or off the function of other endocrine glands.

Growth Hormone

The endocrine system regulates the growth of the human body, protein synthesis, and cellular replication. A major hormone involved in this process is growth hormone (GH), also called somatotropin—a protein hormone produced and secreted by the anterior pituitary gland. Its primary function is anabolic; it promotes protein synthesis and tissue building through direct and indirect mechanisms (Figure 4). GH levels are controlled by the release of GHRH and GHIH (also known as somatostatin) from the hypothalamus.

[caption id="" align="aligncenter" width="550"] Figure 4. Hormonal Regulation of Growth. Growth hormone (GH) directly accelerates the rate of protein synthesis in skeletal muscle and bones. Insulin-like growth factor 1 (IGF-1) is activated by growth hormone and indirectly supports the formation of new proteins in muscle cells and bone.[/caption]

A glucose-sparing effect occurs when GH stimulates lipolysis, or the breakdown of adipose tissue, releasing fatty acids into the blood. As a result, many tissues switch from glucose to fatty acids as their main energy source, which means that less glucose is taken up from the bloodstream.

GH also initiates the diabetogenic effect in which GH stimulates the liver to break down glycogen to glucose, which is then deposited into the blood. The name “diabetogenic” is derived from the similarity in elevated blood glucose levels observed between individuals with untreated diabetes mellitus and individuals experiencing GH excess. Blood glucose levels rise as the result of a combination of glucose-sparing and diabetogenic effects.

GH indirectly mediates growth and protein synthesis by triggering the liver and other tissues to produce a group of proteins called insulin-like growth factors (IGFs). These proteins enhance cellular proliferation and inhibit apoptosis, or programmed cell death. IGFs stimulate cells to increase their uptake of amino acids from the blood for protein synthesis. Skeletal muscle and cartilage cells are particularly sensitive to stimulation from IGFs.

Dysfunction of the endocrine system’s control of growth can result in several disorders. For example, gigantism is a disorder in children that is caused by the secretion of abnormally large amounts of GH, resulting in excessive growth. A similar condition in adults is acromegaly, a disorder that results in the growth of bones in the face, hands, and feet in response to excessive levels of GH in individuals who have stopped growing. Abnormally low levels of GH in children can cause growth impairment—a disorder called pituitary dwarfism (also known as growth hormone deficiency).

Thyroid-Stimulating Hormone

The activity of the thyroid gland is regulated by thyroid-stimulating hormone (TSH), also called thyrotropin. TSH is released from the anterior pituitary in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. As discussed shortly, it triggers the secretion of thyroid hormones by the thyroid gland. In a classic negative feedback loop, elevated levels of thyroid hormones in the bloodstream then trigger a drop in production of TRH and subsequently TSH.

Adrenocorticotropic Hormone

The adrenocorticotropic hormone (ACTH), also called corticotropin, stimulates the adrenal cortex (the more superficial “bark” of the adrenal glands) to secrete corticosteroid hormones such as cortisol. ACTH come from a precursor molecule known as pro-opiomelanotropin (POMC) which produces several biologically active molecules when cleaved, including ACTH, melanocyte-stimulating hormone, and the brain opioid peptides known as endorphins. The release of ACTH is regulated by the corticotropin-releasing hormone (CRH) from the hypothalamus in response to normal physiologic rhythms. A variety of stressors can also influence its release, and the role of ACTH in the stress response is discussed later in this chapter.

Follicle-Stimulating Hormone and Luteinizing Hormone

The endocrine glands secrete a variety of hormones that control the development and regulation of the reproductive system (these glands include the anterior pituitary, the adrenal cortex, and the gonads—the testes in males and the ovaries in females). Much of the development of the reproductive system occurs during puberty and is marked by the development of sex-specific characteristics in both male and female adolescents. Puberty is initiated by gonadotropin-releasing hormone (GnRH), a hormone produced and secreted by the hypothalamus. GnRH stimulates the anterior pituitary to secrete gonadotropins—hormones that regulate the function of the gonads. The levels of GnRH are regulated through a negative feedback loop; high levels of reproductive hormones inhibit the release of GnRH. Throughout life, gonadotropins regulate reproductive function and, in the case of women, the onset and cessation of reproductive capacity.

The gonadotropins include two glycoprotein hormones: follicle-stimulating hormone (FSH) stimulates the production and maturation of sex cells, or gametes, including ova in women and sperm in men. FSH also promotes follicular growth; these follicles then release estrogens in the female ovaries. Luteinizing hormone (LH) triggers ovulation in women, as well as the production of estrogens and progesterone by the ovaries. LH stimulates production of testosterone by the male testes.

Prolactin

As its name implies, prolactin (PRL) promotes lactation (milk production) in women. During pregnancy, it contributes to development of the mammary glands, and after birth, it stimulates the mammary glands to produce breast milk. However, the effects of prolactin depend heavily upon the permissive effects of estrogens, progesterone, and other hormones. And as noted earlier, the let-down of milk occurs in response to stimulation from oxytocin. In a non-pregnant woman, prolactin secretion is inhibited by prolactin-inhibiting hormone (PIH), which is actually the neurotransmitter dopamine, and is released from neurons in the hypothalamus. Only during pregnancy do prolactin levels rise in response to prolactin-releasing hormone (PRH) from the hypothalamus.

Intermediate Pituitary: Melanocyte-Stimulating Hormone

The cells in the zone between the pituitary lobes secrete a hormone known as melanocyte-stimulating hormone (MSH) that is formed by cleavage of the pro-opiomelanocortin (POMC) precursor protein. Local production of MSH in the skin is responsible for melanin production in response to UV light exposure. The role of MSH made by the pituitary is more complicated. For instance, people with lighter skin generally have the same amount of MSH as people with darker skin. Nevertheless, this hormone is capable of darkening of the skin by inducing melanin production in the skin’s melanocytes. Women also show increased MSH production during pregnancy; in combination with estrogens, it can lead to darker skin pigmentation, especially the skin of the areolas and labia minora. Figure 5 is a summary of the pituitary hormones and their principal effects.

[caption id="" align="aligncenter" width="550"] Figure 5. Major Pituitary Hormones. Major pituitary hormones and their target organs.[/caption]

17.4 The Thyroid Gland

barkerj1 — Wed, 06 Sep 2017 01:19:38 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the functions of the thyroid gland
Describe the effects of:
- Hyposecretion of thyroxine in childhood
- Hyposecretion of thyroxine in adulthood
- Hypersecretion of thyroxine in childhood
- Hypersecretion of thyroxine in adulthood
- Lack of iodine in the diet
Describe the homeostatic control of blood calcium levels

A butterfly-shaped organ, the thyroid gland is located anterior to the trachea, just inferior to the larynx (Figure 1). The medial region, called the isthmus, is flanked by wing-shaped left and right lobes. Each of the thyroid lobes are embedded with parathyroid glands, primarily on their posterior surfaces. The tissue of the thyroid gland is composed mostly of thyroid follicles. The follicles are made up of a central cavity filled with a sticky fluid called colloid. Surrounded by a wall of epithelial follicle cells, the colloid is the center of thyroid hormone production, and that production is dependent on the hormones’ essential and unique component: iodine.

[caption id="" align="aligncenter" width="380"] Figure 1. Thyroid Gland. The thyroid gland is located in the neck where it wraps around the trachea. (a) Anterior view of the thyroid gland. (b) Posterior view of the thyroid gland. (c) The glandular tissue is composed primarily of thyroid follicles. The larger parafollicular cells often appear within the matrix of follicle cells. LM × 1332. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Synthesis and Release of Thyroid Hormones

Hormones are produced in the colloid when atoms of the mineral iodine attach to a glycoprotein, called thyroglobulin, that is secreted into the colloid by the follicle cells. The following steps outline the hormones’ assembly:

Binding of TSH to its receptors in the follicle cells of the thyroid gland causes the cells to actively transport iodide ions (I^–) across their cell membrane, from the bloodstream into the cytosol. As a result, the concentration of iodide ions “trapped” in the follicular cells is many times higher than the concentration in the bloodstream.
Iodide ions then move to the lumen of the follicle cells that border the colloid. There, the ions undergo oxidation (their negatively charged electrons are removed). The oxidation of two iodide ions (2 I^–) results in iodine (I₂), which passes through the follicle cell membrane into the colloid.
In the colloid, peroxidase enzymes link the iodine to the tyrosine amino acids in thyroglobulin to produce two intermediaries: a tyrosine attached to one iodine and a tyrosine attached to two iodines. When one of each of these intermediaries is linked by covalent bonds, the resulting compound is triiodothyronine (T₃), a thyroid hormone with three iodines. Much more commonly, two copies of the second intermediary bond, forming tetraiodothyronine, also known as thyroxine (T₄), a thyroid hormone with four iodines.

These hormones remain in the colloid center of the thyroid follicles until TSH stimulates endocytosis of colloid back into the follicle cells. There, lysosomal enzymes break apart the thyroglobulin colloid, releasing free T₃ and T₄, which diffuse across the follicle cell membrane and enter the bloodstream.

In the bloodstream, less than one percent of the circulating T₃ and T₄ remains unbound. This free T₃ and T₄ can cross the lipid bilayer of cell membranes and be taken up by cells. The remaining 99 percent of circulating T₃ and T₄ is bound to specialized transport proteins called thyroxine-binding globulins (TBGs), to albumin, or to other plasma proteins. This “packaging” prevents their free diffusion into body cells. When blood levels of T₃ and T₄begin to decline, bound T₃ and T₄ are released from these plasma proteins and readily cross the membrane of target cells. T₃ is more potent than T₄, and many cells convert T₄ to T₃ through the removal of an iodine atom.

Regulation of TH Synthesis

The release of T₃ and T₄ from the thyroid gland is regulated by thyroid-stimulating hormone (TSH). As shown in Figure 2, low blood levels of T₃ and T₄ stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus, which triggers secretion of TSH from the anterior pituitary. In turn, TSH stimulates the thyroid gland to secrete T₃ and T₄. The levels of TRH, TSH, T₃, and T₄ are regulated by a negative feedback system in which increasing levels of T₃ and T₄ decrease the production and secretion of TSH.

[caption id="" align="aligncenter" width="520"] Figure 2. Classic Negative Feedback Loop. A classic negative feedback loop controls the regulation of thyroid hormone levels.[/caption]

Functions of Thyroid Hormones

The thyroid hormones, T₃ and T₄, are often referred to as metabolic hormones because their levels influence the body’s basal metabolic rate, the amount of energy used by the body at rest. When T₃ and T₄ bind to intracellular receptors located on the mitochondria, they cause an increase in nutrient breakdown and the use of oxygen to produce ATP. In addition, T₃ and T₄ initiate the transcription of genes involved in glucose oxidation. Although these mechanisms prompt cells to produce more ATP, the process is inefficient, and an abnormally increased level of heat is released as a byproduct of these reactions. This so-called calorigenic effect (calor- = “heat”) raises body temperature.

Adequate levels of thyroid hormones are also required for protein synthesis and for fetal and childhood tissue development and growth. They are especially critical for normal development of the nervous system both in utero and in early childhood, and they continue to support neurological function in adults. As noted earlier, these thyroid hormones have a complex interrelationship with reproductive hormones, and deficiencies can influence libido, fertility, and other aspects of reproductive function. Finally, thyroid hormones increase the body’s sensitivity to catecholamines (epinephrine and norepinephrine) from the adrenal medulla by upregulation of receptors in the blood vessels. When levels of T₃ and T₄ hormones are excessive, this effect accelerates the heart rate, strengthens the heartbeat, and increases blood pressure. Because thyroid hormones regulate metabolism, heat production, protein synthesis, and many other body functions, thyroid disorders can have severe and widespread consequences.

Iodine Deficiency, Hypothyroidism, and Hyperthyroidism As discussed above, dietary iodine is required for the synthesis of T₃ and T₄. But for much of the world’s population, foods do not provide adequate levels of this mineral, because the amount varies according to the level in the soil in which the food was grown, as well as the irrigation and fertilizers used. Marine fish and shrimp tend to have high levels because they concentrate iodine from seawater, but many people in landlocked regions lack access to seafood. Thus, the primary source of dietary iodine in many countries is iodized salt. Fortification of salt with iodine began in the United States in 1924, and international efforts to iodize salt in the world’s poorest nations continue today.

Dietary iodine deficiency can result in the impaired ability to synthesize T₃ and T₄, leading to a variety of severe disorders. When T₃ and T₄ cannot be produced, TSH is secreted in increasing amounts. As a result of this hyperstimulation, thyroglobulin accumulates in the thyroid gland follicles, increasing their deposits of colloid. The accumulation of colloid increases the overall size of the thyroid gland, a condition called a goiter (Figure 3). A goiter is only a visible indication of the deficiency. Other iodine deficiency disorders include impaired growth and development, decreased fertility, and prenatal and infant death. Moreover, iodine deficiency is the primary cause of preventable mental retardation worldwide. Neonatal hypothyroidism (cretinism) is characterized by cognitive deficits, short stature, and sometimes deafness and muteness in children and adults born to mothers who were iodine-deficient during pregnancy.

[caption id="" align="aligncenter" width="380"] Figure 3. Goiter. (credit: “Almazi”/Wikimedia Commons)[/caption]

In areas of the world with access to iodized salt, dietary deficiency is rare. Instead, inflammation of the thyroid gland is the more common cause of low blood levels of thyroid hormones. Called hypothyroidism, the condition is characterized by a low metabolic rate, weight gain, cold extremities, constipation, reduced libido, menstrual irregularities, and reduced mental activity. In contrast, hyperthyroidism—an abnormally elevated blood level of thyroid hormones—is often caused by a pituitary or thyroid tumor. In Graves’ disease, the hyperthyroid state results from an autoimmune reaction in which antibodies overstimulate the follicle cells of the thyroid gland. Hyperthyroidism can lead to an increased metabolic rate, excessive body heat and sweating, diarrhea, weight loss, tremors, and increased heart rate. The person’s eyes may bulge (called exophthalmos) as antibodies produce inflammation in the soft tissues of the orbits. The person may also develop a goiter.

Calcitonin

The thyroid gland also secretes a hormone called calcitonin that is produced by the parafollicular cells (also called C cells) that stud the tissue between distinct follicles. Calcitonin is released in response to a rise in blood calcium levels. It appears to have a function in decreasing blood calcium concentrations by:

Inhibiting the activity of osteoclasts, bone cells that release calcium into the circulation by degrading bone matrix
Increasing osteoblastic activity
Decreasing calcium absorption in the intestines
Increasing calcium loss in the urine

However, these functions are usually not significant in maintaining calcium homeostasis, so the importance of calcitonin is not entirely understood. Pharmaceutical preparations of calcitonin are sometimes prescribed to reduce osteoclast activity in people with osteoporosis and to reduce the degradation of cartilage in people with osteoarthritis. The hormones secreted by thyroid are summarized in Table 4.

Thyroid Hormones (Table 4)
Associated hormones	Chemical class	Effect
Thyroxine (T₄), triiodothyronine (T₃)	Amine	Stimulate basal metabolic rate
Calcitonin	Peptide	Reduces blood Ca²⁺ levels

Of course, calcium is critical for many other biological processes. It is a second messenger in many signaling pathways, and is essential for muscle contraction, nerve impulse transmission, and blood clotting. Given these roles, it is not surprising that blood calcium levels are tightly regulated by the endocrine system. The organs involved in the regulation are the parathyroid glands.

17.5 The Parathyroid Glands

barkerj1 — Wed, 06 Sep 2017 01:19:40 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the function of the parathyroid glands
Describe the homeostatic control of blood calcium levels

The parathyroid glands are tiny, round structures usually found embedded in the posterior surface of the thyroid gland (Figure 1). A thick connective tissue capsule separates the glands from the thyroid tissue. Most people have four parathyroid glands, but occasionally there are more in tissues of the neck or chest. The function of one type of parathyroid cells, the oxyphil cells, is not clear. The primary functional cells of the parathyroid glands are the chief cells. These epithelial cells produce and secrete the parathyroid hormone (PTH), the major hormone involved in the regulation of blood calcium levels.

[caption id="" align="aligncenter" width="550"] Figure 1. Parathyroid Glands. The small parathyroid glands are embedded in the posterior surface of the thyroid gland. LM × 760. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

The parathyroid glands produce and secrete PTH, a peptide hormone, in response to low blood calcium levels (Figure 2). PTH secretion causes the release of calcium from the bones by stimulating osteoclasts, which secrete enzymes that degrade bone and release calcium into the interstitial fluid. PTH also inhibits osteoblasts, the cells involved in bone deposition, thereby sparing blood calcium. PTH causes increased reabsorption of calcium (and magnesium) in the kidney tubules from the urine filtrate. In addition, PTH initiates the production of the steroid hormone calcitriol (also known as 1,25-dihydroxyvitamin D), which is the active form of vitamin D₃, in the kidneys. Calcitriol then stimulates increased absorption of dietary calcium by the intestines. A negative feedback loop regulates the levels of PTH, with rising blood calcium levels inhibiting further release of PTH.

[caption id="" align="aligncenter" width="550"] Figure 2. Parathyroid Hormone in Maintaining Blood Calcium Homeostasis. Parathyroid hormone increases blood calcium levels when they drop too low. Conversely, calcitonin, which is released from the thyroid gland, decreases blood calcium levels when they become too high. These two mechanisms constantly maintain blood calcium concentration at homeostasis.[/caption]

Abnormally high activity of the parathyroid gland can cause hyperparathyroidism, a disorder caused by an overproduction of PTH that results in excessive calcium reabsorption from bone. Hyperparathyroidism can significantly decrease bone density, leading to spontaneous fractures or deformities. As blood calcium levels rise, cell membrane permeability to sodium is decreased, and the responsiveness of the nervous system is reduced. At the same time, calcium deposits may collect in the body’s tissues and organs, impairing their functioning. In contrast, abnormally low blood calcium levels may be caused by parathyroid hormone deficiency, called hypoparathyroidism, which may develop following injury or surgery involving the thyroid gland. Low blood calcium increases membrane permeability to sodium, resulting in muscle twitching, cramping, spasms, or convulsions. Severe deficits can paralyze muscles, including those involved in breathing, and can be fatal.

When blood calcium levels are high, calcitonin is produced and secreted by the parafollicular cells of the thyroid gland. As discussed earlier, calcitonin inhibits the activity of osteoclasts, reduces the absorption of dietary calcium in the intestine, and signals the kidneys to reabsorb less calcium, resulting in larger amounts of calcium excreted in the urine.

17.6 The Adrenal Glands

barkerj1 — Wed, 06 Sep 2017 01:19:41 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the endocrine functions of the adrenal glands
Describe how the body responds to stress
Describe the effects of hyposecretion of glucocorticoids
Describe the effects of hypersecretion of glucocorticoids

The adrenal glands are wedges of glandular and neuroendocrine tissue adhering to the top of the kidneys by a fibrous capsule (Figure 1). The adrenal glands have a rich blood supply and experience one of the highest rates of blood flow in the body. They are served by several arteries branching off the aorta, including the suprarenal and renal arteries. Blood flows to each adrenal gland at the adrenal cortex and then drains into the adrenal medulla. Adrenal hormones are released into the circulation via the left and right suprarenal veins.

[caption id="" align="aligncenter" width="550"] Figure 1. Adrenal Glands. Both adrenal glands sit atop the kidneys and are composed of an outer cortex and an inner medulla, all surrounded by a connective tissue capsule. The cortex can be subdivided into additional zones, all of which produce different types of hormones. LM × 204. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

The adrenal gland consists of an outer cortex of glandular tissue and an inner medulla of nervous tissue. The cortex itself is divided into three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis. Each region secretes its own set of hormones.

The adrenal cortex, as a component of the hypothalamic-pituitary-adrenal (HPA) axis, secretes steroid hormones important for the regulation of the long-term stress response, blood pressure and blood volume, nutrient uptake and storage, fluid and electrolyte balance, and inflammation. The HPA axis involves the stimulation of hormone release of adrenocorticotropic hormone (ACTH) from the pituitary by the hypothalamus. ACTH then stimulates the adrenal cortex to produce the hormone cortisol. This pathway will be discussed in more detail below.

The adrenal medulla is neuroendocrine tissue composed of postganglionic sympathetic nervous system (SNS) neurons. It is really an extension of the autonomic nervous system, which regulates homeostasis in the body. The sympathomedullary pathway involves the stimulation of the medulla by impulses from the hypothalamus via neurons from the thoracic spinal cord. The medulla is stimulated to secrete the amine hormones epinephrine and norepinephrine.

One of the major functions of the adrenal gland is to respond to stress. Stress can be either physical or psychological or both. Physical stresses include exposing the body to injury, walking outside in cold and wet conditions without a coat on, or malnutrition. Psychological stresses include the perception of a physical threat, a fight with a loved one, or just a bad day at school.

The body responds in different ways to short-term stress and long-term stress following a pattern known as the general adaptation syndrome. Stage one of the general adaptation syndrome is called the alarm reaction. This "fight-or-flight" response, the result of a short term stressor, is mediated by the hormones epinephrine and norepinephrine from the adrenal medulla via the sympathomedullary pathway. Their function is to prepare the body for extreme physical exertion. Once this stress is relieved, the body quickly returns to normal. The section on the adrenal medulla covers this response in more detail.

If the stress is not soon relieved, the body adapts to the stress in the second stage called the stage of resistance. If a person is starving for example, the body may send signals to the gastrointestinal tract to maximize the absorption of nutrients from food. Such physiological adaptations allow the body to resist the most immediate negative effects of a longer-term stressor.

If the stress continues for a longer term, however, the body's response becomes quite different from the fight-or-flight response. During the stage of exhaustion, individuals may begin to suffer depression, the suppression of their immune response, severe fatigue, or even a fatal heart attack. These symptoms are mediated by the hormones of the adrenal cortex, especially cortisol, released as a result of signals from the HPA axis. While these signals may be helpful or even necessary in the short term, their continued or repeated release over an extended period of time can cause damage to a variety of organ systems.

Adrenal hormones also have several non–stress-related functions, including the increase of blood sodium and glucose levels, which will be described in detail below.

Adrenal Cortex

The adrenal cortex consists of multiple layers of lipid-storing cells that occur in three structurally distinct regions. Each of these regions produces different hormones.

Hormones of the Zona Glomerulosa

The most superficial region of the adrenal cortex is the zona glomerulosa, which produces a group of hormones collectively referred to as mineralocorticoids because of their effect on body minerals, especially sodium and potassium. These hormones are essential for fluid and electrolyte balance.

Aldosterone is the major mineralocorticoid. It is important in the regulation of the concentration of sodium and potassium ions in urine, sweat, and saliva. For example, it is released in response to elevated blood K⁺, low blood Na⁺, low blood pressure, or low blood volume. In response, aldosterone increases the excretion of K⁺ and the retention of Na⁺, which in turn increases blood volume and blood pressure. Its secretion is prompted when CRH from the hypothalamus triggers ACTH release from the anterior pituitary.

Aldosterone is also a key component of the renin-angiotensin-aldosterone system (RAAS) in which specialized cells of the kidneys secrete the enzyme renin in response to low blood volume or low blood pressure. Renin then catalyzes the conversion of the blood protein angiotensinogen, produced by the liver, to the hormone angiotensin I. Angiotensin I is converted in the lungs to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II has three major functions:

Initiating vasoconstriction of the arterioles, decreasing blood flow
Stimulating kidney tubules to reabsorb NaCl and water, increasing blood volume
Signaling the adrenal cortex to secrete aldosterone, the effects of which further contribute to fluid retention, restoring blood pressure and blood volume

For individuals with hypertension, or high blood pressure, drugs are available that block the production of angiotensin II. These drugs, known as ACE inhibitors, block the ACE enzyme from converting angiotensin I to angiotensin II, thus mitigating the latter’s ability to increase blood pressure.

Hormones of the Zona Fasciculata

The intermediate region of the adrenal cortex is the zona fasciculata, named as such because the cells form small fascicles (bundles) separated by tiny blood vessels. The cells of the zona fasciculata produce hormones called glucocorticoids because of their role in glucose metabolism. The most important of these is cortisol, some of which the liver converts to cortisone. A glucocorticoid produced in much smaller amounts is corticosterone. In response to long-term stressors, the hypothalamus secretes CRH, which in turn triggers the release of ACTH by the anterior pituitary. ACTH triggers the release of the glucocorticoids. Their overall effect is to inhibit tissue building while stimulating the breakdown of stored nutrients to maintain adequate fuel supplies. In conditions of long-term stress, for example, cortisol promotes the catabolism of glycogen to glucose, the catabolism of stored triglycerides into fatty acids and glycerol, and the catabolism of muscle proteins into amino acids. These raw materials can then be used to synthesize additional glucose and ketones for use as body fuels. The hippocampus, which is part of the temporal lobe of the cerebral cortices and important in memory formation, is highly sensitive to stress levels because of its many glucocorticoid receptors.

You are probably familiar with prescription and over-the-counter medications containing glucocorticoids, such as cortisone injections into inflamed joints, prednisone tablets and steroid-based inhalers used to manage severe asthma, and hydrocortisone creams applied to relieve itchy skin rashes. These drugs reflect another role of cortisol—the downregulation of the immune system, which inhibits the inflammatory response.

Hormones of the Zona Reticularis

The deepest region of the adrenal cortex is the zona reticularis, which produces small amounts of a class of steroid sex hormones called androgens. During puberty and most of adulthood, androgens are produced in the gonads. The androgens produced in the zona reticularis supplement the gonadal androgens. They are produced in response to ACTH from the anterior pituitary and are converted in the tissues to testosterone or estrogens. In adult women, they may contribute to the sex drive, but their function in adult men is not well understood. In post-menopausal women, as the functions of the ovaries decline, the main source of estrogens becomes the androgens produced by the zona reticularis.

Adrenal Medulla

As noted earlier, the adrenal cortex releases glucocorticoids in response to long-term stress such as severe illness. In contrast, the adrenal medulla releases its hormones in response to acute, short-term stress mediated by the sympathetic nervous system (SNS).

The medullary tissue is composed of unique postganglionic SNS neurons called chromaffin cells, which are large and irregularly shaped, and produce the neurotransmitters epinephrine (also called adrenaline) and norepinephrine (or noradrenaline). Epinephrine is produced in greater quantities—approximately a 4 to 1 ratio with norepinephrine—and is the more powerful hormone. Because the chromaffin cells release epinephrine and norepinephrine into the systemic circulation, where they travel widely and exert effects on distant cells, they are considered hormones. Derived from the amino acid tyrosine, they are chemically classified as catecholamines.

The secretion of medullary epinephrine and norepinephrine is controlled by a neural pathway that originates from the hypothalamus in response to danger or stress (the SAM pathway). Both epinephrine and norepinephrine signal the liver and skeletal muscle cells to convert glycogen into glucose, resulting in increased blood glucose levels. These hormones increase the heart rate, pulse, and blood pressure to prepare the body to fight the perceived threat or flee from it. In addition, the pathway dilates the airways, raising blood oxygen levels. It also prompts vasodilation, further increasing the oxygenation of important organs such as the lungs, brain, heart, and skeletal muscle. At the same time, it triggers vasoconstriction to blood vessels serving less essential organs such as the gastrointestinal tract, kidneys, and skin, and downregulates some components of the immune system. Other effects include a dry mouth, loss of appetite, pupil dilation, and a loss of peripheral vision. The major hormones of the adrenal glands are summarized in Table 5.

Hormones of the Adrenal Glands (Table 5)
Adrenal gland	Associated hormones	Chemical class	Effect
Adrenal cortex	Aldosterone	Steroid	Increases blood Na⁺ levels
Adrenal cortex	Cortisol, corticosterone, cortisone	Steroid	Increase blood glucose levels
Adrenal medulla	Epinephrine, norepinephrine	Amine	Stimulate fight-or-flight response

Disorders Involving the Adrenal Glands

Several disorders are caused by the dysregulation of the hormones produced by the adrenal glands. For example, Cushing’s disease is a disorder characterized by high blood glucose levels and the accumulation of lipid deposits on the face and neck. It is caused by hypersecretion of cortisol. The most common source of Cushing’s disease is a pituitary tumor that secretes cortisol or ACTH in abnormally high amounts. Other common signs of Cushing’s disease include the development of a moon-shaped face, a buffalo hump on the back of the neck, rapid weight gain, and hair loss. Chronically elevated glucose levels are also associated with an elevated risk of developing type 2 diabetes. In addition to hyperglycemia, chronically elevated glucocorticoids compromise immunity, resistance to infection, and memory, and can result in rapid weight gain and hair loss.

In contrast, the hyposecretion of corticosteroids can result in Addison’s disease, a rare disorder that causes low blood glucose levels and low blood sodium levels. The signs and symptoms of Addison’s disease are vague and are typical of other disorders as well, making diagnosis difficult. They may include general weakness, abdominal pain, weight loss, nausea, vomiting, sweating, and cravings for salty food.

17.7 The Pineal Gland

barkerj1 — Wed, 06 Sep 2017 01:19:41 +0000

Learning Objectives

By the end of this section, you will be able to:

Specify the role of the pineal gland

Recall that the hypothalamus, part of the diencephalon of the brain, sits inferior and somewhat anterior to the thalamus. Inferior but somewhat posterior to the thalamus is the pineal gland, a tiny endocrine gland whose functions are not entirely clear. The pinealocyte cells that make up the pineal gland are known to produce and secrete the amine hormone melatonin, which is derived from serotonin.

The secretion of melatonin varies according to the level of light received from the environment. When photons of light stimulate the retinas of the eyes, a nerve impulse is sent to a region of the hypothalamus called the suprachiasmatic nucleus (SCN), which is important in regulating biological rhythms. From the SCN, the nerve signal is carried to the spinal cord and eventually to the pineal gland, where the production of melatonin is inhibited. As a result, blood levels of melatonin fall, promoting wakefulness. In contrast, as light levels decline—such as during the evening—melatonin production increases, boosting blood levels and causing drowsiness.

The secretion of melatonin may influence the body’s circadian rhythms, the dark-light fluctuations that affect not only sleepiness and wakefulness, but also appetite and body temperature. Interestingly, children have higher melatonin levels than adults, which may prevent the release of gonadotropins from the anterior pituitary, thereby inhibiting the onset of puberty. Finally, an antioxidant role of melatonin is the subject of current research.

Jet lag occurs when a person travels across several time zones and feels sleepy during the day or wakeful at night. Traveling across multiple time zones significantly disturbs the light-dark cycle regulated by melatonin. It can take up to several days for melatonin synthesis to adjust to the light-dark patterns in the new environment, resulting in jet lag. Some air travelers take melatonin supplements to induce sleep.

17.8 Gonadal and Placental Hormones

barkerj1 — Wed, 06 Sep 2017 01:19:42 +0000

Learning Objectives

By the end of this section, you will be able to:

Give the endocrine functions of the ovaries and testes

This section briefly discusses the hormonal role of the gonads—the male testes and female ovaries—which produce the sex cells (sperm and ova) and secrete the gonadal hormones. The roles of the gonadotropins released from the anterior pituitary (FSH and LH) were discussed earlier.

The primary hormone produced by the male testes is testosterone, a steroid hormone important in the development of the male reproductive system, the maturation of sperm cells, and the development of male secondary sex characteristics such as a deepened voice, body hair, and increased muscle mass. Interestingly, testosterone is also produced in the female ovaries, but at a much reduced level. In addition, the testes produce the peptide hormone inhibin, which inhibits the secretion of FSH from the anterior pituitary gland. FSH stimulates spermatogenesis.

The primary hormones produced by the ovaries are estrogens, which include estradiol, estriol, and estrone. Estrogens play an important role in a larger number of physiological processes, including the development of the female reproductive system, regulation of the menstrual cycle, the development of female secondary sex characteristics such as increased adipose tissue and the development of breast tissue, and the maintenance of pregnancy. Another significant ovarian hormone is progesterone, which contributes to regulation of the menstrual cycle and is important in preparing the body for pregnancy as well as maintaining pregnancy. In addition, the granulosa cells of the ovarian follicles produce inhibin, which—as in males—inhibits the secretion of FSH.During the initial stages of pregnancy, an organ called the placenta develops within the uterus. The placenta supplies oxygen and nutrients to the fetus, excretes waste products, and produces and secretes estrogens and progesterone. The placenta produces human chorionic gonadotropin (hCG) as well. The hCG hormone promotes progesterone synthesis and reduces the mother’s immune function to protect the fetus from immune rejection. It also secretes human placental lactogen (hPL), which plays a role in preparing the breasts for lactation, and relaxin, which is thought to help soften and widen the pubic symphysis in preparation for childbirth. The hormones controlling reproduction are summarized in Table 6.

Reproductive Hormones (Table 6)
Gonad	Associated hormones	Chemical class	Effect
Testes	Testosterone	Steroid	Stimulates development of male secondary sex characteristics and sperm production
Testes	Inhibin	Protein	Inhibits FSH release from pituitary
Ovaries	Estrogens and progesterone	Steroid	Stimulate development of female secondary sex characteristics and prepare the body for childbirth
Placenta	Human chorionic gonadotropin	Protein	Promotes progesterone synthesis during pregnancy and inhibits immune response against fetus

Everyday Connections

Anabolic SteroidsThe endocrine system can be exploited for illegal or unethical purposes. A prominent example of this is the use of steroid drugs by professional athletes.

Commonly used for performance enhancement, anabolic steroids are synthetic versions of the male sex hormone, testosterone. By boosting natural levels of this hormone, athletes experience increased muscle mass. Synthetic versions of human growth hormone are also used to build muscle mass.

The use of performance-enhancing drugs is banned by all major collegiate and professional sports organizations in the United States because they impart an unfair advantage to athletes who take them. In addition, the drugs can cause significant and dangerous side effects. For example, anabolic steroid use can increase cholesterol levels, raise blood pressure, and damage the liver. Altered testosterone levels (both too low or too high) have been implicated in causing structural damage to the heart, and increasing the risk for cardiac arrhythmias, heart attacks, congestive heart failure, and sudden death. Paradoxically, steroids can have a feminizing effect in males, including shriveled testicles and enlarged breast tissue. In females, their use can cause masculinizing effects such as an enlarged clitoris and growth of facial hair. In both sexes, their use can promote increased aggression (commonly known as “roid-rage”), depression, sleep disturbances, severe acne, and infertility.

17.9 The Endocrine Pancreas

barkerj1 — Wed, 06 Sep 2017 01:19:43 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the endocrine function of the pancreas
Describe the homeostatic control of blood glucose levels

The pancreas is a long, slender organ, most of which is located posterior to the bottom half of the stomach (Figure 1). Although it is primarily an exocrine gland, secreting a variety of digestive enzymes, the pancreas has an endocrine function. Its pancreatic islets—clusters of cells formerly known as the islets of Langerhans—secrete the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide (PP).

[caption id="" align="aligncenter" width="500"] Figure 1. Pancreas. The pancreatic exocrine function involves the acinar cells secreting digestive enzymes that are transported into the small intestine by the pancreatic duct. Its endocrine function involves the secretion of insulin (produced by beta cells) and glucagon (produced by alpha cells) within the pancreatic islets. These two hormones regulate the rate of glucose metabolism in the body. The micrograph reveals pancreatic islets. LM × 760. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Cells and Secretions of the Pancreatic Islets

The pancreatic islets each contain four varieties of cells:

The alpha cell produces the hormone glucagon and makes up approximately 20 percent of each islet. Glucagon plays an important role in blood glucose regulation; low blood glucose levels stimulate its release.
The beta cell produces the hormone insulin and makes up approximately 75 percent of each islet. Elevated blood glucose levels stimulate the release of insulin.
The delta cell accounts for four percent of the islet cells and secretes the peptide hormone somatostatin. Recall that somatostatin is also released by the hypothalamus (as GHIH), and the stomach and intestines also secrete it. An inhibiting hormone, pancreatic somatostatin inhibits the release of both glucagon and insulin.
The PP cell accounts for about one percent of islet cells and secretes the pancreatic polypeptide hormone. It is thought to play a role in appetite, as well as in the regulation of pancreatic exocrine and endocrine secretions. Pancreatic polypeptide released following a meal may reduce further food consumption; however, it is also released in response to fasting.

Regulation of Blood Glucose Levels by Insulin and Glucagon

Glucose is required for cellular respiration and is the preferred fuel for all body cells. The body derives glucose from the breakdown of the carbohydrate-containing foods and drinks we consume. Glucose not immediately taken up by cells for fuel can be stored by the liver and muscles as glycogen, or converted to triglycerides and stored in the adipose tissue. Hormones regulate both the storage and the utilization of glucose as required. Receptors located in the pancreas sense blood glucose levels, and subsequently the pancreatic cells secrete glucagon or insulin to maintain normal levels.

Glucagon

Receptors in the pancreas can sense the decline in blood glucose levels, such as during periods of fasting or during prolonged labor or exercise (Figure 2). In response, the alpha cells of the pancreas secrete the hormone glucagon, which has several effects:

It stimulates the liver to convert its stores of glycogen back into glucose. This response is known as glycogenolysis. The glucose is then released into the circulation for use by body cells.
It stimulates the liver to take up amino acids from the blood and convert them into glucose. This response is known as gluconeogenesis.
It stimulates lipolysis, the breakdown of stored triglycerides into free fatty acids and glycerol. Some of the free glycerol released into the bloodstream travels to the liver, which converts it into glucose. This is also a form of gluconeogenesis.

Taken together, these actions increase blood glucose levels. The activity of glucagon is regulated through a negative feedback mechanism; rising blood glucose levels inhibit further glucagon production and secretion.

[caption id="" align="aligncenter" width="550"] Figure 2. Homeostatic Regulation of Blood Glucose Levels. Blood glucose concentration is tightly maintained between 70 mg/dL and 110 mg/dL. If blood glucose concentration rises above this range, insulin is released, which stimulates body cells to remove glucose from the blood. If blood glucose concentration drops below this range, glucagon is released, which stimulates body cells to release glucose into the blood.[/caption]

Insulin

The primary function of insulin is to facilitate the uptake of glucose into body cells. Red blood cells, as well as cells of the brain, liver, kidneys, and the lining of the small intestine, do not have insulin receptors on their cell membranes and do not require insulin for glucose uptake. Although all other body cells do require insulin if they are to take glucose from the bloodstream, skeletal muscle cells and adipose cells are the primary targets of insulin.

The presence of food in the intestine triggers the release of gastrointestinal tract hormones such as glucose-dependent insulinotropic peptide (previously known as gastric inhibitory peptide). This is in turn the initial trigger for insulin production and secretion by the beta cells of the pancreas. Once nutrient absorption occurs, the resulting surge in blood glucose levels further stimulates insulin secretion.

Precisely how insulin facilitates glucose uptake is not entirely clear. However, insulin appears to activate a tyrosine kinase receptor, triggering the phosphorylation of many substrates within the cell. These multiple biochemical reactions converge to support the movement of intracellular vesicles containing facilitative glucose transporters to the cell membrane. In the absence of insulin, these transport proteins are normally recycled slowly between the cell membrane and cell interior. Insulin triggers the rapid movement of a pool of glucose transporter vesicles to the cell membrane, where they fuse and expose the glucose transporters to the extracellular fluid. The transporters then move glucose by facilitated diffusion into the cell interior.

Insulin also reduces blood glucose levels by stimulating glycolysis, the metabolism of glucose for generation of ATP. Moreover, it stimulates the liver to convert excess glucose into glycogen for storage, and it inhibits enzymes involved in glycogenolysis and gluconeogenesis. Finally, insulin promotes triglyceride and protein synthesis. The secretion of insulin is regulated through a negative feedback mechanism. As blood glucose levels decrease, further insulin release is inhibited. The pancreatic hormones are summarized in Table 7.

Hormones of the Pancreas (Table 7)
Associated hormones	Chemical class	Effect
Insulin (beta cells)	Protein	Reduces blood glucose levels
Glucagon (alpha cells)	Protein	Increases blood glucose levels
Somatostatin (delta cells)	Protein	Inhibits insulin and glucagon release
Pancreatic polypeptide (PP cells)	Protein	Role in appetite

Disorders of the…

Endocrine System: Diabetes Mellitus Dysfunction of insulin production and secretion, as well as the target cells’ responsiveness to insulin, can lead to a condition called diabetes mellitus. An increasingly common disease, diabetes mellitus has been diagnosed in more than 18 million adults in the United States, and more than 200,000 children. It is estimated that up to 7 million more adults have the condition but have not been diagnosed. In addition, approximately 79 million people in the US are estimated to have pre-diabetes, a condition in which blood glucose levels are abnormally high, but not yet high enough to be classified as diabetes.

There are two main forms of diabetes mellitus. Type 1 diabetes is an autoimmune disease affecting the beta cells of the pancreas. Certain genes are recognized to increase susceptibility. The beta cells of people with type 1 diabetes do not produce insulin; thus, synthetic insulin must be administered by injection or infusion. This form of diabetes accounts for less than five percent of all diabetes cases.

Type 2 diabetes accounts for approximately 95 percent of all cases. It is acquired, and lifestyle factors such as poor diet, inactivity, and the presence of pre-diabetes greatly increase a person’s risk. About 80 to 90 percent of people with type 2 diabetes are overweight or obese. In type 2 diabetes, cells become resistant to the effects of insulin. In response, the pancreas increases its insulin secretion, but over time, the beta cells become exhausted. In many cases, type 2 diabetes can be reversed by moderate weight loss, regular physical activity, and consumption of a healthy diet; however, if blood glucose levels cannot be controlled, the diabetic will eventually require insulin.

Two of the early manifestations of diabetes are excessive urination and excessive thirst. They demonstrate how the out-of-control levels of glucose in the blood affect kidney function. The kidneys are responsible for filtering glucose from the blood. Excessive blood glucose draws water into the urine, and as a result the person eliminates an abnormally large quantity of sweet urine. The use of body water to dilute the urine leaves the body dehydrated, and so the person is unusually and continually thirsty. The person may also experience persistent hunger because the body cells are unable to access the glucose in the bloodstream.

Over time, persistently high levels of glucose in the blood injure tissues throughout the body, especially those of the blood vessels and nerves. Inflammation and injury of the lining of arteries lead to atherosclerosis and an increased risk of heart attack and stroke. Damage to the microscopic blood vessels of the kidney impairs kidney function and can lead to kidney failure. Damage to blood vessels that serve the eyes can lead to blindness. Blood vessel damage also reduces circulation to the limbs, whereas nerve damage leads to a loss of sensation, called neuropathy, particularly in the hands and feet. Together, these changes increase the risk of injury, infection, and tissue death (necrosis), contributing to a high rate of toe, foot, and lower leg amputations in people with diabetes. Uncontrolled diabetes can also lead to a dangerous form of metabolic acidosis called ketoacidosis. Deprived of glucose, cells increasingly rely on fat stores for fuel. However, in a glucose-deficient state, the liver is forced to use an alternative lipid metabolism pathway that results in the increased production of ketone bodies (or ketones), which are acidic. The build-up of ketones in the blood causes ketoacidosis, which—if left untreated—may lead to a life-threatening “diabetic coma.” Together, these complications make diabetes the seventh leading cause of death in the United States.

Diabetes is diagnosed when lab tests reveal that blood glucose levels are higher than normal, a condition called hyperglycemia. The treatment of diabetes depends on the type, the severity of the condition, and the ability of the patient to make lifestyle changes. As noted earlier, moderate weight loss, regular physical activity, and consumption of a healthful diet can reduce blood glucose levels. Some patients with type 2 diabetes may be unable to control their disease with these lifestyle changes, and will require medication. Historically, the first-line treatment of type 2 diabetes was insulin. Research advances have resulted in alternative options, including medications that enhance pancreatic function.

17.10 Organs with Secondary Endocrine Functions

barkerj1 — Wed, 06 Sep 2017 01:19:44 +0000

Learning Objectives

By the end of this section, you will be able to:

Specify the endocrine functions of the stomach and the duodenum
Describe the homeostatic control of blood glucose levels
Specify the endocrine role of the thymus

In your study of anatomy and physiology, you have already encountered a few of the many organs of the body that have secondary endocrine functions. Here, you will learn about the hormone-producing activities of the heart, gastrointestinal tract, kidneys, skeleton, adipose tissue, skin, and thymus.

Heart

When the body experiences an increase in blood volume or pressure, the cells of the heart’s atrial wall stretch. In response, specialized cells in the wall of the atria produce and secrete the peptide hormone atrial natriuretic peptide (ANP). ANP signals the kidneys to reduce sodium reabsorption, thereby decreasing the amount of water reabsorbed from the urine filtrate and reducing blood volume. Other actions of ANP include the inhibition of renin secretion and the initiation of the renin-angiotensin-aldosterone system (RAAS) and vasodilation. Therefore, ANP aids in decreasing blood pressure, blood volume, and blood sodium levels.

Gastrointestinal Tract

The endocrine cells of the GI tract are located in the mucosa of the stomach and small intestine. Some of these hormones are secreted in response to eating a meal and aid in digestion. An example of a hormone secreted by the stomach cells is gastrin, a peptide hormone secreted in response to stomach distention that stimulates the release of hydrochloric acid. Secretin is a peptide hormone secreted by the small intestine as acidic chyme (partially digested food and fluid) moves from the stomach. It stimulates the release of bicarbonate from the pancreas, which buffers the acidic chyme, and inhibits the further secretion of hydrochloric acid by the stomach. Cholecystokinin (CCK) is another peptide hormone released from the small intestine. It promotes the secretion of pancreatic enzymes and the release of bile from the gallbladder, both of which facilitate digestion. Other hormones produced by the intestinal cells aid in glucose metabolism, such as by stimulating the pancreatic beta cells to secrete insulin, reducing glucagon secretion from the alpha cells, or enhancing cellular sensitivity to insulin.

Kidneys

The kidneys participate in several complex endocrine pathways and produce certain hormones. A decline in blood flow to the kidneys stimulates them to release the enzyme renin, triggering the renin-angiotensin-aldosterone (RAAS) system, and stimulating the reabsorption of sodium and water. The reabsorption increases blood flow and blood pressure. The kidneys also play a role in regulating blood calcium levels through the production of calcitriol from vitamin D₃, which is released in response to the secretion of parathyroid hormone (PTH). In addition, the kidneys produce the hormone erythropoietin (EPO) in response to low oxygen levels. EPO stimulates the production of red blood cells (erythrocytes) in the bone marrow, thereby increasing oxygen delivery to tissues. You may have heard of EPO as a performance-enhancing drug (in a synthetic form).

Skeleton

Although bone has long been recognized as a target for hormones, only recently have researchers recognized that the skeleton itself produces at least two hormones. Fibroblast growth factor 23 (FGF23) is produced by bone cells in response to increased blood levels of vitamin D₃ or phosphate. It triggers the kidneys to inhibit the formation of calcitriol from vitamin D₃ and to increase phosphorus excretion. Osteocalcin, produced by osteoblasts, stimulates the pancreatic beta cells to increase insulin production. It also acts on peripheral tissues to increase their sensitivity to insulin and their utilization of glucose.

Adipose Tissue

Adipose tissue produces and secretes several hormones involved in lipid metabolism and storage. One important example is leptin, a protein manufactured by adipose cells that circulates in amounts directly proportional to levels of body fat. Leptin is released in response to food consumption and acts by binding to brain neurons involved in energy intake and expenditure. Binding of leptin produces a feeling of satiety after a meal, thereby reducing appetite. It also appears that the binding of leptin to brain receptors triggers the sympathetic nervous system to regulate bone metabolism, increasing deposition of cortical bone. Adiponectin—another hormone synthesized by adipose cells—appears to reduce cellular insulin resistance and to protect blood vessels from inflammation and atherosclerosis. Its levels are lower in people who are obese, and rise following weight loss.

Skin

The skin functions as an endocrine organ in the production of the inactive form of vitamin D₃, cholecalciferol. When cholesterol present in the epidermis is exposed to ultraviolet radiation, it is converted to cholecalciferol, which then enters the blood. In the liver, cholecalciferol is converted to an intermediate that travels to the kidneys and is further converted to calcitriol, the active form of vitamin D₃. Vitamin D is important in a variety of physiological processes, including intestinal calcium absorption and immune system function. In some studies, low levels of vitamin D have been associated with increased risks of cancer, severe asthma, and multiple sclerosis. Vitamin D deficiency in children causes rickets, and in adults, osteomalacia—both of which are characterized by bone deterioration.

Thymus

The thymus is an organ of the immune system that is larger and more active during infancy and early childhood, and begins to atrophy as we age. Its endocrine function is the production of a group of hormones called thymosins that contribute to the development and differentiation of T lymphocytes, which are immune cells. Although the role of thymosins is not yet well understood, it is clear that they contribute to the immune response. Thymosins have been found in tissues other than the thymus and have a wide variety of functions, so the thymosins cannot be strictly categorized as thymic hormones.

Liver

The liver is responsible for secreting at least four important hormones or hormone precursors: insulin-like growth factor (somatomedin), angiotensinogen, thrombopoetin, and hepcidin. Insulin-like growth factor-1 is the immediate stimulus for growth in the body, especially of the bones. Angiotensinogen is the precursor to angiotensin, mentioned earlier, which increases blood pressure. Thrombopoetin stimulates the production of the blood’s platelets. Hepcidins block the release of iron from cells in the body, helping to regulate iron homeostasis in our body fluids. The major hormones of these other organs are summarized in Table 8.

Organs with Secondary Endocrine Functions and Their Major Hormones (Table 8)
Organ	Major hormones	Effects
Heart	Atrial natriuretic peptide (ANP)	Reduces blood volume, blood pressure, and Na⁺ concentration
Gastrointestinal tract	Gastrin, secretin, and cholecystokinin	Aid digestion of food and buffering of stomach acids
Gastrointestinal tract	Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1)	Stimulate beta cells of the pancreas to release insulin
Kidneys	Renin	Stimulates release of aldosterone
Kidneys	Calcitriol	Aids in the absorption of Ca²⁺
Kidneys	Erythropoietin	Triggers the formation of red blood cells in the bone marrow
Skeleton	FGF23	Inhibits production of calcitriol and increases phosphate excretion
Skeleton	Osteocalcin	Increases insulin production
Adipose tissue	Leptin	Promotes satiety signals in the brain
Adipose tissue	Adiponectin	Reduces insulin resistance
Skin	Cholecalciferol	Modified to form vitamin D
Thymus (and other organs)	Thymosins	Among other things, aids in the development of T lymphocytes of the immune system
Liver	Insulin-like growth factor-1	Stimulates bodily growth
Liver	Angiotensinogen	Raises blood pressure
Liver	Thrombopoetin	Causes increase in platelets
Liver	Hepcidin	Blocks release of iron into body fluids

20.6 Development of Blood Vessels and Fetal Circulation

barkerj1 — Wed, 06 Sep 2017 01:19:49 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe fetal circulation
Describe the changes which occur in the fetal circulation following delivery

In a developing embryo,the heart has developed enough by day 21 post-fertilization to begin beating. Circulation patterns are clearly established by the fourth week of embryonic life. It is critical to the survival of the developing human that the circulatory system forms early to supply the growing tissue with nutrients and gases, and to remove waste products. Blood cells and vessel production in structures outside the embryo proper called the yolk sac, chorion, and connecting stalk begin about 15 to 16 days following fertilization. Development of these circulatory elements within the embryo itself begins approximately 2 days later. You will learn more about the formation and function of these early structures when you study the chapter on development. During those first few weeks, blood vessels begin to form from the embryonic mesoderm. The precursor cells are known as hemangioblasts. These in turn differentiate into angioblasts, which give rise to the blood vessels and pluripotent stem cells, which differentiate into the formed elements of blood. (Seek additional content for more detail on fetal development and circulation.) Together, these cells form masses known as blood islands scattered throughout the embryonic disc. Spaces appear on the blood islands that develop into vessel lumens. The endothelial lining of the vessels arise from the angioblasts within these islands. Surrounding mesenchymal cells give rise to the smooth muscle and connective tissue layers of the vessels. While the vessels are developing, the pluripotent stem cells begin to form the blood.

Vascular tubes also develop on the blood islands, and they eventually connect to one another as well as to the developing, tubular heart. Thus, the developmental pattern, rather than beginning from the formation of one central vessel and spreading outward, occurs in many regions simultaneously with vessels later joining together. This angiogenesis—the creation of new blood vessels from existing ones—continues as needed throughout life as we grow and develop.

Blood vessel development often follows the same pattern as nerve development and travels to the same target tissues and organs. This occurs because the many factors directing growth of nerves also stimulate blood vessels to follow a similar pattern. Whether a given vessel develops into an artery or a vein is dependent upon local concentrations of signaling proteins.

As the embryo grows within the mother’s uterus, its requirements for nutrients and gas exchange also grow. The placenta—a circulatory organ unique to pregnancy—develops jointly from the embryo and uterine wall structures to fill this need. Emerging from the placenta is the umbilical vein, which carries oxygen-rich blood from the mother to the fetal inferior vena cava via the ductus venosus to the heart that pumps it into fetal circulation. Two umbilical arteries carry oxygen-depleted fetal blood, including wastes and carbon dioxide, to the placenta. After birth, the umbilical vein and arteries regress to become the ligamentum teres and the medial umbilical ligament, respectively.

There are three major shunts—alternate paths for blood flow—found in the circulatory system of the fetus. Two of these shunts divert blood from the pulmonary to the systemic circuit, whereas the third connects the umbilical vein to the inferior vena cava. The first two shunts are critical during fetal life, when the lungs are compressed, filled with amniotic fluid, and nonfunctional, and gas exchange is provided by the placenta. These shunts close shortly after birth, however, when the newborn begins to breathe. The third shunt persists a bit longer but becomes nonfunctional once the umbilical cord is severed. The three shunts are as follows (Figure 1):

The foramen ovale is an opening in the interatrial septum that allows blood to flow from the right atrium to the left atrium. A valve associated with this opening prevents backflow of blood during the fetal period. As the newborn begins to breathe and blood pressure in the atria increases, this shunt closes. The fossa ovalis remains in the interatrial septum after birth, marking the location of the former foramen ovale.
The ductus arteriosus is a short, muscular vessel that connects the pulmonary trunk to the aorta. Most of the blood pumped from the right ventricle into the pulmonary trunk is thereby diverted into the aorta. Only enough blood reaches the fetal lungs to maintain the developing lung tissue. When the newborn takes the first breath, pressure within the lungs drops dramatically, and both the lungs and the pulmonary vessels expand. As the amount of oxygen increases, the smooth muscles in the wall of the ductus arteriosus constrict, sealing off the passage. Eventually, the muscular and endothelial components of the ductus arteriosus degenerate, leaving only the connective tissue component of the ligamentum arteriosum.
The ductus venosus is a temporary blood vessel that branches from the umbilical vein, allowing much of the freshly oxygenated blood from the placenta—the organ of gas exchange between the mother and fetus—to bypass the fetal liver and go directly to the fetal heart. The ductus venosus closes slowly during the first weeks of infancy and degenerates to become the ligamentum venosum.

[caption id="" align="aligncenter" width="495"] Figure 1. Fetal Shunts. The foramen ovale in the interatrial septum allows blood to flow from the right atrium to the left atrium. The ductus arteriosus is a temporary vessel, connecting the aorta to the pulmonary trunk. The ductus venosus links the umbilical vein to the inferior vena cava largely through the liver.[/caption]

22.4 Gas Exchange

barkerj1 — Wed, 06 Sep 2017 01:19:50 +0000

Learning Objectives

By the end of this section, you will be able to:

Review 1103/1109

The purpose of the respiratory system is to perform gas exchange. Pulmonary ventilation provides air to the alveoli for this gas exchange process. At the respiratory membrane, where the alveolar and capillary walls meet, gases move across the membranes, with oxygen entering the bloodstream and carbon dioxide exiting. It is through this mechanism that blood is oxygenated and carbon dioxide, the waste product of cellular respiration, is removed from the body.

Gas Exchange

In order to understand the mechanisms of gas exchange in the lung, it is important to understand the underlying principles of gases and their behavior. In addition to Boyle’s law, several other gas laws help to describe the behavior of gases.

Gas Laws and Air Composition

Gas molecules exert force on the surfaces with which they are in contact; this force is called pressure. In natural systems, gases are normally present as a mixture of different types of molecules. For example, the atmosphere consists of oxygen, nitrogen, carbon dioxide, and other gaseous molecules, and this gaseous mixture exerts a certain pressure referred to as atmospheric pressure (Table 2). Partial pressure (P_x) is the pressure of a single type of gas in a mixture of gases. For example, in the atmosphere, oxygen exerts a partial pressure, and nitrogen exerts another partial pressure, independent of the partial pressure of oxygen (Figure 1). Total pressure is the sum of all the partial pressures of a gaseous mixture. Dalton’s law describes the behavior of nonreactive gases in a gaseous mixture and states that a specific gas type in a mixture exerts its own pressure; thus, the total pressure exerted by a mixture of gases is the sum of the partial pressures of the gases in the mixture.

Partial Pressures of Atmospheric Gases (Table 2)
Gas	Percent of total composition	Partial pressure (mm Hg)
Nitrogen (N₂)	78.6	597.4
Oxygen (O₂)	20.9	158.8
Water (H₂O)	0.04	3.0
Carbon dioxide (CO₂)	0.004	0.3
Others	0.0006	0.5
Total composition/total atmospheric pressure	100%	760.0

[caption id="" align="aligncenter" width="420"] Figure 1. Partial and Total Pressures of a Gas. Partial pressure is the force exerted by a gas. The sum of the partial pressures of all the gases in a mixture equals the total pressure.[/caption] Partial pressure is extremely important in predicting the movement of gases. Recall that gases tend to equalize their pressure in two regions that are connected. A gas will move from an area where its partial pressure is higher to an area where its partial pressure is lower. In addition, the greater the partial pressure difference between the two areas, the more rapid is the movement of gases.

Solubility of Gases in Liquids

Henry’s law describes the behavior of gases when they come into contact with a liquid, such as blood. Henry’s law states that the concentration of gas in a liquid is directly proportional to the solubility and partial pressure of that gas. The greater the partial pressure of the gas, the greater the number of gas molecules that will dissolve in the liquid. The concentration of the gas in a liquid is also dependent on the solubility of the gas in the liquid. For example, although nitrogen is present in the atmosphere, very little nitrogen dissolves into the blood, because the solubility of nitrogen in blood is very low. The exception to this occurs in scuba divers; the composition of the compressed air that divers breathe causes nitrogen to have a higher partial pressure than normal, causing it to dissolve in the blood in greater amounts than normal. Too much nitrogen in the bloodstream results in a serious condition that can be fatal if not corrected. Gas molecules establish an equilibrium between those molecules dissolved in liquid and those in air. The composition of air in the atmosphere and in the alveoli differs. In both cases, the relative concentration of gases is nitrogen > oxygen > water vapor > carbon dioxide. The amount of water vapor present in alveolar air is greater than that in atmospheric air (Table 3). Recall that the respiratory system works to humidify incoming air, thereby causing the air present in the alveoli to have a greater amount of water vapor than atmospheric air. In addition, alveolar air contains a greater amount of carbon dioxide and less oxygen than atmospheric air. This is no surprise, as gas exchange removes oxygen from and adds carbon dioxide to alveolar air. Both deep and forced breathing cause the alveolar air composition to be changed more rapidly than during quiet breathing. As a result, the partial pressures of oxygen and carbon dioxide change, affecting the diffusion process that moves these materials across the membrane. This will cause oxygen to enter and carbon dioxide to leave the blood more quickly.

Composition and Partial Pressures of Alveolar Air (Table 3)
Gas	Percent of total composition	Partial pressure (mm Hg)
Nitrogen (N₂)	74.9	569
Oxygen (O₂)	13.7	104
Water (H₂O)	6.2	40
Carbon dioxide (CO₂)	5.2	47
Total composition/total alveolar pressure	100%	760.0

Ventilation and Perfusion

Two important aspects of gas exchange in the lung are ventilation and perfusion. Ventilation is the movement of air into and out of the lungs, and perfusion is the flow of blood in the pulmonary capillaries. For gas exchange to be efficient, the volumes involved in ventilation and perfusion should be compatible. However, factors such as regional gravity effects on blood, blocked alveolar ducts, or disease can cause ventilation and perfusion to be imbalanced. The partial pressure of oxygen in alveolar air is about 104 mm Hg, whereas the partial pressure of the oxygenated pulmonary venous blood is about 100 mm Hg. When ventilation is sufficient, oxygen enters the alveoli at a high rate, and the partial pressure of oxygen in the alveoli remains high. In contrast, when ventilation is insufficient, the partial pressure of oxygen in the alveoli drops. Without the large difference in partial pressure between the alveoli and the blood, oxygen does not diffuse efficiently across the respiratory membrane. The body has mechanisms that counteract this problem. In cases when ventilation is not sufficient for an alveolus, the body redirects blood flow to alveoli that are receiving sufficient ventilation. This is achieved by constricting the pulmonary arterioles that serves the dysfunctional alveolus, which redirects blood to other alveoli that have sufficient ventilation. At the same time, the pulmonary arterioles that serve alveoli receiving sufficient ventilation vasodilate, which brings in greater blood flow. Factors such as carbon dioxide, oxygen, and pH levels can all serve as stimuli for adjusting blood flow in the capillary networks associated with the alveoli. Ventilation is regulated by the diameter of the airways, whereas perfusion is regulated by the diameter of the blood vessels. The diameter of the bronchioles is sensitive to the partial pressure of carbon dioxide in the alveoli. A greater partial pressure of carbon dioxide in the alveoli causes the bronchioles to increase their diameter as will a decreased level of oxygen in the blood supply, allowing carbon dioxide to be exhaled from the body at a greater rate. As mentioned above, a greater partial pressure of oxygen in the alveoli causes the pulmonary arterioles to dilate, increasing blood flow.

Gas Exchange

Gas exchange occurs at two sites in the body: in the lungs, where oxygen is picked up and carbon dioxide is released at the respiratory membrane, and at the tissues, where oxygen is released and carbon dioxide is picked up. External respiration is the exchange of gases with the external environment, and occurs in the alveoli of the lungs. Internal respiration is the exchange of gases with the internal environment, and occurs in the tissues. The actual exchange of gases occurs due to simple diffusion. Energy is not required to move oxygen or carbon dioxide across membranes. Instead, these gases follow pressure gradients that allow them to diffuse. The anatomy of the lung maximizes the diffusion of gases: The respiratory membrane is highly permeable to gases; the respiratory and blood capillary membranes are very thin; and there is a large surface area throughout the lungs.

External Respiration

The pulmonary artery carries deoxygenated blood into the lungs from the heart, where it branches and eventually becomes the capillary network composed of pulmonary capillaries. These pulmonary capillaries create the respiratory membrane with the alveoli (Figure 2). As the blood is pumped through this capillary network, gas exchange occurs. Although a small amount of the oxygen is able to dissolve directly into plasma from the alveoli, most of the oxygen is picked up by erythrocytes (red blood cells) and binds to a protein called hemoglobin, a process described later in this chapter. Oxygenated hemoglobin is red, causing the overall appearance of bright red oxygenated blood, which returns to the heart through the pulmonary veins. Carbon dioxide is released in the opposite direction of oxygen, from the blood to the alveoli. Some of the carbon dioxide is returned on hemoglobin, but can also be dissolved in plasma or is present as a converted form, also explained in greater detail later in this chapter. External respiration occurs as a function of partial pressure differences in oxygen and carbon dioxide between the alveoli and the blood in the pulmonary capillaries.

[caption id="" align="aligncenter" width="425"] Figure 3. External Respiration. In external respiration, oxygen diffuses across the respiratory membrane from the alveolus to the capillary, whereas carbon dioxide diffuses out of the capillary into the alveolus.[/caption] Although the solubility of oxygen in blood is not high, there is a drastic difference in the partial pressure of oxygen in the alveoli versus in the blood of the pulmonary capillaries. This difference is about 64 mm Hg: The partial pressure of oxygen in the alveoli is about 104 mm Hg, whereas its partial pressure in the blood of the capillary is about 40 mm Hg. This large difference in partial pressure creates a very strong pressure gradient that causes oxygen to rapidly cross the respiratory membrane from the alveoli into the blood. The partial pressure of carbon dioxide is also different between the alveolar air and the blood of the capillary. However, the partial pressure difference is less than that of oxygen, about 5 mm Hg. The partial pressure of carbon dioxide in the blood of the capillary is about 45 mm Hg, whereas its partial pressure in the alveoli is about 40 mm Hg. However, the solubility of carbon dioxide is much greater than that of oxygen—by a factor of about 20—in both blood and alveolar fluids. As a result, the relative concentrations of oxygen and carbon dioxide that diffuse across the respiratory membrane are similar.

Internal Respiration

Internal respiration is gas exchange that occurs at the level of body tissues (Figure 3). Similar to external respiration, internal respiration also occurs as simple diffusion due to a partial pressure gradient. However, the partial pressure gradients are opposite of those present at the respiratory membrane. The partial pressure of oxygen in tissues is low, about 40 mm Hg, because oxygen is continuously used for cellular respiration. In contrast, the partial pressure of oxygen in the blood is about 100 mm Hg. This creates a pressure gradient that causes oxygen to dissociate from hemoglobin, diffuse out of the blood, cross the interstitial space, and enter the tissue. Hemoglobin that has little oxygen bound to it loses much of its brightness, so that blood returning to the heart is more burgundy in color. Considering that cellular respiration continuously produces carbon dioxide, the partial pressure of carbon dioxide is lower in the blood than it is in the tissue, causing carbon dioxide to diffuse out of the tissue, cross the interstitial fluid, and enter the blood. It is then carried back to the lungs either bound to hemoglobin, dissolved in plasma, or in a converted form. By the time blood returns to the heart, the partial pressure of oxygen has returned to about 40 mm Hg, and the partial pressure of carbon dioxide has returned to about 45 mm Hg. The blood is then pumped back to the lungs to be oxygenated once again during external respiration.

[caption id="" align="aligncenter" width="425"] Figure 4. Internal Respiration. Oxygen diffuses out of the capillary and into cells, whereas carbon dioxide diffuses out of cells and into the capillary.[/caption]

22.5 Transport of Gases

barkerj1 — Wed, 06 Sep 2017 01:19:50 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the changes in the composition of the blood that occur with the onset of neonatal life
Describe the carbonic acid - bicarbonate buffer system

The other major activity in the lungs is the process of respiration, the process of gas exchange. The function of respiration is to provide oxygen for use by body cells during cellular respiration and to eliminate carbon dioxide, a waste product of cellular respiration, from the body. In order for the exchange of oxygen and carbon dioxide to occur, both gases must be transported between the external and internal respiration sites. Although carbon dioxide is more soluble than oxygen in blood, both gases require a specialized transport system for the majority of the gas molecules to be moved between the lungs and other tissues.

Oxygen Transport in the Blood

Even though oxygen is transported via the blood, you may recall that oxygen is not very soluble in liquids. A small amount of oxygen does dissolve in the blood and is transported in the bloodstream, but it is only about 1.5% of the total amount. The majority of oxygen molecules are carried from the lungs to the body’s tissues by a specialized transport system, which relies on the erythrocyte—the red blood cell. Erythrocytes contain a metalloprotein, hemoglobin, which serves to bind oxygen molecules to the erythrocyte (Figure 1). Heme is the portion of hemoglobin that contains iron, and it is heme that binds oxygen. One hemoglobin molecule contains iron-containing Heme molecules, and because of this, each hemoglobin molecule is capable of carrying up to four molecules of oxygen. As oxygen diffuses across the respiratory membrane from the alveolus to the capillary, it also diffuses into the red blood cell and is bound by hemoglobin. The following reversible chemical reaction describes the production of the final product, oxyhemoglobin (Hb–O₂), which is formed when oxygen binds to hemoglobin. Oxyhemoglobin is a bright red-colored molecule that contributes to the bright red color of oxygenated blood.

Hb + O₂ ↔ Hb − O₂

In this formula, Hb represents reduced hemoglobin, that is, hemoglobin that does not have oxygen bound to it. There are multiple factors involved in how readily heme binds to and dissociates from oxygen, which will be discussed in the subsequent sections.

[caption id="" align="aligncenter" width="300"] Figure 1. Erythrocyte and Hemoglobin. Hemoglobin consists of four subunits, each of which contains one molecule of iron.[/caption]

Function of Hemoglobin

Hemoglobin is composed of subunits, a protein structure that is referred to as a quaternary structure. Each of the four subunits that make up hemoglobin is arranged in a ring-like fashion, with an iron atom covalently bound to the heme in the center of each subunit. Binding of the first oxygen molecule causes a conformational change in hemoglobin that allows the second molecule of oxygen to bind more readily. As each molecule of oxygen is bound, it further facilitates the binding of the next molecule, until all four heme sites are occupied by oxygen. The opposite occurs as well: After the first oxygen molecule dissociates and is “dropped off” at the tissues, the next oxygen molecule dissociates more readily. When all four heme sites are occupied, the hemoglobin is said to be saturated. When one to three heme sites are occupied, the hemoglobin is said to be partially saturated. Therefore, when considering the blood as a whole, the percent of the available heme units that are bound to oxygen at a given time is called hemoglobin saturation. Hemoglobin saturation of 100 percent means that every heme unit in all of the erythrocytes of the body is bound to oxygen. In a healthy individual with normal hemoglobin levels, hemoglobin saturation generally ranges from 95 percent to 99 percent.

Oxygen Dissociation from Hemoglobin

Partial pressure is an important aspect of the binding of oxygen to and disassociation from heme. An oxygen–hemoglobin dissociation curve is a graph that describes the relationship of partial pressure to the binding of oxygen to heme and its subsequent dissociation from heme (Figure 2). Remember that gases travel from an area of higher partial pressure to an area of lower partial pressure. In addition, the affinity of an oxygen molecule for heme increases as more oxygen molecules are bound. Therefore, in the oxygen–hemoglobin saturation curve, as the partial pressure of oxygen increases, a proportionately greater number of oxygen molecules are bound by heme. Not surprisingly, the oxygen–hemoglobin saturation/dissociation curve also shows that the lower the partial pressure of oxygen, the fewer oxygen molecules are bound to heme. As a result, the partial pressure of oxygen plays a major role in determining the degree of binding of oxygen to heme at the site of the respiratory membrane, as well as the degree of dissociation of oxygen from heme at the site of body tissues.

[caption id="" align="aligncenter" width="400"] Figure 2. Oxygen-Hemoglobin Dissociation and Effects of pH and Temperature. These three graphs show (a) the relationship between the partial pressure of oxygen and hemoglobin saturation, (b) the effect of pH on the oxygen–hemoglobin dissociation curve, and (c) the effect of temperature on the oxygen–hemoglobin dissociation curve.[/caption]

The mechanisms behind the oxygen–hemoglobin saturation/dissociation curve also serve as automatic control mechanisms that regulate how much oxygen is delivered to different tissues throughout the body. This is important because some tissues have a higher metabolic rate than others. Highly active tissues, such as muscle, rapidly use oxygen to produce ATP, lowering the partial pressure of oxygen in the tissue to about 20 mm Hg. The partial pressure of oxygen inside capillaries is about 100 mm Hg, so the difference between the two becomes quite high, about 80 mm Hg. As a result, a greater number of oxygen molecules dissociate from hemoglobin and enter the tissues. The reverse is true of tissues, such as adipose (body fat), which have lower metabolic rates. Because less oxygen is used by these cells, the partial pressure of oxygen within such tissues remains relatively high, resulting in fewer oxygen molecules dissociating from hemoglobin and entering the tissue interstitial fluid. Although venous blood is said to be deoxygenated, some oxygen is still bound to hemoglobin in its red blood cells. This provides an oxygen reserve that can be used when tissues suddenly demand more oxygen. Factors other than partial pressure also affect the oxygen–hemoglobin saturation/dissociation curve. For example, a higher temperature promotes hemoglobin and oxygen to dissociate faster, whereas a lower temperature inhibits dissociation (see Figure 2, middle). However, the human body tightly regulates temperature, so this factor may not affect gas exchange throughout the body. The exception to this is in highly active tissues, which may release a larger amount of energy than is given off as heat. As a result, oxygen readily dissociates from hemoglobin, which is a mechanism that helps to provide active tissues with more oxygen. Certain hormones, such as androgens, epinephrine, thyroid hormones, and growth hormone, can affect the oxygen–hemoglobin saturation/disassociation curve by stimulating the production of a compound called 2,3-bisphosphoglycerate (BPG) by erythrocytes. BPG is a byproduct of glycolysis. Because erythrocytes do not contain mitochondria, glycolysis is the sole method by which these cells produce ATP. BPG promotes the disassociation of oxygen from hemoglobin. Therefore, the greater the concentration of BPG, the more readily oxygen dissociates from hemoglobin, despite its partial pressure. The pH of the blood is another factor that influences the oxygen–hemoglobin saturation/dissociation curve (see Figure 2). The Bohr effect is a phenomenon that arises from the relationship between pH and oxygen’s affinity for hemoglobin: A lower, more acidic pH promotes oxygen dissociation from hemoglobin. In contrast, a higher, or more basic, pH inhibits oxygen dissociation from hemoglobin. The greater the amount of carbon dioxide in the blood, the more molecules that must be converted, which in turn generates hydrogen ions and thus lowers blood pH. Furthermore, blood pH may become more acidic when certain byproducts of cell metabolism, such as lactic acid, carbonic acid, and carbon dioxide, are released into the bloodstream.

Hemoglobin of the Fetus

The fetus has its own circulation with its own erythrocytes; however, it is dependent on the mother for oxygen. Blood is supplied to the fetus by way of the umbilical cord, which is connected to the placenta and separated from maternal blood by the chorion. The mechanism of gas exchange at the chorion is similar to gas exchange at the respiratory membrane. However, the partial pressure of oxygen is lower in the maternal blood in the placenta, at about 35 to 50 mm Hg, than it is in maternal arterial blood. The difference in partial pressures between maternal and fetal blood is not large, as the partial pressure of oxygen in fetal blood at the placenta is about 20 mm Hg. Therefore, there is not as much diffusion of oxygen into the fetal blood supply. The fetus’ hemoglobin overcomes this problem by having a greater affinity for oxygen than maternal hemoglobin (Figure 3). Both fetal and adult hemoglobin have four subunits, but two of the subunits of fetal hemoglobin have a different structure that causes fetal hemoglobin to have a greater affinity for oxygen than does adult hemoglobin.

[caption id="" align="aligncenter" width="430"] Figure 3. Oxygen-Hemoglobin Dissociation Curves in Fetus and Adult. Fetal hemoglobin has a greater affinity for oxygen than does adult hemoglobin.[/caption]

Carbon Dioxide Transport in the Blood

Carbon dioxide is transported by three major mechanisms. The first mechanism of carbon dioxide transport is by blood plasma, as some carbon dioxide molecules dissolve in the blood. The second mechanism is transport in the form of bicarbonate (HCO₃^–), which also dissolves in plasma. The third mechanism of carbon dioxide transport is similar to the transport of oxygen by erythrocytes (Figure 4).

[caption id="" align="aligncenter" width="435"] Figure 4: Carbon Dioxide Transport Carbon dioxide is transported by three different methods: (a) in erythrocytes; (b) after forming carbonic acid (H₂CO₃ ), which is dissolved in plasma; (c) and in plasma.[/caption]

Dissolved Carbon Dioxide

Although carbon dioxide is not considered to be highly soluble in blood, a small fraction—about 7 to 10 percent—of the carbon dioxide that diffuses into the blood from the tissues dissolves in plasma. The dissolved carbon dioxide then travels in the bloodstream and when the blood reaches the pulmonary capillaries, the dissolved carbon dioxide diffuses across the respiratory membrane into the alveoli, where it is then exhaled during pulmonary ventilation.

Bicarbonate Buffer

A large fraction—about 70 percent—of the carbon dioxide molecules that diffuse into the blood is transported to the lungs as bicarbonate. Most bicarbonate is produced in erythrocytes after carbon dioxide diffuses into the capillaries, and subsequently into red blood cells. Carbonic anhydrase (CA) causes carbon dioxide and water to form carbonic acid (H₂CO₃), which dissociates into two ions: bicarbonate (HCO₃^–) and hydrogen (H⁺). The following formula depicts this reaction:

CO₂ + H₂O CA ↔ H₂CO₃↔H⁺ + HCO₃₋

Bicarbonate tends to build up in the erythrocytes, so that there is a greater concentration of bicarbonate in the erythrocytes than in the surrounding blood plasma. As a result, some of the bicarbonate will leave the erythrocytes and move down its concentration gradient into the plasma in exchange for chloride (Cl^–) ions. This phenomenon is referred to as the chloride shift and occurs because by exchanging one negative ion for another negative ion, neither the electrical charge of the erythrocytes nor that of the blood is altered. At the pulmonary capillaries, the chemical reaction that produced bicarbonate (shown above) is reversed, and carbon dioxide and water are the products. Much of the bicarbonate in the plasma re-enters the erythrocytes in exchange for chloride ions. Hydrogen ions and bicarbonate ions join to form carbonic acid, which is converted into carbon dioxide and water by carbonic anhydrase. Carbon dioxide diffuses out of the erythrocytes and into the plasma, where it can further diffuse across the respiratory membrane into the alveoli to be exhaled during pulmonary ventilation.

Carbaminohemoglobin

About 20 percent of carbon dioxide is bound by hemoglobin and is transported to the lungs. Carbon dioxide does not bind to iron as oxygen does; instead, carbon dioxide binds amino acid moieties on the globin portions of hemoglobin to form carbaminohemoglobin, which forms when hemoglobin and carbon dioxide bind. When hemoglobin is not transporting oxygen, it tends to have a bluish-purple tone to it, creating the darker maroon color typical of deoxygenated blood. The following formula depicts this reversible reaction:

CO₂ + Hb ↔ HbCO₂

Similar to the transport of oxygen by heme, the binding and dissociation of carbon dioxide to and from hemoglobin is dependent on the partial pressure of carbon dioxide. Because carbon dioxide is released from the lungs, blood that leaves the lungs and reaches body tissues has a lower partial pressure of carbon dioxide than is found in the tissues. As a result, carbon dioxide leaves the tissues because of its higher partial pressure, enters the blood, and then moves into red blood cells, binding to hemoglobin. In contrast, in the pulmonary capillaries, the partial pressure of carbon dioxide is high compared to within the alveoli. As a result, carbon dioxide dissociates readily from hemoglobin and diffuses across the respiratory membrane into the air. In addition to the partial pressure of carbon dioxide, the oxygen saturation of hemoglobin and the partial pressure of oxygen in the blood also influence the affinity of hemoglobin for carbon dioxide. The Haldane effect is a phenomenon that arises from the relationship between the partial pressure of oxygen and the affinity of hemoglobin for carbon dioxide. Hemoglobin that is saturated with oxygen does not readily bind carbon dioxide. However, when oxygen is not bound to heme and the partial pressure of oxygen is low, hemoglobin readily binds to carbon dioxide.

[caption id="" align="aligncenter" width="120"] Watch this video to see the transport of oxygen from the lungs to the tissues.[/caption] [caption id="attachment_3013" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about the transport of oxygen in the body![/caption]

22.6 Modifications in Respiratory Functions

barkerj1 — Wed, 06 Sep 2017 01:19:51 +0000

Learning Objectives

By the end of this section, you will be able to:

Specify one cause of alkalosis

At rest, the respiratory system performs its functions at a constant, rhythmic pace, as regulated by the respiratory centers of the brain. At this pace, ventilation provides sufficient oxygen to all the tissues of the body. However, there are times that the respiratory system must alter the pace of its functions in order to accommodate the oxygen demands of the body.

Hyperpnea

Hyperpnea is an increased depth and rate of ventilation to meet an increase in oxygen demand as might be seen in exercise or disease, particularly diseases that target the respiratory or digestive tracts. This does not significantly alter blood oxygen or carbon dioxide levels, but merely increases the depth and rate of ventilation to meet the demand of the cells. In contrast, hyperventilation is an increased ventilation rate that is independent of the cellular oxygen needs and leads to abnormally low blood carbon dioxide levels and high (alkaline) blood pH. Interestingly, exercise does not cause hyperpnea as one might think. Muscles that perform work during exercise do increase their demand for oxygen, stimulating an increase in ventilation. However, hyperpnea during exercise appears to occur before a drop in oxygen levels within the muscles can occur. Therefore, hyperpnea must be driven by other mechanisms, either instead of or in addition to a drop in oxygen levels. The exact mechanisms behind exercise hyperpnea are not well understood, and some hypotheses are somewhat controversial. However, in addition to low oxygen, high carbon dioxide, and low pH levels, there appears to be a complex interplay of factors related to the nervous system and the respiratory centers of the brain. First, a conscious decision to partake in exercise, or another form of physical exertion, results in a psychological stimulus that may trigger the respiratory centers of the brain to increase ventilation. In addition, the respiratory centers of the brain may be stimulated through the activation of motor neurons that innervate muscle groups that are involved in the physical activity. Finally, physical exertion stimulates proprioceptors, which are receptors located within the muscles, joints, and tendons, which sense movement and stretching; proprioceptors thus create a stimulus that may also trigger the respiratory centers of the brain. These neural factors are consistent with the sudden increase in ventilation that is observed immediately as exercise begins. Because the respiratory centers are stimulated by psychological, motor neuron, and proprioceptor inputs throughout exercise, the fact that there is also a sudden decrease in ventilation immediately after the exercise ends when these neural stimuli cease, further supports the idea that they are involved in triggering the changes of ventilation.

High Altitude Effects

An increase in altitude results in a decrease in atmospheric pressure. Although the proportion of oxygen relative to gases in the atmosphere remains at 21 percent, its partial pressure decreases (Table 4). As a result, it is more difficult for a body to achieve the same level of oxygen saturation at high altitude than at low altitude, due to lower atmospheric pressure. In fact, hemoglobin saturation is lower at high altitudes compared to hemoglobin saturation at sea level. For example, hemoglobin saturation is about 67 percent at 19,000 feet above sea level, whereas it reaches about 98 percent at sea level.

Partial Pressure of Oxygen at Different Altitudes (Table 4)
Example location	Altitude (feet above sea level)	Atmospheric pressure (mm Hg)	Partial pressure of oxygen (mm Hg)
New York City, New York	0	760	159
Boulder, Colorado	5000	632	133
Aspen, Colorado	8000	565	118
Pike’s Peak, Colorado	14,000	447	94
Denali (Mt. McKinley), Alaska	20,000	350	73
Mt. Everest, Tibet	29,000	260	54

As you recall, partial pressure is extremely important in determining how much gas can cross the respiratory membrane and enter the blood of the pulmonary capillaries. A lower partial pressure of oxygen means that there is a smaller difference in partial pressures between the alveoli and the blood, so less oxygen crosses the respiratory membrane. As a result, fewer oxygen molecules are bound by hemoglobin. Despite this, the tissues of the body still receive a sufficient amount of oxygen during rest at high altitudes. This is due to two major mechanisms. First, the number of oxygen molecules that enter the tissue from the blood is nearly equal between sea level and high altitudes. At sea level, hemoglobin saturation is higher, but only a quarter of the oxygen molecules are actually released into the tissue. At high altitudes, a greater proportion of molecules of oxygen are released into the tissues. Secondly, at high altitudes, a greater amount of BPG is produced by erythrocytes, which enhances the dissociation of oxygen from hemoglobin. Physical exertion, such as skiing or hiking, can lead to altitude sickness due to the low amount of oxygen reserves in the blood at high altitudes. At sea level, there is a large amount of oxygen reserve in venous blood (even though venous blood is thought of as “deoxygenated”) from which the muscles can draw during physical exertion. Because the oxygen saturation is much lower at higher altitudes, this venous reserve is small, resulting in pathological symptoms of low blood oxygen levels. You may have heard that it is important to drink more water when traveling at higher altitudes than you are accustomed to. This is because your body will increase micturition (urination) at high altitudes to counteract the effects of lower oxygen levels. By removing fluids, blood plasma levels drop but not the total number of erythrocytes. In this way, the overall concentration of erythrocytes in the blood increases, which helps tissues obtain the oxygen they need. Acute mountain sickness (AMS), or altitude sickness, is a condition that results from acute exposure to high altitudes due to a low partial pressure of oxygen at high altitudes. AMS typically can occur at 2400 meters (8000 feet) above sea level. AMS is a result of low blood oxygen levels, as the body has acute difficulty adjusting to the low partial pressure of oxygen. In serious cases, AMS can cause pulmonary or cerebral edema. Symptoms of AMS include nausea, vomiting, fatigue, lightheadedness, drowsiness, feeling disoriented, increased pulse, and nosebleeds. The only treatment for AMS is descending to a lower altitude; however, pharmacologic treatments and supplemental oxygen can improve symptoms. AMS can be prevented by slowly ascending to the desired altitude, allowing the body to acclimate, as well as maintaining proper hydration.

Acclimatization

Especially in situations where the ascent occurs too quickly, traveling to areas of high altitude can cause AMS. Acclimatization is the process of adjustment that the respiratory system makes due to chronic exposure to a high altitude. Over a period of time, the body adjusts to accommodate the lower partial pressure of oxygen. The low partial pressure of oxygen at high altitudes results in a lower oxygen saturation level of hemoglobin in the blood. In turn, the tissue levels of oxygen are also lower. As a result, the kidneys are stimulated to produce the hormone erythropoietin (EPO), which stimulates the production of erythrocytes, resulting in a greater number of circulating erythrocytes in an individual at a high altitude over a long period. With more red blood cells, there is more hemoglobin to help transport the available oxygen. Even though there is low saturation of each hemoglobin molecule, there will be more hemoglobin present, and therefore more oxygen in the blood. Over time, this allows the person to partake in physical exertion without developing AMS.

22.7 Embryonic Development of the Respiratory System

barkerj1 — Wed, 06 Sep 2017 01:19:52 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the respiratory system of the neonate with respect to:
- The importance of surfactant
- Fluid in the lungs
- Initiation of ventilation

Development of the respiratory system begins early in the fetus. It is a complex process that includes many structures, most of which arise from the endoderm. Towards the end of development, the fetus can be observed making breathing movements. Until birth, however, the mother provides all of the oxygen to the fetus as well as removes all of the fetal carbon dioxide via the placenta.

Time Line

The development of the respiratory system begins at about week 4 of gestation. By week 28, enough alveoli have matured that a baby born prematurely at this time can usually breathe on its own. The respiratory system, however, is not fully developed until early childhood, when a full complement of mature alveoli is present.

Weeks 4–7

Respiratory development in the embryo begins around week 4. Ectodermal tissue from the anterior head region invaginates posteriorly to form olfactory pits, which fuse with endodermal tissue of the developing pharynx. An olfactory pit is one of a pair of structures that will enlarge to become the nasal cavity. At about this same time, the lung bud forms. The lung bud is a dome-shaped structure composed of tissue that bulges from the foregut. The foregut is endoderm just inferior to the pharyngeal pouches. The laryngotracheal bud is a structure that forms from the longitudinal extension of the lung bud as development progresses. The portion of this structure nearest the pharynx becomes the trachea, whereas the distal end becomes more bulbous, forming bronchial buds. A bronchial bud is one of a pair of structures that will eventually become the bronchi and all other lower respiratory structures (Figure 1).

[caption id="" align="aligncenter" width="440"] Figure 1. Development of the Lower Respiratory System.[/caption]

Weeks 7–16

Bronchial buds continue to branch as development progresses until all of the segmental bronchi have been formed. Beginning around week 13, the lumens of the bronchi begin to expand in diameter. By week 16, respiratory bronchioles form. The fetus now has all major lung structures involved in the airway.

Weeks 16–24

Once the respiratory bronchioles form, further development includes extensive vascularization, or the development of the blood vessels, as well as the formation of alveolar ducts and alveolar precursors. At about week 19, the respiratory bronchioles have formed. In addition, cells lining the respiratory structures begin to differentiate to form type I and type II pneumocytes. Once type II cells have differentiated, they begin to secrete small amounts of pulmonary surfactant. Around week 20, fetal breathing movements may begin.

Weeks 24–Term

Major growth and maturation of the respiratory system occurs from week 24 until term. More alveolar precursors develop, and larger amounts of pulmonary surfactant are produced. Surfactant levels are not generally adequate to create effective lung compliance until about the eighth month of pregnancy. The respiratory system continues to expand, and the surfaces that will form the respiratory membrane develop further. At this point, pulmonary capillaries have formed and continue to expand, creating a large surface area for gas exchange. The major milestone of respiratory development occurs at around week 28, when sufficient alveolar precursors have matured so that a baby born prematurely at this time can usually breathe on its own. However, alveoli continue to develop and mature into childhood. A full complement of functional alveoli does not appear until around 8 years of age.

Fetal “Breathing”

Although the function of fetal breathing movements is not entirely clear, they can be observed starting at 20–21 weeks of development. Fetal breathing movements involve muscle contractions that cause the inhalation of amniotic fluid and exhalation of the same fluid, with pulmonary surfactant and mucus. Fetal breathing movements are not continuous and may include periods of frequent movements and periods of no movements. Maternal factors can influence the frequency of breathing movements. For example, high blood glucose levels, called hyperglycemia, can boost the number of breathing movements. Conversely, low blood glucose levels, called hypoglycemia, can reduce the number of fetal breathing movements. Tobacco use is also known to lower fetal breathing rates. Fetal breathing may help tone the muscles in preparation for breathing movements once the fetus is born. It may also help the alveoli to form and mature. Fetal breathing movements are considered a sign of robust health.

Birth

Prior to birth, the lungs are filled with amniotic fluid, mucus, and surfactant. As the fetus is squeezed through the birth canal, the fetal thoracic cavity is compressed, expelling much of this fluid. Some fluid remains, however, but is rapidly absorbed by the body shortly after birth. The first inhalation occurs within 10 seconds after birth and not only serves as the first inspiration, but also acts to inflate the lungs. Pulmonary surfactant is critical for inflation to occur, as it reduces the surface tension of the alveoli. Preterm birth around 26 weeks frequently results in severe respiratory distress, although with current medical advancements, some babies may survive. Prior to 26 weeks, sufficient pulmonary surfactant is not produced, and the surfaces for gas exchange have not formed adequately; therefore, survival is low.

Respiratory Distress Syndrome

Respiratory distress syndrome (RDS) primarily occurs in infants born prematurely. Up to 50 percent of infants born between 26 and 28 weeks and fewer than 30 percent of infants born between 30 and 31 weeks develop RDS. RDS results from insufficient production of pulmonary surfactant, thereby preventing the lungs from properly inflating at birth. A small amount of pulmonary surfactant is produced beginning at around 20 weeks; however, this is not sufficient for inflation of the lungs. As a result, dyspnea occurs and gas exchange cannot be performed properly. Blood oxygen levels are low, whereas blood carbon dioxide levels and pH are high.

The primary cause of RDS is premature birth, which may be due to a variety of known or unknown causes. Other risk factors include gestational diabetes, cesarean delivery, second-born twins, and family history of RDS. The presence of RDS can lead to other serious disorders, such as septicemia (infection of the blood) or pulmonary hemorrhage. Therefore, it is important that RDS is immediately recognized and treated to prevent death and reduce the risk of developing other disorders.

Medical advances have resulted in an improved ability to treat RDS and support the infant until proper lung development can occur. At the time of delivery, treatment may include resuscitation and intubation if the infant does not breathe on his or her own. These infants would need to be placed on a ventilator to mechanically assist with the breathing process. If spontaneous breathing occurs, application of nasal continuous positive airway pressure (CPAP) may be required. In addition, pulmonary surfactant is typically administered. Death due to RDS has been reduced by 50 percent due to the introduction of pulmonary surfactant therapy. Other therapies may include corticosteroids, supplemental oxygen, and assisted ventilation. Supportive therapies, such as temperature regulation, nutritional support, and antibiotics, may be administered to the premature infant as well.

Ch. 23 Introduction

barkerj1 — Wed, 06 Sep 2017 01:19:53 +0000

[caption id="" align="aligncenter" width="600"] Eating Apples Eating may be one of the simple pleasures in life, but digesting even one apple requires the coordinated work of many organs. (credit: “Aimanness Photography”/Flickr)[/caption] The digestive system is continually at work, yet people seldom appreciate the complex tasks it performs in a choreographed biologic symphony. Consider what happens when you eat an apple. Of course, you enjoy the apple’s taste as you chew it, but in the hours that follow, unless something goes amiss and you get a stomachache, you don’t notice that your digestive system is working. You may be taking a walk or studying or sleeping, having forgotten all about the apple, but your stomach and intestines are busy digesting it and absorbing its vitamins and other nutrients. By the time any waste material is excreted, the body has appropriated all it can use from the apple. In short, whether you pay attention or not, the organs of the digestive system perform their specific functions, allowing you to use the food you eat to keep you going. This chapter examines the structure and functions of these organs, and explores the mechanics and chemistry of the digestive processes.

23.1 Overview of the Digestive System

barkerj1 — Wed, 06 Sep 2017 01:19:54 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the major functions of the digestive system
Describe the general anatomical characteristics of the organs of the digestive system

The function of the digestive system is to break down the foods you eat, release their nutrients, and absorb those nutrients into the body. Although the small intestine is the workhorse of the system, where the majority of digestion occurs, and where most of the released nutrients are absorbed into the blood or lymph, each of the digestive system organs makes a vital contribution to this process (Figure 1).

[caption id="" align="aligncenter" width="400"] Figure 1. Components of the Digestive System. All digestive organs play integral roles in the life-sustaining process of digestion.[/caption]

As is the case with all body systems, the digestive system does not work in isolation; it functions cooperatively with the other systems of the body. Consider for example, the interrelationship between the digestive and cardiovascular systems. Arteries supply the digestive organs with oxygen and processed nutrients, and veins drain the digestive tract. These intestinal veins, constituting the hepatic portal system, are unique; they do not return blood directly to the heart. Rather, this blood is diverted to the liver where its nutrients are off-loaded for processing before blood completes its circuit back to the heart. At the same time, the digestive system provides nutrients to the heart muscle and vascular tissue to support their functioning. The interrelationship of the digestive and endocrine systems is also critical. Hormones secreted by several endocrine glands, as well as endocrine cells of the pancreas, the stomach, and the small intestine, contribute to the control of digestion and nutrient metabolism. In turn, the digestive system provides the nutrients to fuel endocrine function. Table 1 gives a quick glimpse at how these other systems contribute to the functioning of the digestive system.

Contribution of Other Body Systems to the Digestive System (Table 1)
Body system	Benefits received by the digestive system
Cardiovascular	Blood supplies digestive organs with oxygen and processed nutrients
Endocrine	Endocrine hormones help regulate secretion in digestive glands and accessory organs
Integumentary	Skin helps protect digestive organs and synthesizes vitamin D for calcium absorption
Lymphatic	Mucosa-associated lymphoid tissue and other lymphatic tissue defend against entry of pathogens; lacteals absorb lipids; and lymphatic vessels transport lipids to bloodstream
Muscular	Skeletal muscles support and protect abdominal organs
Nervous	Sensory and motor neurons help regulate secretions and muscle contractions in the digestive tract
Respiratory	Respiratory organs provide oxygen and remove carbon dioxide
Skeletal	Bones help protect and support digestive organs
Urinary	Kidneys convert vitamin D into its active form, allowing calcium absorption in the small intestine

Digestive System Organs

The easiest way to understand the digestive system is to divide its organs into two main categories. The first group is the organs that make up the alimentary canal. Accessory digestive organs comprise the second group and are critical for orchestrating the breakdown of food and the assimilation of its nutrients into the body. Accessory digestive organs, despite their name, are critical to the function of the digestive system.

Alimentary Canal Organs

Also called the gastrointestinal (GI) tract or gut, the alimentary canal (aliment- = “to nourish”) is a one-way tube about 7.62 meters (25 feet) in length during life and closer to 10.67 meters (35 feet) in length when measured after death, once smooth muscle tone is lost. The main function of the organs of the alimentary canal is to nourish the body. This tube begins at the mouth and terminates at the anus. Between those two points, the canal is modified as the pharynx, esophagus, stomach, and small and large intestines to fit the functional needs of the body. Both the mouth and anus are open to the external environment; thus, food and wastes within the alimentary canal are technically considered to be outside the body. Only through the process of absorption do the nutrients in food enter into and nourish the body’s “inner space.”

Accessory Structures

Each accessory digestive organ aids in the breakdown of food (Figure 2). Within the mouth, the teeth and tongue begin mechanical digestion, whereas the salivary glands begin chemical digestion. Once food products enter the small intestine, the gallbladder, liver, and pancreas release secretions—such as bile and enzymes—essential for digestion to continue. Together, these are called accessory organs because they sprout from the lining cells of the developing gut (mucosa) and augment its function; indeed, you could not live without their vital contributions, and many significant diseases result from their malfunction. Even after development is complete, they maintain a connection to the gut by way of ducts.

Histology of the Alimentary Canal

Throughout its length, the alimentary tract is composed of the same four tissue layers; the details of their structural arrangements vary to fit their specific functions. Starting from the lumen and moving outwards, these layers are the mucosa, submucosa, muscularis, and serosa, which is continuous with the mesentery (see Figure 2).

[caption id="" align="aligncenter" width="480"] Figure 2. Layers of the Alimentary Canal. The wall of the alimentary canal has four basic tissue layers: the mucosa, submucosa, muscularis, and serosa.[/caption]

The mucosa is referred to as a mucous membrane, because mucus production is a characteristic feature of gut epithelium. The membrane consists of epithelium, which is in direct contact with ingested food, and the lamina propria, a layer of connective tissue analogous to the dermis. In addition, the mucosa has a thin, smooth muscle layer, called the muscularis mucosa (not to be confused with the muscularis layer, described below).

Epithelium—In the mouth, pharynx, esophagus, and anal canal, the epithelium is primarily a non-keratinized, stratified squamous epithelium. In the stomach and intestines, it is a simple columnar epithelium. Notice that the epithelium is in direct contact with the lumen, the space inside the alimentary canal. Interspersed among its epithelial cells are goblet cells, which secrete mucus and fluid into the lumen, and enteroendocrine cells, which secrete hormones into the interstitial spaces between cells. Epithelial cells have a very brief lifespan, averaging from only a couple of days (in the mouth) to about a week (in the gut). This process of rapid renewal helps preserve the health of the alimentary canal, despite the wear and tear resulting from continued contact with foodstuffs.

Lamina propria—In addition to loose connective tissue, the lamina propria contains numerous blood and lymphatic vessels that transport nutrients absorbed through the alimentary canal to other parts of the body. The lamina propria also serves an immune function by housing clusters of lymphocytes, making up the mucosa-associated lymphoid tissue (MALT). These lymphocyte clusters are particularly substantial in the distal ileum where they are known as Peyer’s patches. When you consider that the alimentary canal is exposed to foodborne bacteria and other foreign matter, it is not hard to appreciate why the immune system has evolved a means of defending against the pathogens encountered within it.

Muscularis mucosa—This thin layer of smooth muscle is in a constant state of tension, pulling the mucosa of the stomach and small intestine into undulating folds. These folds dramatically increase the surface area available for digestion and absorption.

As its name implies, the submucosa lies immediately beneath the mucosa. A broad layer of dense connective tissue, it connects the overlying mucosa to the underlying muscularis. It includes blood and lymphatic vessels (which transport absorbed nutrients), and a scattering of submucosal glands that release digestive secretions. Additionally, it serves as a conduit for a dense branching network of nerves, the submucosal plexus, which functions as described below.

The third layer of the alimentary canal is the muscalaris (also called the muscularis externa). The muscularis in the small intestine is made up of a double layer of smooth muscle: an inner circular layer and an outer longitudinal layer. The contractions of these layers promote mechanical digestion, expose more of the food to digestive chemicals, and move the food along the canal. In the most proximal and distal regions of the alimentary canal, including the mouth, pharynx, anterior part of the esophagus, and external anal sphincter, the muscularis is made up of skeletal muscle, which gives you voluntary control over swallowing and defecation. The basic two-layer structure found in the small intestine is modified in the organs proximal and distal to it. The stomach is equipped for its churning function by the addition of a third layer, the oblique muscle. While the colon has two layers like the small intestine, its longitudinal layer is segregated into three narrow parallel bands, the tenia coli, which make it look like a series of pouches rather than a simple tube.

The serosa is the portion of the alimentary canal superficial to the muscularis. Present only in the region of the alimentary canal within the abdominal cavity, it consists of a layer of visceral peritoneum overlying a layer of loose connective tissue. Instead of serosa, the mouth, pharynx, and esophagus have a dense sheath of collagen fibers called the adventitia. These tissues serve to hold the alimentary canal in place near the ventral surface of the vertebral column.

Nerve Supply

As soon as food enters the mouth, it is detected by receptors that send impulses along the sensory neurons of cranial nerves. Without these nerves, not only would your food be without taste, but you would also be unable to feel either the food or the structures of your mouth, and you would be unable to avoid biting yourself as you chew, an action enabled by the motor branches of cranial nerves.

Intrinsic innervation of much of the alimentary canal is provided by the enteric nervous system, which runs from the esophagus to the anus, and contains approximately 100 million motor, sensory, and interneurons (unique to this system compared to all other parts of the peripheral nervous system). These enteric neurons are grouped into two plexuses. The myenteric plexus (plexus of Auerbach) lies in the muscularis layer of the alimentary canal and is responsible for motility, especially the rhythm and force of the contractions of the muscularis. The submucosal plexus (plexus of Meissner) lies in the submucosal layer and is responsible for regulating digestive secretions and reacting to the presence of food (see [link]).

Extrinsic innervations of the alimentary canal are provided by the autonomic nervous system, which includes both sympathetic and parasympathetic nerves. In general, sympathetic activation (the fight-or-flight response) restricts the activity of enteric neurons, thereby decreasing GI secretion and motility. In contrast, parasympathetic activation (the rest-and-digest response) increases GI secretion and motility by stimulating neurons of the enteric nervous system.

Blood Supply

The blood vessels serving the digestive system have two functions. They transport the protein and carbohydrate nutrients absorbed by mucosal cells after food is digested in the lumen. Lipids are absorbed via lacteals, tiny structures of the lymphatic system. The blood vessels’ second function is to supply the organs of the alimentary canal with the nutrients and oxygen needed to drive their cellular processes.

Specifically, the more anterior parts of the alimentary canal are supplied with blood by arteries branching off the aortic arch and thoracic aorta. Below this point, the alimentary canal is supplied with blood by arteries branching from the abdominal aorta. The celiac trunk services the liver, stomach, and duodenum, whereas the superior and inferior mesenteric arteries supply blood to the remaining small and large intestines.

The veins that collect nutrient-rich blood from the small intestine (where most absorption occurs) empty into the hepatic portal system. This venous network takes the blood into the liver where the nutrients are either processed or stored for later use. Only then does the blood drained from the alimentary canal viscera circulate back to the heart. To appreciate just how demanding the digestive process is on the cardiovascular system, consider that while you are “resting and digesting,” about one-fourth of the blood pumped with each heartbeat enters arteries serving the intestines.

The Peritoneum

The digestive organs within the abdominal cavity are held in place by the peritoneum, a broad serous membranous sac made up of squamous epithelial tissue surrounded by connective tissue. It is composed of two different regions: the parietal peritoneum, which lines the abdominal wall, and the visceral peritoneum, which envelopes the abdominal organs (Figure 3). The peritoneal cavity is the space bounded by the visceral and parietal peritoneal surfaces. A few milliliters of watery fluid act as a lubricant to minimize friction between the serosal surfaces of the peritoneum.

[caption id="" align="aligncenter" width="420"] Figure 3. The Peritoneum. A cross-section of the abdomen shows the relationship between abdominal organs and the peritoneum (darker lines).[/caption]

[caption id="attachment_3015" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of the digestive system![/caption]

23.2 Digestive System Processes and Regulation

barkerj1 — Wed, 06 Sep 2017 01:19:55 +0000

Learning Objectives

By the end of this section, you will be able to:

Distinguish between extracellular digestion and intracellular digestion
Describe the six major functions of the digestive system
Describe the functional relationships between ingestion, digestion, absorption, and defecation
Describe the nervous control of the secretion of digestive juices
Describe the hormonal control of the secretion of digestive juices

The digestive system uses mechanical and chemical activities to break food down into absorbable substances during its journey through the digestive system. Table 3 provides an overview of the basic functions of the digestive organs.

[caption id="" align="aligncenter" width="120"] Visit this site for an overview of digestion of food in different regions of the digestive tract.[/caption]

Functions of the Digestive Organs (Table 3)
Organ	Major functions	Other functions
Mouth	Ingests food Chews and mixes food Begins chemical breakdown of carbohydrates Moves food into the pharynx Begins breakdown of lipids via lingual lipase	Moistens and dissolves food, allowing you to taste it Cleans and lubricates the teeth and oral cavity Has some antimicrobial activity
Pharynx	Propels food from the oral cavity to the esophagus	Lubricates food and passageways
Esophagus	Propels food to the stomach	Lubricates food and passageways
Stomach	Mixes and churns food with gastric juices to form chyme Begins chemical breakdown of proteins Releases food into the duodenum as chyme Absorbs some fat-soluble substances (for example, alcohol, aspirin) Possesses antimicrobial functions	Stimulates protein-digesting enzymes Secretes intrinsic factor required for vitamin B₁₂ absorption in small intestine
Small intestine	Mixes chyme with digestive juices Propels food at a rate slow enough for digestion and absorption Absorbs breakdown products of carbohydrates, proteins, lipids, and nucleic acids, along with vitamins, minerals, and water Performs physical digestion via segmentation	Provides optimal medium for enzymatic activity
Accessory organs	Liver: produces bile salts, which emulsify lipids, aiding their digestion and absorption Gallbladder: stores, concentrates, and releases bile Pancreas: produces digestive enzymes and bicarbonate	Bicarbonate-rich pancreatic juices help neutralize acidic chyme and provide optimal environment for enzymatic activity
Large intestine	Further breaks down food residues Absorbs most residual water, electrolytes, and vitamins produced by enteric bacteria Propels feces toward rectum Eliminates feces	Food residue is concentrated and temporarily stored prior to defecation Mucus eases passage of feces through colon

Digestive Processes

The processes of digestion include six activities: ingestion, propulsion, mechanical or physical digestion, chemical digestion, absorption, and defecation.

The first of these processes, ingestion, refers to the entry of food into the alimentary canal through the mouth. There, the food is chewed and mixed with saliva, which contains enzymes that begin breaking down the carbohydrates in the food plus some lipid digestion via lingual lipase. Chewing increases the surface area of the food and allows an appropriately sized bolus to be produced.

Food leaves the mouth when the tongue and pharyngeal muscles propel it into the esophagus. This act of swallowing, the last voluntary act until defecation, is an example of propulsion, which refers to the movement of food through the digestive tract. It includes both the voluntary process of swallowing and the involuntary process of peristalsis. Peristalsis consists of sequential, alternating waves of contraction and relaxation of alimentary wall smooth muscles, which act to propel food along (Figure 1). These waves also play a role in mixing food with digestive juices. Peristalsis is so powerful that foods and liquids you swallow enter your stomach even if you are standing on your head.

[caption id="" align="aligncenter" width="280"] Figure 1. Peristalsis. Peristalsis moves food through the digestive tract with alternating waves of muscle contraction and relaxation.[/caption]

Digestion includes both mechanical and chemical processes. Mechanical digestion is a purely physical process that does not change the chemical nature of the food. Instead, it makes the food smaller to increase both surface area and mobility. It includes mastication, or chewing, as well as tongue movements that help break food into smaller bits and mix food with saliva. Although there may be a tendency to think that mechanical digestion is limited to the first steps of the digestive process, it occurs after the food leaves the mouth, as well. The mechanical churning of food in the stomach serves to further break it apart and expose more of its surface area to digestive juices, creating an acidic “soup” called chyme. Segmentation, which occurs mainly in the small intestine, consists of localized contractions of circular muscle of the muscularis layer of the alimentary canal. These contractions isolate small sections of the intestine, moving their contents back and forth while continuously subdividing, breaking up, and mixing the contents. By moving food back and forth in the intestinal lumen, segmentation mixes food with digestive juices and facilitates absorption.

In chemical digestion, starting in the mouth, digestive secretions break down complex food molecules into their chemical building blocks (for example, proteins into separate amino acids). These secretions vary in composition, but typically contain water, various enzymes, acids, and salts. The process is completed in the small intestine. Since this chemical digestion occurs in the lumen of the gastrointestinal tract as a result of secretions into the lumen, it is a form of extracellular digestion. (Contrast this with the intracellular digestion that occurs after phagocytosis, for example.)

Food that has been broken down is of no value to the body unless it enters the bloodstream and its nutrients are put to work. This occurs through the process of absorption, which takes place primarily within the small intestine. There, most nutrients are absorbed from the lumen of the alimentary canal into the bloodstream through the epithelial cells that make up the mucosa. Lipids are absorbed into lacteals and are transported via the lymphatic vessels to the bloodstream (the subclavian veins near the heart). The details of these processes will be discussed later.

In defecation, the final step in digestion, undigested materials are removed from the body as feces.

In some cases, a single organ is in charge of a digestive process. For example, ingestion occurs only in the mouth and defecation only in the anus. However, most digestive processes involve the interaction of several organs and occur gradually as food moves through the alimentary canal (Figure 2).

[caption id="" align="aligncenter" width="420"] Figure 2. Digestive Processes. The digestive processes are ingestion, propulsion, mechanical digestion, chemical digestion, absorption, and defecation.[/caption]

Regulatory Mechanisms

Neural and endocrine regulatory mechanisms work to maintain the optimal conditions in the lumen needed for digestion and absorption. These regulatory mechanisms, which stimulate digestive activity through mechanical and chemical activity, are controlled both extrinsically and intrinsically.

Neural Controls

The walls of the alimentary canal contain a variety of sensors that help regulate digestive functions. These include mechanoreceptors, chemoreceptors, and osmoreceptors, which are capable of detecting mechanical, chemical, and osmotic stimuli, respectively. For example, these receptors can sense when the presence of food has caused the stomach to expand, whether food particles have been sufficiently broken down, how much liquid is present, and the type of nutrients in the food (lipids, carbohydrates, and/or proteins). Stimulation of these receptors provokes an appropriate reflex that furthers the process of digestion. This may entail sending a message that activates the glands that secrete digestive juices into the lumen, or it may mean the stimulation of muscles within the alimentary canal, thereby activating peristalsis and segmentation that move food along the intestinal tract. The walls of the entire alimentary canal are embedded with nerve plexuses that interact with the central nervous system and other nerve plexuses—either within the same digestive organ or in different ones. These interactions prompt several types of reflexes. Extrinsic nerve plexuses orchestrate long reflexes, which involve the central and autonomic nervous systems and work in response to stimuli from outside the digestive system. Short reflexes, on the other hand, are orchestrated by intrinsic nerve plexuses within the alimentary canal wall. These two plexuses and their connections were introduced earlier as the enteric nervous system. Short reflexes regulate activities in one area of the digestive tract and may coordinate local peristaltic movements and stimulate digestive secretions. For example, the sight, smell, and taste of food initiate long reflexes that begin with a sensory neuron delivering a signal to the medulla oblongata. The response to the signal is to stimulate cells in the stomach to begin secreting digestive juices in preparation for incoming food. In contrast, food that distends the stomach initiates short reflexes that cause cells in the stomach wall to increase their secretion of digestive juices.

Hormonal Controls

A variety of hormones are involved in the digestive process. The main digestive hormone of the stomach is gastrin, which is secreted in response to the presence of food. Gastrin stimulates the secretion of gastric acid by the parietal cells of the stomach mucosa. Other GI hormones are produced and act upon the gut and its accessory organs. Hormones produced by the duodenum include secretin, which stimulates a watery secretion of bicarbonate by the pancreas; cholecystokinin (CCK), which stimulates the secretion of pancreatic enzymes and bile from the liver and release of bile from the gallbladder; and gastric inhibitory peptide, which inhibits gastric secretion and slows gastric emptying and motility. These GI hormones are secreted by specialized epithelial cells, called endocrinocytes, located in the mucosal epithelium of the stomach and small intestine. These hormones then enter the bloodstream, through which they can reach their target organs.

[caption id="attachment_3017" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about digestion![/caption]

23.3 The Mouth, Pharynx, and Esophagus

barkerj1 — Wed, 06 Sep 2017 01:19:56 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the anatomy of the buccal cavity
Explain the functions of the buccal cavity in digestion
Describe the process of deglutition (swallowing), explaining why food does not enter the respiratory tract when swallowed
Describe the anatomy and function of the esophagus

In this section, you will examine the anatomy and functions of the three main organs of the upper alimentary canal—the mouth, pharynx, and esophagus—as well as three associated accessory organs—the tongue, salivary glands, and teeth.

The Mouth

The cheeks, tongue, and palate frame the mouth, which is also called the oral cavity (or buccal cavity). The structures of the mouth are illustrated in Figure 1.

At the entrance to the mouth are the lips, or labia (singular = labium). Their outer covering is skin, which transitions to a mucous membrane in the mouth proper. Lips are very vascular with a thin layer of keratin; hence, the reason they are "red." They have a huge representation on the cerebral cortex, which probably explains the human fascination with kissing! The lips cover the orbicularis oris muscle, which regulates what comes in and goes out of the mouth. The labial frenulum is a midline fold of mucous membrane that attaches the inner surface of each lip to the gum. The cheeks make up the oral cavity’s sidewalls. While their outer covering is skin, their inner covering is mucous membrane. This membrane is made up of non-keratinized, stratified squamous epithelium. Between the skin and mucous membranes are connective tissue and buccinator muscles. The next time you eat some food, notice how the buccinator muscles in your cheeks and the orbicularis oris muscle in your lips contract, helping you keep the food from falling out of your mouth. Additionally, notice how these muscles work when you are speaking.

The pocket-like part of the mouth that is framed on the inside by the gums and teeth, and on the outside by the cheeks and lips is called the oral vestibule. Moving farther into the mouth, the opening between the oral cavity and throat (oropharynx) is called the fauces (like the kitchen "faucet"). The main open area of the mouth, or oral cavity proper, runs from the gums and teeth to the fauces.

When you are chewing, you do not find it difficult to breathe simultaneously. The next time you have food in your mouth, notice how the arched shape of the roof of your mouth allows you to handle both digestion and respiration at the same time. This arch is called the palate. The anterior region of the palate serves as a wall (or septum) between the oral and nasal cavities as well as a rigid shelf against which the tongue can push food. It is created by the maxillary and palatine bones of the skull and, given its bony structure, is known as the hard palate. If you run your tongue along the roof of your mouth, you’ll notice that the hard palate ends in the posterior oral cavity, and the tissue becomes fleshier. This part of the palate, known as the soft palate, is composed mainly of skeletal muscle. You can therefore manipulate, subconsciously, the soft palate—for instance, to yawn, swallow, or sing (see Figure 1).

[caption id="" align="aligncenter" width="480"] Figure 1. Mouth. The mouth includes the lips, tongue, palate, gums, and teeth.[/caption]

A fleshy bead of tissue called the uvula drops down from the center of the posterior edge of the soft palate. Although some have suggested that the uvula is a vestigial organ, it serves an important purpose. When you swallow, the soft palate and uvula move upward, helping to keep foods and liquid from entering the nasal cavity. Unfortunately, it can also contribute to the sound produced by snoring. Two muscular folds extend downward from the soft palate, on either side of the uvula. Toward the front, the palatoglossal arch lies next to the base of the tongue; behind it, the palatopharyngeal arch forms the superior and lateral margins of the fauces. Between these two arches are the palatine tonsils, clusters of lymphoid tissue that protect the pharynx. The lingual tonsils are located at the base of the tongue.

The Tongue

Perhaps you have heard it said that the tongue is the strongest muscle in the body. Those who stake this claim cite its strength proportionate to its size. Although it is difficult to quantify the relative strength of different muscles, it remains indisputable that the tongue is a workhorse, facilitating ingestion, mechanical digestion, chemical digestion (lingual lipase), sensation (of taste, texture, and temperature of food), swallowing, and vocalization.

The tongue is attached to the mandible, the styloid processes of the temporal bones, and the hyoid bone. The hyoid is unique in that it only distantly/indirectly articulates with other bones. The tongue is positioned over the floor of the oral cavity. A medial septum extends the entire length of the tongue, dividing it into symmetrical halves.

Beneath its mucous membrane covering, each half of the tongue is composed of the same number and type of intrinsic and extrinsic skeletal muscles. The intrinsic muscles (those within the tongue) are the longitudinalis inferior, longitudinalis superior, transversus linguae, and verticalis linguae muscles. These allow you to change the size and shape of your tongue, as well as to stick it out, if you wish. Having such a flexible tongue facilitates both swallowing and speech.

As you learned in your study of the muscular system, the extrinsic muscles of the tongue are the mylohyoid, hyoglossus, styloglossus, and genioglossus muscles. These muscles originate outside the tongue and insert into connective tissues within the tongue. The mylohyoid is responsible for raising the tongue, the hyoglossus pulls it down and back, the styloglossus pulls it up and back, and the genioglossus pulls it forward. Working in concert, these muscles perform three important digestive functions in the mouth: (1) position food for optimal chewing, (2) gather food into a bolus (rounded mass), and (3) position food so it can be swallowed.

The top and sides of the tongue are studded with papillae, extensions of lamina propria of the mucosa, which are covered in stratified squamous epithelium (Figure 2). Fungiform papillae, which are mushroom shaped, cover a large area of the tongue; they tend to be larger toward the rear of the tongue and smaller on the tip and sides. In contrast, filiform papillae are long and thin. Fungiform papillae contain taste buds, and filiform papillae have touch receptors that help the tongue move food around in the mouth. The filiform papillae create an abrasive surface that performs mechanically, much like a cat’s rough tongue that is used for grooming. Lingual glands in the lamina propria of the tongue secrete mucus and a watery serous fluid that contains the enzyme lingual lipase, which plays a minor role in breaking down triglycerides but does not begin working until it is activated in the stomach. A fold of mucous membrane on the underside of the tongue, the lingual frenulum, tethers the tongue to the floor of the mouth. People with the congenital anomaly ankyloglossia, also known by the non-medical term “tongue tie,” have a lingual frenulum that is too short or otherwise malformed. Severe ankyloglossia can impair speech and must be corrected with surgery.

[caption id="" align="aligncenter" width="330"] Figure 2. Tongue. This superior view of the tongue shows the locations and types of lingual papillae.[/caption]

The Salivary Glands

Many small salivary glands are housed within the mucous membranes of the mouth and tongue. These minor exocrine glands are constantly secreting saliva, either directly into the oral cavity or indirectly through ducts, even while you sleep. In fact, an average of 1 to 1.5 liters of saliva is secreted each day. Usually just enough saliva is present to moisten the mouth and teeth. Secretion increases when you eat, because saliva is essential to moisten food and initiate the chemical breakdown of carbohydrates. Small amounts of saliva are also secreted by the labial glands in the lips. In addition, the buccal glands in the cheeks, palatal glands in the palate, and lingual glands in the tongue help ensure that all areas of the mouth are supplied with adequate saliva.

The Major Salivary Glands

Outside the oral mucosa are three pairs of major salivary glands, which secrete the majority of saliva into ducts that open into the mouth:

The submandibular glands, which are in the floor of the mouth, secrete saliva into the mouth through the submandibular ducts.
The sublingual glands, which lie below the tongue, use the lesser sublingual ducts to secrete saliva into the oral cavity.
The parotid glands lie between the skin and the masseter muscle, near the ears. They secrete saliva into the mouth through the parotid duct, which is located near the second upper molar tooth (Figure 3).

Saliva

Saliva is essentially (95.5 percent) water. The remaining 4.5 percent is a complex mixture of ions, glycoproteins, enzymes, growth factors, and waste products. Perhaps the most important ingredient in salvia from the perspective of digestion is the enzyme salivary amylase, which initiates the breakdown of carbohydrates. Food does not spend enough time in the mouth to allow all the carbohydrates to break down, but salivary amylase continues acting until it is inactivated by stomach acids. Bicarbonate and phosphate ions function as chemical buffers, maintaining saliva at a pH between 6.35 and 6.85. Salivary mucus helps lubricate food, facilitating movement in the mouth, bolus formation, and swallowing. Saliva contains immunoglobulin A, which prevents microbes from penetrating the epithelium, and lysozyme, which makes saliva antimicrobial. Saliva also contains epidermal growth factor, which might have given rise to the adage “a mother’s kiss can heal a wound.”

Each of the major salivary glands secretes a unique formulation of saliva according to its cellular makeup. For example, the parotid glands secrete a watery solution that contains salivary amylase. The submandibular glands have cells similar to those of the parotid glands, as well as mucus-secreting cells. Therefore, saliva secreted by the submandibular glands also contains amylase but in a liquid thickened with mucus. The sublingual glands contain mostly mucous cells, and they secrete the thickest saliva with the least amount of salivary amylase.

[caption id="" align="aligncenter" width="300"] Figure 3. Salivary glands. The major salivary glands are located outside the oral mucosa and deliver saliva into the mouth through ducts.[/caption]

Regulation of Salivation

The autonomic nervous system regulates salivation (the secretion of saliva). In the absence of food, parasympathetic stimulation keeps saliva flowing at just the right level for comfort as you speak, swallow, sleep, and generally go about life. Over-salivation can occur, for example, if you are stimulated by the smell of food, but that food is not available for you to eat. Drooling is an extreme instance of the overproduction of saliva. During times of stress, such as before speaking in public, sympathetic stimulation takes over, reducing salivation and producing the symptom of dry mouth often associated with anxiety. When you are dehydrated, salivation is reduced, causing the mouth to feel dry and prompting you to take action to quench your thirst.

Salivation can be stimulated by the sight, smell, and taste of food. It can even be stimulated by thinking about food. You might notice whether reading about food and salivation right now has had any effect on your production of saliva.

How does the salivation process work while you are eating? Food contains chemicals that stimulate taste receptors on the tongue, which send impulses to the superior and inferior salivatory nuclei in the brain stem. These two nuclei then send back parasympathetic impulses through fibers in the glossopharyngeal and facial nerves, which stimulate salivation. Even after you swallow food, salivation is increased to cleanse the mouth and to water down and neutralize any irritating chemical remnants, such as that hot sauce in your burrito. Most saliva is swallowed along with food and is reabsorbed, so that fluid is not lost.

The Teeth

The teeth, or dentes (singular = dens), are organs similar to bones that you use to tear, grind, and otherwise mechanically break down food.

Types of Teeth

During the course of your lifetime, you have two sets of teeth (one set of teeth is a dentition). Your 20 deciduous teeth, or baby teeth, first begin to appear at about 6 months of age. Between approximately age 6 and 12, these teeth are replaced by 32 permanent teeth. Moving from the center of the mouth toward the side, these are as follows (Figure 4):

The eight incisors, four top and four bottom, are the sharp front teeth you use for biting into food.
The four cuspids (or canines) flank the incisors and have a pointed edge (cusp) to tear up food. These fang-like teeth are superb for piercing tough or fleshy foods.
Posterior to the cuspids are the eight premolars (or bicuspids), which have an overall flatter shape with two rounded cusps useful for mashing foods.
The most posterior and largest are the 12 molars, which have several pointed cusps used to crush food so it is ready for swallowing. The third members of each set of three molars, top and bottom, are commonly referred to as the wisdom teeth, because their eruption is commonly delayed until early adulthood. It is not uncommon for wisdom teeth to fail to erupt; that is, they remain impacted. In these cases, the teeth are typically removed by orthodontic surgery.

[caption id="" align="aligncenter" width="350"] Figure 4. Permanent and Deciduous Teeth. This figure of two human dentitions shows the arrangement of teeth in the maxilla and mandible, and the relationship between the deciduous and permanent teeth.[/caption]

Anatomy of a Tooth

The teeth are secured in the alveolar processes (sockets) of the maxilla and the mandible. Gingivae (commonly called the gums) are soft tissues that line the alveolar processes and surround the necks of the teeth. Teeth are also held in their sockets by a connective tissue called the periodontal ligament.

The two main parts of a tooth are the crown, which is the portion projecting above the gum line, and the root, which is embedded within the maxilla and mandible. Both parts contain an inner pulp cavity, containing loose connective tissue through which run nerves and blood vessels. The region of the pulp cavity that runs through the root of the tooth is called the root canal. Surrounding the pulp cavity is dentin, a bone-like tissue. In the root of each tooth, the dentin is covered by an even harder bone-like layer called cementum. In the crown of each tooth, the dentin is covered by an outer layer of enamel, the hardest substance in the body (Figure 5).

Although enamel protects the underlying dentin and pulp cavity, it is still nonetheless susceptible to mechanical and chemical erosion, or what is known as tooth decay. The most common form, dental caries (cavities) develops when colonies of bacteria feeding on sugars in the mouth release acids that cause soft tissue inflammation and degradation of the calcium crystals of the enamel. The digestive functions of the mouth are summarized in Table 4.

[caption id="" align="aligncenter" width="350"] Figure 5. The Structure of the Tooth. This longitudinal section through a molar in its alveolar socket shows the relationships between enamel, dentin, and pulp.[/caption]

Digestive Functions of the Mouth (Table 4)
Structure	Action	Outcome
Lips and cheeks	Confine food between teeth	Food is chewed evenly during mastication
Salivary glands	Secrete saliva	Moisten and lubricate the lining of the mouth and pharynx Moisten, soften, and dissolve food Clean the mouth and teeth Salivary amylase breaks down starch
Tongue’s extrinsic muscles	Move tongue sideways, and in and out	Manipulate food for chewing Shape food into a bolus Manipulate food for swallowing
Tongue’s intrinsic muscles	Change tongue shape	Manipulate food for swallowing
Taste buds	Sense food in mouth and sense taste	Nerve impulses from taste buds are conducted to salivary nuclei in the brain stem and then to salivary glands, stimulating saliva secretion
Lingual glands	Secrete lingual lipase	Activated in the stomach Break down triglycerides into fatty acids and diglycerides
Teeth	Shred and crush food	Break down solid food into smaller particles for deglutition

The Pharynx

The pharynx (throat) is involved in both digestion and respiration. It receives food and air from the mouth, and air from the nasal cavities. When food enters the pharynx, involuntary muscle contractions close off the air passageways.

A short tube of skeletal muscle lined with a mucous membrane, the pharynx runs from the posterior oral and nasal cavities to the opening of the esophagus and larynx. It has three subdivisions. The most superior, the nasopharynx, is involved only in breathing and speech. The other two subdivisions, the oropharynx and the laryngopharynx, are used for both breathing and digestion. The oropharynx begins inferior to the nasopharynx and is continuous below with the laryngopharynx (Figure 6). The inferior border of the laryngopharynx connects to the esophagus, whereas the anterior portion connects to the larynx, allowing air to flow into the bronchial tree.

[caption id="" align="aligncenter" width="380"] Figure 6. Pharynx. The pharynx runs from the nostrils to the esophagus and the larynx.[/caption]

Histologically, the wall of the oropharynx is similar to that of the oral cavity. The mucosa includes a stratified squamous epithelium that is endowed with mucus-producing glands. During swallowing, the elevator skeletal muscles of the pharynx contract, raising and expanding the pharynx to receive the bolus of food. Once received, these muscles relax and the constrictor muscles of the pharynx contract, forcing the bolus into the esophagus and initiating peristalsis.

Usually during swallowing, the soft palate and uvula rise reflexively to close off the entrance to the nasopharynx. At the same time, the larynx is pulled superiorly and the cartilaginous epiglottis, its most superior structure, folds inferiorly, covering the glottis (the opening to the larynx); this process effectively blocks access to the trachea and bronchi. When the food “goes down the wrong way,” it goes into the trachea. When food enters the trachea, the reaction is to cough, which usually forces the food up and out of the trachea, and back into the pharynx.

The Esophagus

The esophagus is a muscular tube that connects the pharynx to the stomach. It is approximately 25.4 cm (10 in) in length, located posterior to the trachea, and remains in a collapsed form when not engaged in swallowing. As you can see in Figure 7, the esophagus runs a mainly straight route through the mediastinum of the thorax. To enter the abdomen, the esophagus penetrates the diaphragm through an opening called the esophageal hiatus.

Passage of Food through the Esophagus

The upper esophageal sphincter, which is continuous with the inferior pharyngeal constrictor, controls the movement of food from the pharynx into the esophagus. The upper two-thirds of the esophagus consists of both smooth and skeletal muscle fibers, with the latter fading out in the bottom third of the esophagus. Rhythmic waves of peristalsis, which begin in the upper esophagus, propel the bolus of food toward the stomach. Meanwhile, secretions from the esophageal mucosa lubricate the esophagus and food. Food passes from the esophagus into the stomach at the lower esophageal sphincter (also called the gastroesophageal or cardiac sphincter). Recall that sphincters are muscles that surround tubes and serve as valves, closing the tube when the sphincters contract and opening it when they relax. The lower esophageal sphincter relaxes to let food pass into the stomach, and then contracts to prevent stomach acids from backing up into the esophagus. Surrounding this sphincter is the muscular diaphragm, which helps close off the sphincter when no food is being swallowed. When the lower esophageal sphincter does not completely close, the stomach’s contents can reflux (that is, back up into the esophagus), causing heartburn or gastroesophageal reflux disease (GERD).

[caption id="" align="aligncenter" width="320"] Figure 7. Esophagus. The upper esophageal sphincter controls the movement of food from the pharynx to the esophagus. The lower esophageal sphincter controls the movement of food from the esophagus to the stomach.[/caption]

Histology of the Esophagus

The mucosa of the esophagus is made up of an epithelial lining that contains non-keratinized, stratified squamous epithelium, with a layer of basal and parabasal cells. This epithelium protects against erosion from food particles. The mucosa’s lamina propria contains mucus-secreting glands. The muscularis layer changes according to location: In the upper third of the esophagus, the muscularis is skeletal muscle. In the middle third, it is both skeletal and smooth muscle. In the lower third, it is smooth muscle. As mentioned previously, the most superficial layer of the esophagus is called the adventitia, not the serosa. In contrast to the stomach and intestines, the loose connective tissue of the adventitia is not covered by a fold of visceral peritoneum. The digestive functions of the esophagus are identified in Table 5.

Digestive Functions of the Esophagus (Table 5)
Action	Outcome
Upper esophageal sphincter relaxation	Allows the bolus to move from the laryngopharynx to the esophagus
Peristalsis	Propels the bolus through the esophagus
Lower esophageal sphincter relaxation	Allows the bolus to move from the esophagus into the stomach and prevents chime from entering the esophagus
Mucus secretion	Lubricates the esophagus, allowing easy passage of the bolus

Deglutition

Deglutition is another word for swallowing—the movement of food from the mouth to the stomach. The entire process takes about 4 to 8 seconds for solid or semisolid food, and about 1 second for very soft food and liquids. Although this sounds quick and effortless, deglutition is, in fact, a complex process that involves both the skeletal muscle of the tongue and the muscles of the pharynx and esophagus. It is aided by the presence of mucus and saliva. There are three stages in deglutition: the voluntary phase, the pharyngeal phase, and the esophageal phase (Figure 8). The autonomic nervous system controls the latter two phases.

[caption id="" align="aligncenter" width="520"] Figure 8. Deglutition. Deglutition includes the voluntary phase and two involuntary phases: the pharyngeal phase and the esophageal phase.[/caption]

The Voluntary Phase

The voluntary phase of deglutition (also known as the oral or buccal phase) is so called because you can control when you swallow food. In this phase, chewing has been completed and swallowing is set in motion. The tongue moves upward and backward against the palate, pushing the bolus to the back of the oral cavity and into the oropharynx. Other muscles keep the mouth closed and prevent food from falling out. At this point, the two involuntary phases of swallowing begin.

The Pharyngeal Phase

In the pharyngeal phase, stimulation of receptors in the oropharynx sends impulses to the deglutition center (a collection of neurons that controls swallowing) in the medulla oblongata. Impulses are then sent back to the uvula and soft palate, causing them to move upward and close off the nasopharynx. The laryngeal muscles also constrict to prevent aspiration of food into the trachea. At this point, deglutition apnea takes place, which means that breathing ceases for a very brief time. Contractions of the pharyngeal constrictor muscles move the bolus through the oropharynx and laryngopharynx. Relaxation of the upper esophageal sphincter then allows food to enter the esophagus.

The Esophageal Phase

The entry of food into the esophagus marks the beginning of the esophageal phase of deglutition and the initiation of peristalsis. As in the previous phase, the complex neuromuscular actions are controlled by the medulla oblongata. Peristalsis propels the bolus through the esophagus and toward the stomach. The circular muscle layer of the muscularis contracts, pinching the esophageal wall and forcing the bolus forward. At the same time, the longitudinal muscle layer of the muscularis also contracts, shortening this area and pushing out its walls to receive the bolus. In this way, a series of contractions keeps moving food toward the stomach. When the bolus nears the stomach, distention of the esophagus initiates a short reflex relaxation of the lower esophageal sphincter that allows the bolus to pass into the stomach. During the esophageal phase, esophageal glands secrete mucus that lubricates the bolus and minimizes friction.

[caption id="" align="aligncenter" width="120"] Watch this animation to see how swallowing is a complex process that involves the nervous system to coordinate the actions of upper respiratory and digestive activities.[/caption]

23.4 The Stomach

barkerj1 — Wed, 06 Sep 2017 01:19:57 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the anatomy of the stomach
Describe the functions of the stomach
Describe the control of the secretion of gastric juices

Although a minimal amount of carbohydrate digestion occurs in the mouth, chemical digestion really gets underway in the stomach. An expansion of the alimentary canal that lies immediately inferior to the esophagus, the stomach links the esophagus to the first part of the small intestine (the duodenum) and is relatively fixed in place at its esophageal and duodenal ends. In between, however, it can be a highly active structure, contracting and continually changing position and size. These contractions provide mechanical assistance to digestion. The empty stomach is only about the size of your fist, but can stretch to hold as much as 4 liters of food and fluid, or more than 75 times its empty volume, and then return to its resting size when empty. Although you might think that the size of a person’s stomach is related to how much food that individual consumes, body weight does not correlate with stomach size. Rather, when you eat greater quantities of food—such as at holiday dinner—you stretch the stomach more than when you eat less.

Popular culture tends to refer to the stomach as the location where all digestion takes place. Of course, this is not true. An important function of the stomach is to serve as a temporary holding chamber. You can ingest a meal far more quickly than it can be digested and absorbed by the small intestine. Thus, the stomach holds food and parses only small amounts into the small intestine at a time. Foods are not processed in the order they are eaten; rather, they are mixed together with digestive juices in the stomach until they are converted into chyme, which is released into the small intestine.

As you will see in the sections that follow, the stomach plays several important roles in chemical digestion, including the continued digestion of carbohydrates and the initial digestion of proteins and triglycerides. Little if any nutrient absorption occurs in the stomach, with the exception of the negligible amount of nutrients in alcohol.

Structure

There are four main regions in the stomach: the cardia, fundus, body, and pylorus (Figure 1). The cardia (or cardiac region) is the point where the esophagus connects to the stomach and through which food passes into the stomach. Located inferior to the diaphragm, above and to the left of the cardia, is the dome-shaped fundus. Below the fundus is the body, the main part of the stomach. The funnel-shaped pylorus connects the stomach to the duodenum. The wider end of the funnel, the pyloric antrum, connects to the body of the stomach. The narrower end is called the pyloric canal, which connects to the duodenum. The smooth muscle pyloric sphincter is located at this latter point of connection and controls stomach emptying. In the absence of food, the stomach deflates inward, and its mucosa and submucosa fall into a large fold called a ruga.

[caption id="" align="aligncenter" width="520"] Figure 1. Stomach. The stomach has four major regions: the cardia, fundus, body, and pylorus. The addition of an inner oblique smooth muscle layer gives the muscularis the ability to vigorously churn and mix food.[/caption]

The convex lateral surface of the stomach is called the greater curvature; the concave medial border is the lesser curvature. The stomach is held in place by the lesser omentum, which extends from the liver to the lesser curvature, and the greater omentum, which runs from the greater curvature to the posterior abdominal wall.

Histology

The wall of the stomach is made of the same four layers as most of the rest of the alimentary canal, but with adaptations to the mucosa and muscularis for the unique functions of this organ. In addition to the typical circular and longitudinal smooth muscle layers, the muscularis has an inner oblique smooth muscle layer (Figure 2). As a result, in addition to moving food through the canal, the stomach can vigorously churn food, mechanically breaking it down into smaller particles.

[caption id="" align="aligncenter" width="500"] Figure 2. Histology of the Stomach. The stomach wall is adapted for the functions of the stomach. In the epithelium, gastric pits lead to gastric glands that secrete gastric juice. The gastric glands (one gland is shown enlarged on the right) contain different types of cells that secrete a variety of enzymes, including hydrochloride acid, which activates the protein-digesting enzyme pepsin.[/caption]

The stomach mucosa’s epithelial lining consists only of surface mucus cells, which secrete a protective coat of alkaline mucus. A vast number of gastric pits dot the surface of the epithelium, giving it the appearance of a well-used pincushion, and mark the entry to each gastric gland, which secretes a complex digestive fluid referred to as gastric juice.

Although the walls of the gastric pits are made up primarily of mucus cells, the gastric glands are made up of different types of cells. The glands of the cardia and pylorus are composed primarily of mucus-secreting cells. Cells that make up the pyloric antrum secrete mucus and a number of hormones, including the majority of the stimulatory hormone, gastrin. The much larger glands of the fundus and body of the stomach, the site of most chemical digestion, produce most of the gastric secretions. These glands are made up of a variety of secretory cells. These include parietal cells, chief cells, mucous neck cells, and enteroendocrine cells.

Parietal cells—Located primarily in the middle region of the gastric glands are parietal cells, which are among the most highly differentiated of the body’s epithelial cells. These relatively large cells produce both hydrochloric acid (HCl) and intrinsic factor. HCl is responsible for the high acidity (pH 1.5 to 3.5) of the stomach contents and is needed to activate the protein-digesting enzyme, pepsin. The acidity also kills much of the bacteria you ingest with food and helps to denature proteins, making them more available for enzymatic digestion. Intrinsic factor is a glycoprotein necessary for the absorption of vitamin B₁₂ in the small intestine.

Chief cells—Located primarily in the basal regions of gastric glands are chief cells, which secrete pepsinogen, the inactive proenzyme form of pepsin. HCl is necessary for the conversion of pepsinogen to pepsin.

Mucous neck cells—Gastric glands in the upper part of the stomach contain mucous neck cells that secrete thin, acidic mucus that is much different from the mucus secreted by the goblet cells of the surface epithelium. The role of this mucus is not currently known.

Enteroendocrine cells—Finally, enteroendocrine cells found in the gastric glands secrete various hormones into the interstitial fluid of the lamina propria. These include gastrin, which is released mainly by enteroendocrine G cells.

Table 6 describes the digestive functions of important hormones secreted by the stomach.

Hormones Secreted by the Stomach (Table 6)
Hormone	Production site	Production stimulus	Target organ	Action
Gastrin	Stomach mucosa, mainly G cells of the pyloric antrum	Presence of peptides and amino acids in stomach	Stomach	Increases secretion by gastric glands; promotes gastric emptying
Gastrin	Stomach mucosa, mainly G cells of the pyloric antrum	Presence of peptides and amino acids in stomach	Small intestine	Promotes intestinal muscle contraction
Gastrin	Stomach mucosa, mainly G cells of the pyloric antrum	Presence of peptides and amino acids in stomach	Ileocecal valve	Relaxes valve
Gastrin	Stomach mucosa, mainly G cells of the pyloric antrum	Presence of peptides and amino acids in stomach	Large intestine	Triggers mass movements
Ghrelin	Stomach mucosa, mainly fundus	Fasting state (levels increase just prior to meals)	Hypothalamus	Regulates food intake, primarily by stimulating hunger and satiety
Histamine	Stomach mucosa	Presence of food in the stomach	Stomach	Stimulates parietal cells to release HCl
Serotonin	Stomach mucosa	Presence of food in the stomach	Stomach	Contracts stomach muscle
Somatostatin	Mucosa of stomach, especially pyloric antrum; also duodenum	Presence of food in the stomach; sympathetic axon stimulation	Stomach	Restricts all gastric secretions, gastric motility, and emptying
Somatostatin	Mucosa of stomach, especially pyloric antrum; also duodenum	Presence of food in the stomach; sympathetic axon stimulation	Pancreas	Restricts pancreatic secretions
Somatostatin	Mucosa of stomach, especially pyloric antrum; also duodenum	Presence of food in the stomach; sympathetic axon stimulation	Small intestine	Reduces intestinal absorption by reducing blood flow

Gastric Secretion

The secretion of gastric juice is controlled by both nerves and hormones. Stimuli in the brain, stomach, and small intestine activate or inhibit gastric juice production. This is why the three phases of gastric secretion are called the cephalic, gastric, and intestinal phases (Figure 3). However, once gastric secretion begins, all three phases can occur simultaneously.

[caption id="" align="aligncenter" width="450"] Figure 3. The Three Phases of Gastric Secretion. Gastric secretion occurs in three phases: cephalic, gastric, and intestinal. During each phase, the secretion of gastric juice can be stimulated or inhibited.[/caption]

The cephalic phase (reflex phase) of gastric secretion, which is relatively brief, takes place before food enters the stomach. The smell, taste, sight, or thought of food triggers this phase. For example, when you bring a piece of sushi to your lips, impulses from receptors in your taste buds or the nose are relayed to your brain, which returns signals that increase gastric secretion to prepare your stomach for digestion. This enhanced secretion is a conditioned reflex, meaning it occurs only if you like or want a particular food. Depression and loss of appetite can suppress the cephalic reflex.

The gastric phase of secretion lasts 3 to 4 hours, and is set in motion by local neural and hormonal mechanisms triggered by the entry of food into the stomach. For example, when your sushi reaches the stomach, it creates distention that activates the stretch receptors. This stimulates parasympathetic neurons to release acetylcholine, which then provokes increased secretion of gastric juice. Partially digested proteins, caffeine, and rising pH stimulate the release of gastrin from enteroendocrine G cells, which in turn induces parietal cells to increase their production of HCl, which is needed to create an acidic environment for the conversion of pepsinogen to pepsin, and protein digestion. Additionally, the release of gastrin activates vigorous smooth muscle contractions. However, it should be noted that the stomach does have a natural means of avoiding excessive acid secretion and potential heartburn. Whenever pH levels drop too low, cells in the stomach react by suspending HCl secretion and increasing mucous secretions.

The intestinal phase of gastric secretion has both excitatory and inhibitory elements. The duodenum has a major role in regulating the stomach and its emptying. When partially digested food fills the duodenum, intestinal mucosal cells release a hormone called intestinal (enteric) gastrin, which further excites gastric juice secretion. This stimulatory activity is brief, however, because when the intestine distends with chyme, the enterogastric reflex inhibits secretion. One of the effects of this reflex is to close the pyloric sphincter, which blocks additional chyme from entering the duodenum.

The Mucosal Barrier

The mucosa of the stomach is exposed to the highly corrosive acidity of gastric juice. Gastric enzymes that can digest protein can also digest the stomach itself. The stomach is protected from self-digestion by the mucosal barrier. This barrier has several components. First, the stomach wall is covered by a thick coating of bicarbonate-rich mucus. This mucus forms a physical barrier, and its bicarbonate ions neutralize acid. Second, the epithelial cells of the stomach's mucosa meet at tight junctions, which block gastric juice from penetrating the underlying tissue layers. Finally, stem cells located where gastric glands join the gastric pits quickly replace damaged epithelial mucosal cells, when the epithelial cells are shed. In fact, the surface epithelium of the stomach is completely replaced every 3 to 6 days.

Homeostatic Imbalances

Ulcers: When the Mucosal Barrier Breaks Down As effective as the mucosal barrier is, it is not a “fail-safe” mechanism. Sometimes, gastric juice eats away at the superficial lining of the stomach mucosa, creating erosions, which mostly heal on their own. Deeper and larger erosions are called ulcers.

Why does the mucosal barrier break down? A number of factors can interfere with its ability to protect the stomach lining. The majority of all ulcers are caused by either excessive intake of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, or Helicobacter pylori infection.

Antacids help relieve symptoms of ulcers such as “burning” pain and indigestion. When ulcers are caused by NSAID use, switching to other classes of pain relievers allows healing. When caused by H. pylori infection, antibiotics are effective.

A potential complication of ulcers is perforation: Perforated ulcers create a hole in the stomach wall, resulting in peritonitis (inflammation of the peritoneum). These ulcers must be repaired surgically.

Digestive Functions of the Stomach

The stomach participates in virtually all the digestive activities with the exception of ingestion and defecation. Although almost all absorption takes place in the small intestine, the stomach does absorb some nonpolar substances, such as alcohol and aspirin.

Mechanical Digestion

Within a few moments after food after enters your stomach, mixing waves begin to occur at intervals of approximately 20 seconds. A mixing wave is a unique type of peristalsis that mixes and softens the food with gastric juices to create chyme. The initial mixing waves are relatively gentle, but these are followed by more intense waves, starting at the body of the stomach and increasing in force as they reach the pylorus. It is fair to say that long before your sushi exits through the pyloric sphincter, it bears little resemblance to the sushi you ate. The pylorus, which holds around 30 mL (1 fluid ounce) of chyme, acts as a filter, permitting only liquids and small food particles to pass through the mostly, but not fully, closed pyloric sphincter. In a process called gastric emptying, rhythmic mixing waves force about 3 mL of chyme at a time through the pyloric sphincter and into the duodenum. Release of a greater amount of chyme at one time would overwhelm the capacity of the small intestine to handle it. The rest of the chyme is pushed back into the body of the stomach, where it continues mixing. This process is repeated when the next mixing waves force more chyme into the duodenum.

Gastric emptying is regulated by both the stomach and the duodenum. The presence of chyme in the duodenum activates receptors that inhibit gastric secretion. This prevents additional chyme from being released by the stomach before the duodenum is ready to process it.

Chemical Digestion

The fundus plays an important role, because it stores both undigested food and gases that are released during the process of chemical digestion. Food may sit in the fundus of the stomach for a while before being mixed with the chyme. While the food is in the fundus, the digestive activities of salivary amylase continue until the food begins mixing with the acidic chyme. Ultimately, mixing waves incorporate this food with the chyme, the acidity of which inactivates salivary amylase and activates lingual lipase. Lingual lipase then begins breaking down triglycerides into free fatty acids, and mono- and diglycerides.

The breakdown of protein begins in the stomach through the actions of HCl and the enzyme pepsin. During infancy, gastric glands also produce rennin, an enzyme that helps digest milk protein.

Its numerous digestive functions notwithstanding, there is only one stomach function necessary to life: the production of intrinsic factor. The intestinal absorption of vitamin B₁₂, which is necessary for both the production of mature red blood cells and normal neurological functioning, cannot occur without intrinsic factor. People who undergo total gastrectomy (stomach removal)—for life-threatening stomach cancer, for example—can survive with minimal digestive dysfunction if they receive vitamin B₁₂ injections.

The contents of the stomach are completely emptied into the duodenum within 2 to 4 hours after you eat a meal. Different types of food take different amounts of time to process. Foods heavy in carbohydrates empty fastest, followed by high-protein foods. Meals with a high triglyceride content remain in the stomach the longest. Since enzymes in the small intestine digest fats slowly, food can stay in the stomach for 6 hours or longer when the duodenum is processing fatty chyme. However, note that this is still a fraction of the 24 to 72 hours that full digestion typically takes from start to finish.

23.5 The Small and Large Intestines

barkerj1 — Wed, 06 Sep 2017 01:19:58 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the anatomy of the small intestine
Describe the functions of the small intestine
Describe the anatomy of the large intestine
Describe the functions of the large intestine
Describe the process of defecation

The word intestine is derived from a Latin root meaning “internal,” and indeed, the two organs together nearly fill the interior of the abdominal cavity. In addition, called the small and large bowel, or colloquially the “guts,” they constitute the greatest mass and length of the alimentary canal and, with the exception of ingestion, perform all digestive system functions.

The Small Intestine

Chyme released from the stomach enters the small intestine, which is the primary digestive organ in the body. Not only is this where most digestion occurs, it is also where practically all absorption occurs. The longest part of the alimentary canal, the small intestine is about 3.05 meters (10 feet) long in a living person (but about twice as long in a cadaver due to the loss of muscle tone). Since this makes it about five times longer than the large intestine, you might wonder why it is called “small.” In fact, its name derives from its relatively smaller diameter of only about 2.54 cm (1 in), compared with 7.62 cm (3 in) for the large intestine. As we’ll see shortly, in addition to its length, the folds and projections of the lining of the small intestine work to give it an enormous surface area, which is approximately 200 m², more than 100 times the surface area of your skin. This large surface area is necessary for complex processes of digestion and absorption that occur within it.

Structure

The coiled tube of the small intestine is subdivided into three regions. From proximal (at the stomach) to distal, these are the duodenum, jejunum, and ileum (Figure 1).

The shortest region is the 25.4-cm (10-in) duodenum, which begins at the pyloric sphincter. Just past the pyloric sphincter, it bends posteriorly behind the peritoneum, becoming retroperitoneal, and then makes a C-shaped curve around the head of the pancreas before ascending anteriorly again to return to the peritoneal cavity and join the jejunum. The duodenum can therefore be subdivided into four segments: the superior, descending, horizontal, and ascending duodenum.

Of particular interest is the hepatopancreatic ampulla (ampulla of Vater). Located in the duodenal wall, the ampulla marks the transition from the anterior portion of the alimentary canal to the mid-region, and is where the bile duct (through which bile passes from the liver) and the main pancreatic duct (through which pancreatic juice passes from the pancreas) join. This ampulla opens into the duodenum at a tiny volcano-shaped structure called the major duodenal papilla. The hepatopancreatic sphincter (sphincter of Oddi) regulates the flow of both bile and pancreatic juice from the ampulla into the duodenum.

[caption id="" align="aligncenter" width="420"] Figure 1. Small Intestine. The three regions of the small intestine are the duodenum, jejunum, and ileum.[/caption]

The jejunum is about 0.9 meters (3 feet) long (in life) and runs from the duodenum to the ileum. Jejunum means “empty” in Latin and supposedly was so named by the ancient Greeks who noticed it was always empty at death. No clear demarcation exists between the jejunum and the final segment of the small intestine, the ileum.

The ileum is the longest part of the small intestine, measuring about 1.8 meters (6 feet) in length. It is thicker, more vascular, and has more developed mucosal folds than the jejunum. The ileum joins the cecum, the first portion of the large intestine, at the ileocecal sphincter (or valve). The jejunum and ileum are tethered to the posterior abdominal wall by the mesentery. The large intestine frames these three parts of the small intestine.

Parasympathetic nerve fibers from the vagus nerve and sympathetic nerve fibers from the thoracic splanchnic nerve provide extrinsic innervation to the small intestine. The superior mesenteric artery is its main arterial supply. Veins run parallel to the arteries and drain into the superior mesenteric vein. Nutrient-rich blood from the small intestine is then carried to the liver via the hepatic portal vein.

Histology

The wall of the small intestine is composed of the same four layers typically present in the alimentary system. However, three features of the mucosa and submucosa are unique. These features, which increase the absorptive surface area of the small intestine more than 600-fold, include circular folds, villi, and microvilli (Figure 2). These adaptations are most abundant in the proximal two-thirds of the small intestine, where the majority of absorption occurs.

[caption id="" align="aligncenter" width="550"] Figure 2. Histology of the Small Intestine. (a) The absorptive surface of the small intestine is vastly enlarged by the presence of circular folds, villi, and microvilli. (b) Micrograph of the circular folds. (c) Micrograph of the villi. (d) Electron micrograph of the microvilli. From left to right, LM x 56, LM x 508, EM x 196,000. (credit b-d: Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Circular folds

Also called a plica circulare, a circular fold is a deep ridge in the mucosa and submucosa. Beginning near the proximal part of the duodenum and ending near the middle of the ileum, these folds facilitate absorption. Their shape causes the chyme to spiral, rather than move in a straight line, through the small intestine. Spiraling slows the movement of chyme and provides the time needed for nutrients to be fully absorbed.

Villi

Within the circular folds are small (0.5–1 mm long) hairlike vascularized projections called villi (singular = villus) that give the mucosa a furry texture. There are about 20 to 40 villi per square millimeter, increasing the surface area of the epithelium tremendously. The mucosal epithelium, primarily composed of absorptive cells, covers the villi. In addition to muscle and connective tissue to support its structure, each villus contains a capillary bed composed of one arteriole and one venule, as well as a lymphatic capillary called a lacteal. The breakdown products of carbohydrates and proteins (sugars and amino acids) can enter the bloodstream directly, but lipid breakdown products are absorbed by the lacteals and transported to the bloodstream via the lymphatic system.

Microvilli

As their name suggests, microvilli (singular = microvillus) are much smaller (1 µm) than villi. They are cylindrical apical surface extensions of the plasma membrane of the mucosa’s epithelial cells, and are supported by microfilaments within those cells. Although their small size makes it difficult to see each microvillus, their combined microscopic appearance suggests a mass of bristles, which is termed the brush border. Fixed to the surface of the microvilli membranes are enzymes that finish digesting carbohydrates and proteins. There are an estimated 200 million microvilli per square millimeter of small intestine, greatly expanding the surface area of the plasma membrane and thus greatly enhancing absorption.

Intestinal Glands

In addition to the three specialized absorptive features just discussed, the mucosa between the villi is dotted with deep crevices that each lead into a tubular intestinal gland (crypt of Lieberkühn), which is formed by cells that line the crevices (see Figure 2). These produce intestinal juice, a slightly alkaline (pH 7.4 to 7.8) mixture of water and mucus. Each day, about 0.95 to 1.9 liters (1 to 2 quarts) are secreted in response to the distention of the small intestine or the irritating effects of chyme on the intestinal mucosa.

The submucosa of the duodenum is the only site of the complex mucus-secreting duodenal glands (Brunner’s glands), which produce a bicarbonate-rich alkaline mucus that buffers the acidic chyme as it enters from the stomach.

The roles of the cells in the small intestinal mucosa are detailed in Table 7.

Cells of the Small Intestinal Mucosa (Table 7)
Cell type	Location in the mucosa	Function
Absorptive	Epithelium/intestinal glands	Digestion and absorption of nutrients in chyme
Goblet	Epithelium/intestinal glands	Secretion of mucus
Paneth	Intestinal glands	Secretion of the bactericidal enzyme lysozyme; phagocytosis
G cells	Intestinal glands of duodenum	Secretion of the hormone intestinal gastrin
I cells	Intestinal glands of duodenum	Secretion of the hormone cholecystokinin, which stimulates release of pancreatic juices and bile
K cells	Intestinal glands	Secretion of the hormone glucose-dependent insulinotropic peptide, which stimulates the release of insulin
M cells	Intestinal glands of duodenum and jejunum	Secretion of the hormone motilin, which accelerates gastric emptying, stimulates intestinal peristalsis, and stimulates the production of pepsin
S cells	Intestinal glands	Secretion of the hormone secretin

Intestinal MALT

The lamina propria of the small intestine mucosa is studded with quite a bit of MALT. In addition to solitary lymphatic nodules, aggregations of intestinal MALT, which are typically referred to as Peyer’s patches, are concentrated in the distal ileum, and serve to keep bacteria from entering the bloodstream. Peyer’s patches are most prominent in young people and become less distinct as you age, which coincides with the general activity of our immune system.

[caption id="" align="aligncenter" width="120"] Watch this animation that depicts the structure of the small intestine, and, in particular, the villi.[/caption]

Mechanical Digestion in the Small Intestine

The movement of intestinal smooth muscles includes both segmentation and a form of peristalsis called migrating motility complexes. The kind of peristaltic mixing waves seen in the stomach are not observed here.

If you could see into the small intestine when it was going through segmentation, it would look as if the contents were being shoved incrementally back and forth, as the rings of smooth muscle repeatedly contract and then relax. Segmentation in the small intestine does not force chyme through the tract. Instead, it combines the chyme with digestive juices and pushes food particles against the mucosa to be absorbed. The duodenum is where the most rapid segmentation occurs, at a rate of about 12 times per minute. In the ileum, segmentations are only about eight times per minute (Figure 3).

[caption id="" align="aligncenter" width="250"] Figure 3. Segmentation. Segmentation separates chyme and then pushes it back together, mixing it and providing time for digestion and absorption.[/caption]

When most of the chyme has been absorbed, the small intestinal wall becomes less distended. At this point, the localized segmentation process is replaced by transport movements. The duodenal mucosa secretes the hormone motilin, which initiates peristalsis in the form of a migrating motility complex. These complexes, which begin in the duodenum, force chyme through a short section of the small intestine and then stop. The next contraction begins a little bit farther down than the first, forces chyme a bit farther through the small intestine, then stops. These complexes move slowly down the small intestine, forcing chyme on the way, taking around 90 to 120 minutes to finally reach the end of the ileum. At this point, the process is repeated, starting in the duodenum.

The ileocecal valve, a sphincter, is usually in a constricted state, but when motility in the ileum increases, this sphincter relaxes, allowing food residue to enter the first portion of the large intestine, the cecum. Relaxation of the ileocecal sphincter is controlled by both nerves and hormones. First, digestive activity in the stomach provokes the gastroileal reflex, which increases the force of ileal segmentation. Second, the stomach releases the hormone gastrin, which enhances ileal motility, thus relaxing the ileocecal sphincter. After chyme passes through, backward pressure helps close the sphincter, preventing backflow into the ileum. Because of this reflex, your lunch is completely emptied from your stomach and small intestine by the time you eat your dinner. It takes about 3 to 5 hours for all chyme to leave the small intestine.

Chemical Digestion in the Small Intestine

The digestion of proteins and carbohydrates, which partially occurs in the stomach, is completed in the small intestine with the aid of intestinal and pancreatic juices. Lipids arrive in the intestine largely undigested, so much of the focus here is on lipid digestion, which is facilitated by bile and the enzyme pancreatic lipase.

Moreover, intestinal juice combines with pancreatic juice to provide a liquid medium that facilitates absorption. The intestine is also where most water is absorbed, via osmosis. The small intestine’s absorptive cells also synthesize digestive enzymes and then place them in the plasma membranes of the microvilli. This distinguishes the small intestine from the stomach; that is, enzymatic digestion occurs not only in the lumen, but also on the luminal surfaces of the mucosal cells.

For optimal chemical digestion, chyme must be delivered from the stomach slowly and in small amounts. This is because chyme from the stomach is typically hypertonic, and if large quantities were forced all at once into the small intestine, the resulting osmotic water loss from the blood into the intestinal lumen would result in potentially life-threatening low blood volume. In addition, continued digestion requires an upward adjustment of the low pH of stomach chyme, along with rigorous mixing of the chyme with bile and pancreatic juices. Both processes take time, so the pumping action of the pylorus must be carefully controlled to prevent the duodenum from being overwhelmed with chyme.

The Large Intestine

The large intestine is the terminal part of the alimentary canal. The primary function of this organ is to finish absorption of nutrients and water, synthesize certain vitamins, form feces, and eliminate feces from the body.

Structure

The large intestine runs from the appendix to the anus. It frames the small intestine on three sides. Despite its being about one-half as long as the small intestine, it is called large because it is more than twice the diameter of the small intestine, about 3 inches.

Subdivisions

The large intestine is subdivided into four main regions: the cecum, the colon, the rectum, and the anus. The ileocecal valve, located at the opening between the ileum and the large intestine, controls the flow of chyme from the small intestine to the large intestine.

Cecum

The first part of the large intestine is the cecum, a sac-like structure that is suspended inferior to the ileocecal valve. It is about 6 cm (2.4 in) long, receives the contents of the ileum, and continues the absorption of water and salts. The appendix (or vermiform appendix) is a winding tube that attaches to the cecum. Although the 7.6-cm (3-in) long appendix contains lymphoid tissue, suggesting an immunologic function, this organ is generally considered vestigial. However, at least one recent report postulates a survival advantage conferred by the appendix: In diarrheal illness, the appendix may serve as a bacterial reservoir to repopulate the enteric bacteria for those surviving the initial phases of the illness. Moreover, its twisted anatomy provides a haven for the accumulation and multiplication of enteric bacteria. The mesoappendix, the mesentery of the appendix, tethers it to the mesentery of the ileum.

Colon

The cecum blends seamlessly with the colon. Upon entering the colon, the food residue first travels up the ascending colon on the right side of the abdomen. At the inferior surface of the liver, the colon bends to form the right colic flexure (hepatic flexure) and becomes the transverse colon. The region defined as hindgut begins with the last third of the transverse colon and continues on. Food residue passing through the transverse colon travels across to the left side of the abdomen, where the colon angles sharply immediately inferior to the spleen, at the left colic flexure (splenic flexure). From there, food residue passes through the descending colon, which runs down the left side of the posterior abdominal wall. After entering the pelvis inferiorly, it becomes the s-shaped sigmoid colon, which extends medially to the midline (Figure 4). The ascending and descending colon, and the rectum (discussed next) are located in the retroperitoneum. The transverse and sigmoid colon are tethered to the posterior abdominal wall by the mesocolon.

[caption id="" align="aligncenter" width="350"] Figure 4. Large Intestine. The large intestine includes the cecum, colon, and rectum.[/caption]

Rectum

Food residue leaving the sigmoid colon enters the rectum in the pelvis, near the third sacral vertebra. The final 20.3 cm (8 in) of the alimentary canal, the rectum extends anterior to the sacrum and coccyx. Even though rectum is Latin for “straight,” this structure follows the curved contour of the sacrum and has three lateral bends that create a trio of internal transverse folds called the rectal valves. These valves help separate the feces from gas to prevent the simultaneous passage of feces and gas.

Anal Canal

Finally, food residue reaches the last part of the large intestine, the anal canal, which is located in the perineum, completely outside of the abdominopelvic cavity. This 3.8–5 cm (1.5–2 in) long structure opens to the exterior of the body at the anus. The anal canal includes two sphincters. The internal anal sphincter is made of smooth muscle, and its contractions are involuntary. The external anal sphincter is made of skeletal muscle, which is under voluntary control. Except when defecating, both usually remain closed.

Histology

There are several notable differences between the walls of the large and small intestines (Figure 5). For example, few enzyme-secreting cells are found in the wall of the large intestine, and there are no circular folds or villi. Other than in the anal canal, the mucosa of the colon is simple columnar epithelium made mostly of enterocytes (absorptive cells) and goblet cells. In addition, the wall of the large intestine has far more intestinal glands, which contain a vast population of enterocytes and goblet cells. These goblet cells secrete mucus that eases the movement of feces and protects the intestine from the effects of the acids and gases produced by enteric bacteria. The enterocytes absorb water and salts as well as vitamins produced by your intestinal bacteria.

[caption id="" align="aligncenter" width="480"] Figure 5. Histology of the large Intestine. (a) The histologies of the large intestine and small intestine (not shown) are adapted for the digestive functions of each organ. (b) This micrograph shows the colon’s simple columnar epithelium and goblet cells. LM x 464. (credit b: Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Anatomy

Three features are unique to the large intestine: teniae coli, haustra, and epiploic appendages (Figure 6). The teniae coli are three bands of smooth muscle that make up the longitudinal muscle layer of the muscularis of the large intestine, except at its terminal end. Tonic contractions of the teniae coli bunch up the colon into a succession of pouches called haustra (singular = hostrum), which are responsible for the wrinkled appearance of the colon. Attached to the teniae coli are small, fat-filled sacs of visceral peritoneum called epiploic appendages. The purpose of these is unknown. Although the rectum and anal canal have neither teniae coli nor haustra, they do have well-developed layers of muscularis that create the strong contractions needed for defecation.

[caption id="" align="aligncenter" width="320"] Figure 6. Teniae Coli, Haustra, and Epiploic Appendages[/caption] The stratified squamous epithelial mucosa of the anal canal connects to the skin on the outside of the anus. This mucosa varies considerably from that of the rest of the colon to accommodate the high level of abrasion as feces pass through. The anal canal’s mucous membrane is organized into longitudinal folds, each called an anal column, which house a grid of arteries and veins. Two superficial venous plexuses are found in the anal canal: one within the anal columns and one at the anus.

Depressions between the anal columns, each called an anal sinus, secrete mucus that facilitates defecation. The pectinate line (or dentate line) is a horizontal, jagged band that runs circumferentially just below the level of the anal sinuses, and represents the junction between the hindgut and external skin. The mucosa above this line is fairly insensitive, whereas the area below is very sensitive. The resulting difference in pain threshold is due to the fact that the upper region is innervated by visceral sensory fibers, and the lower region is innervated by somatic sensory fibers.

Bacterial Flora

Most bacteria that enter the alimentary canal are killed by lysozyme, defensins, HCl, or protein-digesting enzymes. However, trillions of bacteria live within the large intestine and are referred to as the bacterial flora. Most of the more than 700 species of these bacteria are nonpathogenic commensal organisms that cause no harm as long as they stay in the gut lumen. In fact, many facilitate chemical digestion and absorption, and some synthesize certain vitamins, mainly biotin, pantothenic acid, and vitamin K. Some are linked to increased immune response. A refined system prevents these bacteria from crossing the mucosal barrier. First, peptidoglycan, a component of bacterial cell walls, activates the release of chemicals by the mucosa’s epithelial cells, which draft immune cells, especially dendritic cells, into the mucosa. Dendritic cells open the tight junctions between epithelial cells and extend probes into the lumen to evaluate the microbial antigens. The dendritic cells with antigens then travel to neighboring lymphoid follicles in the mucosa where T cells inspect for antigens. This process triggers an IgA-mediated response, if warranted, in the lumen that blocks the commensal organisms from infiltrating the mucosa and setting off a far greater, widespread systematic reaction.

Digestive Functions of the Large Intestine

The residue of chyme that enters the large intestine contains few nutrients except water, which is reabsorbed as the residue lingers in the large intestine, typically for 12 to 24 hours. Thus, it may not surprise you that the large intestine can be completely removed without significantly affecting digestive functioning. For example, in severe cases of inflammatory bowel disease, the large intestine can be removed by a procedure known as a colectomy. Often, a new fecal pouch can be crafted from the small intestine and sutured to the anus, but if not, an ileostomy can be created by bringing the distal ileum through the abdominal wall, allowing the watery chyme to be collected in a bag-like adhesive appliance.

Mechanical Digestion

In the large intestine, mechanical digestion begins when chyme moves from the ileum into the cecum, an activity regulated by the ileocecal sphincter. Right after you eat, peristalsis in the ileum forces chyme into the cecum. When the cecum is distended with chyme, contractions of the ileocecal sphincter strengthen. Once chyme enters the cecum, colon movements begin.

Mechanical digestion in the large intestine includes a combination of three types of movements. The presence of food residues in the colon stimulates a slow-moving haustral contraction. This type of movement involves sluggish segmentation, primarily in the transverse and descending colons. When a haustrum is distended with chyme, its muscle contracts, pushing the residue into the next haustrum. These contractions occur about every 30 minutes, and each last about 1 minute. These movements also mix the food residue, which helps the large intestine absorb water. The second type of movement is peristalsis, which, in the large intestine, is slower than in the more proximal portions of the alimentary canal. The third type is a mass movement. These strong waves start midway through the transverse colon and quickly force the contents toward the rectum. Mass movements usually occur three or four times per day, either while you eat or immediately afterward. Distension in the stomach and the breakdown products of digestion in the small intestine provoke the gastrocolic reflex, which increases motility, including mass movements, in the colon. Fiber in the diet both softens the stool and increases the power of colonic contractions, optimizing the activities of the colon.

Chemical Digestion

Although the glands of the large intestine secrete mucus, they do not secrete digestive enzymes. Therefore, chemical digestion in the large intestine occurs exclusively because of bacteria in the lumen of the colon. Through the process of saccharolytic fermentation, bacteria break down some of the remaining carbohydrates. This results in the discharge of hydrogen, carbon dioxide, and methane gases that create flatus (gas) in the colon; flatulence is excessive flatus. Each day, up to 1500 mL of flatus is produced in the colon. More is produced when you eat foods such as beans, which are rich in otherwise indigestible sugars and complex carbohydrates like soluble dietary fiber.

Absorption, Feces Formation, and Defecation

The small intestine absorbs about 90 percent of the water you ingest (either as liquid or within solid food). The large intestine absorbs most of the remaining water, a process that converts the liquid chyme residue into semisolid feces (“stool”). Feces is composed of undigested food residues, unabsorbed digested substances, millions of bacteria, old epithelial cells from the GI mucosa, inorganic salts, and enough water to let it pass smoothly out of the body. Of every 500 mL (17 ounces) of food residue that enters the cecum each day, about 150 mL (5 ounces) become feces.

Feces are eliminated through contractions of the rectal muscles. You help this process by a voluntary procedure called Valsalva’s maneuver, in which you increase intra-abdominal pressure by contracting your diaphragm and abdominal wall muscles, and closing your glottis.

The process of defecation begins when mass movements force feces from the colon into the rectum, stretching the rectal wall and provoking the defecation reflex, which eliminates feces from the rectum. This parasympathetic reflex is mediated by the spinal cord. It contracts the sigmoid colon and rectum, relaxes the internal anal sphincter, and initially contracts the external anal sphincter. The presence of feces in the anal canal sends a signal to the brain, which gives you the choice of voluntarily opening the external anal sphincter (defecating) or keeping it temporarily closed. If you decide to delay defecation, it takes a few seconds for the reflex contractions to stop and the rectal walls to relax. The next mass movement will trigger additional defecation reflexes until you defecate.

If defecation is delayed for an extended time, additional water is absorbed, making the feces firmer and potentially leading to constipation. On the other hand, if the waste matter moves too quickly through the intestines, not enough water is absorbed, and diarrhea can result. This can be caused by the ingestion of foodborne pathogens. In general, diet, health, and stress determine the frequency of bowel movements. The number of bowel movements varies greatly between individuals, ranging from two or three per day to three or four per week.

[caption id="attachment_3019" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about the role of the intestines in digestion![/caption]

23.6 Accessory Organs in Digestion: The Liver, Pancreas, and Gallbladder

barkerj1 — Wed, 06 Sep 2017 01:19:59 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the anatomy of the liver
Describe the function of the liver as part of the digestive system
Describe the blood supply of the liver
Describe the connection from the liver to the gallbladder and to the duodenum
Describe the control of bile secretion
Describe the anatomy of the pancreas
Describe the functions of the pancreas as a part of the digestive system
Describe the control of pancreatic juice secretion

Chemical digestion in the small intestine relies on the activities of three accessory digestive organs: the liver, pancreas, and gallbladder (Figure 1). The digestive role of the liver is to produce bile and export it to the duodenum. The gallbladder primarily stores, concentrates, and releases bile. The pancreas produces pancreatic juice, which contains digestive enzymes and bicarbonate ions, and delivers it to the duodenum.

[caption id="" align="aligncenter" width="390"] Figure 1. Accessory Organs. The liver, pancreas, and gallbladder are considered accessory digestive organs, but their roles in the digestive system are vital.[/caption]

The Liver

The liver is the largest gland in the body, weighing about three pounds in an adult. It is also one of the most important organs. In addition to being an accessory digestive organ, it plays a number of roles in metabolism and regulation. The liver lies inferior to the diaphragm in the right upper quadrant of the abdominal cavity and receives protection from the surrounding ribs.

The liver is divided into two primary lobes: a large right lobe and a much smaller left lobe. In the right lobe, some anatomists also identify an inferior quadrate lobe and a posterior caudate lobe, which are defined by internal features. The liver is connected to the abdominal wall and diaphragm by five peritoneal folds referred to as ligaments. These are the falciform ligament, the coronary ligament, two lateral ligaments, and the ligamentum teres hepatis. The falciform ligament and ligamentum teres hepatis are actually remnants of the umbilical vein, and separate the right and left lobes anteriorly. The lesser omentum tethers the liver to the lesser curvature of the stomach.

The porta hepatis (“gate to the liver”) is where the hepatic artery and hepatic portal vein enter the liver. These two vessels, along with the common hepatic duct, run behind the lateral border of the lesser omentum on the way to their destinations. As shown in Figure 2, the hepatic artery delivers oxygenated blood from the heart to the liver. The hepatic portal vein delivers partially deoxygenated blood containing nutrients absorbed from the small intestine and actually supplies more oxygen to the liver than do the much smaller hepatic arteries. In addition to nutrients, drugs and toxins are also absorbed. After processing the bloodborne nutrients and toxins, the liver releases nutrients needed by other cells back into the blood, which drains into the central vein and then through the hepatic vein to the inferior vena cava. With this hepatic portal circulation, all blood from the alimentary canal passes through the liver. This largely explains why the liver is the most common site for the metastasis of cancers that originate in the alimentary canal.

[caption id="" align="aligncenter" width="420"] Figure 2. Microscopic Anatomy of the Liver. The liver receives oxygenated blood from the hepatic artery and nutrient-rich deoxygenated blood from the hepatic portal vein.[/caption]

Histology

The liver has three main components: hepatocytes, bile canaliculi, and hepatic sinusoids. A hepatocyte is the liver’s main cell type, accounting for around 80 percent of the liver's volume. These cells play a role in a wide variety of secretory, metabolic, and endocrine functions. Plates of hepatocytes called hepatic laminae radiate outward from the portal vein in each hepatic lobule.

Between adjacent hepatocytes, grooves in the cell membranes provide room for each bile canaliculus (plural = canaliculi). These small ducts accumulate the bile produced by hepatocytes. From here, bile flows first into bile ductules and then into bile ducts. The bile ducts unite to form the larger right and left hepatic ducts, which themselves merge and exit the liver as the common hepatic duct. This duct then joins with the cystic duct from the gallbladder, forming the common bile duct through which bile flows into the small intestine. A hepatic sinusoid is an open, porous blood space formed by fenestrated capillaries from nutrient-rich hepatic portal veins and oxygen-rich hepatic arteries. Hepatocytes are tightly packed around the fenestrated endothelium of these spaces, giving them easy access to the blood. From their central position, hepatocytes process the nutrients, toxins, and waste materials carried by the blood. Materials such as bilirubin are processed and excreted into the bile canaliculi. Other materials including proteins, lipids, and carbohydrates are processed and secreted into the sinusoids or just stored in the cells until called upon. The hepatic sinusoids combine and send blood to a central vein. Blood then flows through a hepatic vein into the inferior vena cava. This means that blood and bile flow in opposite directions. The hepatic sinusoids also contain star-shaped reticuloendothelial cells (Kupffer cells), phagocytes that remove dead red and white blood cells, bacteria, and other foreign material that enter the sinusoids. The portal triad is a distinctive arrangement around the perimeter of hepatic lobules, consisting of three basic structures: a bile duct, a hepatic artery branch, and a hepatic portal vein branch.

Bile

Recall that lipids are hydrophobic, that is, they do not dissolve in water. Thus, before they can be digested in the watery environment of the small intestine, large lipid globules must be broken down into smaller lipid globules, a process called emulsification. Bile is a mixture secreted by the liver to accomplish the emulsification of lipids in the small intestine.

Hepatocytes secrete about one liter of bile each day. A yellow-brown or yellow-green alkaline solution (pH 7.6 to 8.6), bile is a mixture of water, bile salts, bile pigments, phospholipids (such as lecithin), electrolytes, cholesterol, and triglycerides. The components most critical to emulsification are bile salts and phospholipids, which have a nonpolar (hydrophobic) region as well as a polar (hydrophilic) region. The hydrophobic region interacts with the large lipid molecules, whereas the hydrophilic region interacts with the watery chyme in the intestine. This results in the large lipid globules being pulled apart into many tiny lipid fragments of about 1 µm in diameter. This change dramatically increases the surface area available for lipid-digesting enzyme activity. This is the same way dish soap works on fats mixed with water.

Bile salts act as emulsifying agents, so they are also important for the absorption of digested lipids. While most constituents of bile are eliminated in feces, bile salts are reclaimed by the enterohepatic circulation. Once bile salts reach the ileum, they are absorbed and returned to the liver in the hepatic portal blood. The hepatocytes then excrete the bile salts into newly formed bile. Thus, this precious resource is recycled.

Bilirubin, the main bile pigment, is a waste product produced when the spleen removes old or damaged red blood cells from the circulation. These breakdown products, including proteins, iron, and toxic bilirubin, are transported to the liver via the splenic vein of the hepatic portal system. In the liver, proteins and iron are recycled, whereas bilirubin is excreted in the bile. It accounts for the green color of bile. Bilirubin is eventually transformed by intestinal bacteria into stercobilin, a brown pigment that gives your stool its characteristic color! In some disease states, bile does not enter the intestine, resulting in white (‘acholic’) stool with a high fat content, since virtually no fats are broken down or absorbed.

Hepatocytes work non-stop, but bile production increases when fatty chyme enters the duodenum and stimulates the secretion of the gut hormone secretin. Between meals, bile is produced but conserved. The valve-like hepatopancreatic ampulla closes, allowing bile to divert to the gallbladder, where it is concentrated and stored until the next meal.

The Gallbladder

The gallbladder is 8–10 cm (~3–4 in) long and is nested in a shallow area on the posterior aspect of the right lobe of the liver. This muscular sac stores, concentrates, and, when stimulated by cholecystokinin (CCK) or parasympathetic nervous system activity, contracts to propel the bile into the duodenum via the common bile duct. It is divided into three regions. The fundus is the widest portion and tapers medially into the body, which in turn narrows to become the neck. The neck angles slightly superiorly as it approaches the hepatic duct. The cystic duct is 1–2 cm (less than 1 in) long and turns inferiorly as it bridges the neck and hepatic duct.

The simple columnar epithelium of the gallbladder mucosa is organized in rugae, similar to those of the stomach. There is no submucosa in the gallbladder wall. The wall’s middle, muscular coat is made of smooth muscle fibers. When these fibers contract, the gallbladder’s contents are ejected through the cystic duct and into the bile duct (Figure 4). Visceral peritoneum reflected from the liver capsule holds the gallbladder against the liver and forms the outer coat of the gallbladder. The gallbladder's mucosa absorbs water and ions from bile, concentrating it by up to 10-fold.

[caption id="" align="aligncenter" width="380"] Figure 4. Gallbladder. The gallbladder stores and concentrates bile, and releases it into the two-way cystic duct when it is needed by the small intestine.[/caption]

The Pancreas

The soft, oblong, glandular pancreas lies transversely in the retroperitoneum behind the stomach. Its head is nestled into the “c-shaped” curvature of the duodenum with the body extending to the left about 15.2 cm (6 in) and ending as a tapering tail in the hilum of the spleen. It is a curious mix of exocrine (secreting digestive enzymes) and endocrine (releasing hormones into the blood) functions (Figure 3).

[caption id="" align="aligncenter" width="350"] Figure 3. Exocrine and Endocrine Pancreas. The pancreas has a head, a body, and a tail. It delivers pancreatic juice to the duodenum through the pancreatic duct.[/caption]

The exocrine part of the pancreas arises as little grape-like cell clusters, each called an acinus (plural = acini), located at the terminal ends of pancreatic ducts. These acinar cells secrete enzyme-rich pancreatic juice into tiny merging ducts that form two dominant ducts. The larger duct fuses with the common bile duct (carrying bile from the liver and gallbladder) just before entering the duodenum via a common opening (the hepatopancreatic ampulla). The smooth muscle sphincter of the hepatopancreatic ampulla controls the release of pancreatic juice and bile into the small intestine. The second and smaller pancreatic duct, the accessory duct (duct of Santorini), runs from the pancreas directly into the duodenum, approximately 1 inch above the hepatopancreatic ampulla. When present, it is a persistent remnant of pancreatic development.

Scattered through the sea of exocrine acini are small islands of endocrine cells, the islets of Langerhans. These vital cells produce the hormones pancreatic polypeptide, insulin, glucagon, and somatostatin.

Pancreatic Juice

The pancreas produces over a liter of pancreatic juice each day. Unlike bile, it is clear and composed mostly of water along with some salts, sodium bicarbonate, and several digestive enzymes. Sodium bicarbonate is responsible for the slight alkalinity of pancreatic juice (pH 7.1 to 8.2), which serves to buffer the acidic gastric juice in chyme, inactivate pepsin from the stomach, and create an optimal environment for the activity of pH-sensitive digestive enzymes in the small intestine. Pancreatic enzymes are active in the digestion of sugars, proteins, and fats.

The pancreas produces protein-digesting enzymes in their inactive forms. These enzymes are activated in the duodenum. If produced in an active form, they would digest the pancreas (which is exactly what occurs in the disease, pancreatitis). The intestinal brush border enzyme enteropeptidase stimulates the activation of trypsin from trypsinogen of the pancreas, which in turn changes the pancreatic enzymes procarboxypeptidase and chymotrypsinogen into their active forms, carboxypeptidase and chymotrypsin.

The enzymes that digest starch (amylase), fat (lipase), and nucleic acids (nuclease) are secreted in their active forms, since they do not attack the pancreas as do the protein-digesting enzymes.

Pancreatic Secretion

Regulation of pancreatic secretion is the job of hormones and the parasympathetic nervous system. The entry of acidic chyme into the duodenum stimulates the release of secretin, which in turn causes the duct cells to release bicarbonate-rich pancreatic juice. The presence of proteins and fats in the duodenum stimulates the secretion of CCK, which then stimulates the acini to secrete enzyme-rich pancreatic juice and enhances the activity of secretin. Parasympathetic regulation occurs mainly during the cephalic and gastric phases of gastric secretion, when vagal stimulation prompts the secretion of pancreatic juice.

Usually, the pancreas secretes just enough bicarbonate to counterbalance the amount of HCl produced in the stomach. Hydrogen ions enter the blood when bicarbonate is secreted by the pancreas. Thus, the acidic blood draining from the pancreas neutralizes the alkaline blood draining from the stomach, maintaining the pH of the venous blood that flows to the liver.

23.7 Chemical Digestion and Absorption: A Closer Look

barkerj1 — Wed, 06 Sep 2017 01:19:59 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the chemical digestion, including the source and function of the principle enzymes involved, of:
- Carbohydrates
- Proteins
- Lipids
Specify the end products of digestion of each of the following, and explain how they are absorbed:
- Carbohydrates
- Proteins
- Lipids

As you have learned, the process of mechanical digestion is relatively simple. It involves the physical breakdown of food but does not alter its chemical makeup. Chemical digestion, on the other hand, is a complex process that reduces food into its chemical building blocks, which are then absorbed to nourish the cells of the body (Figure 1). In this section, you will look more closely at the processes of chemical digestion and absorption.

[caption id="" align="aligncenter" width="350"] Figure 1. Digestion and Absorption. Digestion begins in the mouth and continues as food travels through the small intestine. Most absorption occurs in the small intestine.[/caption]

Chemical Digestion

Large food molecules (for example, proteins, lipids, nucleic acids, and starches) must be broken down into subunits that are small enough to be absorbed by the lining of the alimentary canal. This is accomplished by enzymes through hydrolysis. The many enzymes involved in chemical digestion are summarized in Table 8.

*These enzymes have been activated by other substances.
The Digestive Enzymes (Table 8)
Enzyme Category	Enzyme Name	Source	Substrate	Product
Salivary Enzymes	Lingual lipase	Lingual glands	Triglycerides	Free fatty acids, and mono- and diglycerides
Salivary Enzymes	Salivary amylase	Salivary glands	Polysaccharides	Disaccharides and trisaccharides
Gastric enzymes	Gastric lipase	Chief cells	Triglycerides	Fatty acids and monoacylglycerides
Gastric enzymes	Pepsin*	Chief cells	Proteins	Peptides
Brush border enzymes	α-Dextrinase	Small intestine	α-Dextrins	Glucose
Brush border enzymes	Enteropeptidase	Small intestine	Trypsinogen	Trypsin
Brush border enzymes	Lactase	Small intestine	Lactose	Glucose and galactose
Brush border enzymes	Maltase	Small intestine	Maltose	Glucose
Brush border enzymes	Nucleosidases and phosphatases	Small intestine	Nucleotides	Phosphates, nitrogenous bases, and pentoses
Brush border enzymes	Peptidases	Small intestine	Aminopeptidase: amino acids at the amino end of peptides Dipeptidase: dipeptides	Aminopeptidase: amino acids and peptides Dipeptidase: amino acids
Brush border enzymes	Sucrase	Small intestine	Sucrose	Glucose and fructose
Pancreatic enzymes	Carboxy-peptidase*	Pancreatic acinar cells	Amino acids at the carboxyl end of peptides	Amino acids and peptides
Pancreatic enzymes	Chymotrypsin*	Pancreatic acinar cells	Proteins	Peptides
Pancreatic enzymes	Elastase*	Pancreatic acinar cells	Proteins	Peptides
Pancreatic enzymes	Nucleases	Pancreatic acinar cells	Ribonuclease: ribonucleic acids Deoxyribonuclease: deoxyribonucleic acids	Nucleotides
Pancreatic enzymes	Pancreatic amylase	Pancreatic acinar cells	Polysaccharides (starches)	α-Dextrins, disaccharides (maltose), trisaccharides (maltotriose)
Pancreatic enzymes	Pancreatic lipase	Pancreatic acinar cells	Triglycerides that have been emulsified by bile salts	Fatty acids and monoacylglycerides
Pancreatic enzymes	Trypsin*	Pancreatic acinar cells	Proteins	Peptides

Carbohydrate Digestion

The average American diet is about 50 percent carbohydrates, which may be classified according to the number of monomers they contain of simple sugars (monosaccharides and disaccharides) and/or complex sugars (polysaccharides). Glucose, galactose, and fructose are the three monosaccharides that are commonly consumed and are readily absorbed. Your digestive system is also able to break down the disaccharide sucrose (regular table sugar: glucose + fructose), lactose (milk sugar: glucose + galactose), and maltose (grain sugar: glucose + glucose), and the polysaccharides glycogen and starch (chains of monosaccharides). Your bodies do not produce enzymes that can break down most fibrous polysaccharides, such as cellulose. While indigestible polysaccharides do not provide any nutritional value, they do provide dietary fiber, which helps propel food through the alimentary canal.

The chemical digestion of starches begins in the mouth and has been reviewed above.

In the small intestine, pancreatic amylase does the ‘heavy lifting’ for starch and carbohydrate digestion (Figure 2). After amylases break down starch into smaller fragments, the brush border enzyme α-dextrinase starts working on α-dextrin, breaking off one glucose unit at a time. Three brush border enzymes hydrolyze sucrose, lactose, and maltose into monosaccharides. Sucrase splits sucrose into one molecule of fructose and one molecule of glucose; maltase breaks down maltose and maltotriose into two and three glucose molecules, respectively; and lactase breaks down lactose into one molecule of glucose and one molecule of galactose. Insufficient lactase can lead to lactose intolerance.

[caption id="" align="aligncenter" width="280"] Figure 2. Carbohydrate Digestion Flow Chart. Carbohydrates are broken down into their monomers in a series of steps.[/caption]

Protein Digestion

Proteins are polymers composed of amino acids linked by peptide bonds to form long chains. Digestion reduces them to their constituent amino acids. You usually consume about 15 to 20 percent of your total calorie intake as protein.

The digestion of protein starts in the stomach, where HCl and pepsin break proteins into smaller polypeptides, which then travel to the small intestine (Figure 3). Chemical digestion in the small intestine is continued by pancreatic enzymes, including chymotrypsin and trypsin, each of which act on specific bonds in amino acid sequences. At the same time, the cells of the brush border secrete enzymes such as aminopeptidase and dipeptidase, which further break down peptide chains. This results in molecules small enough to enter the bloodstream (Figure 4).

[caption id="" align="aligncenter" width="380"] Figure 3. Digestion of Protein. The digestion of protein begins in the stomach and is completed in the small intestine.[/caption]

[caption id="" align="aligncenter" width="180"] Figure 4. Digestion of Protein Flow Chart. Proteins are successively broken down into their amino acid components.[/caption]

Lipid Digestion

A healthy diet limits lipid intake to 35 percent of total calorie intake. The most common dietary lipids are triglycerides, which are made up of a glycerol molecule bound to three fatty acid chains. Small amounts of dietary cholesterol and phospholipids are also consumed.

The three lipases responsible for lipid digestion are lingual lipase, gastric lipase, and pancreatic lipase. However, because the pancreas is the only consequential source of lipase, virtually all lipid digestion occurs in the small intestine. Pancreatic lipase breaks down each triglyceride into two free fatty acids and a monoglyceride. The fatty acids include both short-chain (less than 10 to 12 carbons) and long-chain fatty acids.

Nucleic Acid Digestion

The nucleic acids DNA and RNA are found in most of the foods you eat. Two types of pancreatic nuclease are responsible for their digestion: deoxyribonuclease, which digests DNA, and ribonuclease, which digests RNA. The nucleotides produced by this digestion are further broken down by two intestinal brush border enzymes (nucleosidase and phosphatase) into pentoses, phosphates, and nitrogenous bases, which can be absorbed through the alimentary canal wall. The large food molecules that must be broken down into subunits are summarized Table 9

Absorbable Food Substances (Table 9)
Source	Substance
Carbohydrates	Monosaccharides: glucose, galactose, and fructose
Proteins	Single amino acids, dipeptides, and tripeptides
Triglycerides	Monoacylglycerides, glycerol, and free fatty acids
Nucleic acids	Pentose sugars, phosphates, and nitrogenous bases

Absorption

The mechanical and digestive processes have one goal: to convert food into molecules small enough to be absorbed by the epithelial cells of the intestinal villi. The absorptive capacity of the alimentary canal is almost endless. Each day, the alimentary canal processes up to 10 liters of food, liquids, and GI secretions, yet less than one liter enters the large intestine. Almost all ingested food, 80 percent of electrolytes, and 90 percent of water are absorbed in the small intestine. Although the entire small intestine is involved in the absorption of water and lipids, most absorption of carbohydrates and proteins occurs in the jejunum. Notably, bile salts and vitamin B₁₂ are absorbed in the terminal ileum. By the time chyme passes from the ileum into the large intestine, it is essentially indigestible food residue (mainly plant fibers like cellulose), some water, and millions of bacteria (Figure 5).

[caption id="" align="aligncenter" width="380"] Figure 5. Digestive Secretions and Absorption of Water. Absorption is a complex process, in which nutrients from digested food are harvested.[/caption]

Absorption can occur through five mechanisms: (1) active transport, (2) passive diffusion, (3) facilitated diffusion, (4) co-transport (or secondary active transport), and (5) endocytosis. As you will recall from Chapter 3, active transport refers to the movement of a substance across a cell membrane going from an area of lower concentration to an area of higher concentration (up the concentration gradient). In this type of transport, proteins within the cell membrane act as “pumps,” using cellular energy (ATP) to move the substance. Passive diffusion refers to the movement of substances from an area of higher concentration to an area of lower concentration, while facilitated diffusion refers to the movement of substances from an area of higher to an area of lower concentration using a carrier protein in the cell membrane. Co-transport uses the movement of one molecule through the membrane from higher to lower concentration to power the movement of another from lower to higher. Finally, endocytosis is a transportation process in which the cell membrane engulfs material. It requires energy, generally in the form of ATP.

Because the cell’s plasma membrane is made up of hydrophobic phospholipids, water-soluble nutrients must use transport molecules embedded in the membrane to enter cells. Moreover, substances cannot pass between the epithelial cells of the intestinal mucosa because these cells are bound together by tight junctions. Thus, substances can only enter blood capillaries by passing through the apical surfaces of epithelial cells and into the interstitial fluid. Water-soluble nutrients enter the capillary blood in the villi and travel to the liver via the hepatic portal vein.

In contrast to the water-soluble nutrients, lipid-soluble nutrients can diffuse through the plasma membrane. Once inside the cell, they are packaged for transport via the base of the cell and then enter the lacteals of the villi to be transported by lymphatic vessels to the systemic circulation via the thoracic duct. The absorption of most nutrients through the mucosa of the intestinal villi requires active transport fueled by ATP. The routes of absorption for each food category are summarized in Table 10.

Absorption in the Alimentary Canal (Table 10)
Food	Breakdown products	Absorption mechanism	Entry to bloodstream	Destination
Carbohydrates	Glucose	Co-transport with sodium ions	Capillary blood in villi	Liver via hepatic portal vein
Carbohydrates	Galactose	Co-transport with sodium ions	Capillary blood in villi	Liver via hepatic portal vein
Carbohydrates	Fructose	Facilitated diffusion	Capillary blood in villi	Liver via hepatic portal vein
Protein	Amino acids	Co-transport with sodium ions	Capillary blood in villi	Liver via hepatic portal vein
Lipids	Long-chain fatty acids	Diffusion into intestinal cells, where they are combined with proteins to create chylomicrons	Lacteals of villi	Systemic circulation via lymph entering thoracic duct
Lipids	Monoacylglycerides	Diffusion into intestinal cells, where they are combined with proteins to create chylomicrons	Lacteals of villi	Systemic circulation via lymph entering thoracic duct
Lipids	Short-chain fatty acids	Simple diffusion	Capillary blood in villi	Liver via hepatic portal vein
Lipids	Glycerol	Simple diffusion	Capillary blood in villi	Liver via hepatic portal vein
Lipids	Nucleic acid digestion products	Active transport via membrane carriers	Capillary blood in villi	Liver via hepatic portal vein

Carbohydrate Absorption

All carbohydrates are absorbed in the form of monosaccharides. The small intestine is highly efficient at this, absorbing monosaccharides at an estimated rate of 120 grams per hour. All normally digested dietary carbohydrates are absorbed; indigestible fibers are eliminated in the feces. The monosaccharides glucose and galactose are transported into the epithelial cells by common protein carriers via secondary active transport (that is, co-transport with sodium ions). The monosaccharides leave these cells via facilitated diffusion and enter the capillaries through intercellular clefts. The monosaccharide fructose (which is in fruit) is absorbed and transported by facilitated diffusion alone. The monosaccharides combine with the transport proteins immediately after the disaccharides are broken down.

Protein Absorption

Active transport mechanisms, primarily in the duodenum and jejunum, absorb most proteins as their breakdown products, amino acids. Almost all (95 to 98 percent) protein is digested and absorbed in the small intestine. The type of carrier that transports an amino acid varies. Most carriers are linked to the active transport of sodium. Short chains of two amino acids (dipeptides) or three amino acids (tripeptides) are also transported actively. However, after they enter the absorptive epithelial cells, they are broken down into their amino acids before leaving the cell and entering the capillary blood via diffusion.

Lipid Absorption

About 95 percent of lipids are absorbed in the small intestine. Bile salts not only speed up lipid digestion, they are also essential to the absorption of the end products of lipid digestion. Short-chain fatty acids are relatively water soluble and can enter the absorptive cells (enterocytes) directly. Despite being hydrophobic, the small size of short-chain fatty acids enables them to be absorbed by enterocytes via simple diffusion, and then take the same path as monosaccharides and amino acids into the blood capillary of a villus. The large and hydrophobic long-chain fatty acids and monoacylglycerides are not so easily suspended in the watery intestinal chyme. However, bile salts and lecithin resolve this issue by enclosing them in a micelle, which is a tiny sphere with polar (hydrophilic) ends facing the watery environment and hydrophobic tails turned to the interior, creating a receptive environment for the long-chain fatty acids. The core also includes cholesterol and fat-soluble vitamins. Without micelles, lipids would sit on the surface of chyme and never come in contact with the absorptive surfaces of the epithelial cells. Micelles can easily squeeze between microvilli and get very near the luminal cell surface. At this point, lipid substances exit the micelle and are absorbed via simple diffusion. The free fatty acids and monoacylglycerides that enter the epithelial cells are reincorporated into triglycerides. The triglycerides are mixed with phospholipids and cholesterol, and surrounded with a protein coat. This new complex, called a chylomicron, is a water-soluble lipoprotein. After being processed by the Golgi apparatus, chylomicrons are released from the cell (Figure 6). Too big to pass through the basement membranes of blood capillaries, chylomicrons instead enter the large pores of lacteals. The lacteals come together to form the lymphatic vessels. The chylomicrons are transported in the lymphatic vessels and empty through the thoracic duct into the subclavian vein of the circulatory system. Once in the bloodstream, the enzyme lipoprotein lipase breaks down the triglycerides of the chylomicrons into free fatty acids and glycerol. These breakdown products then pass through capillary walls to be used for energy by cells or stored in adipose tissue as fat. Liver cells combine the remaining chylomicron remnants with proteins, forming lipoproteins that transport cholesterol in the blood.

[caption id="" align="aligncenter" width="320"] Figure 6. Lipid Absorption. Unlike amino acids and simple sugars, lipids are transformed as they are absorbed through epithelial cells.[/caption]

Nucleic Acid Absorption

The products of nucleic acid digestion—pentose sugars, nitrogenous bases, and phosphate ions—are transported by carriers across the villus epithelium via active transport. These products then enter the bloodstream.

Mineral Absorption

The electrolytes absorbed by the small intestine are from both GI secretions and ingested foods. Since electrolytes dissociate into ions in water, most are absorbed via active transport throughout the entire small intestine. During absorption, co-transport mechanisms result in the accumulation of sodium ions inside the cells, whereas anti-port mechanisms reduce the potassium ion concentration inside the cells. To restore the sodium-potassium gradient across the cell membrane, a sodium-potassium pump requiring ATP pumps sodium out and potassium in.

In general, all minerals that enter the intestine are absorbed, whether you need them or not. Iron and calcium are exceptions; they are absorbed in the duodenum in amounts that meet the body’s current requirements, as follows: Iron—The ionic iron needed for the production of hemoglobin is absorbed into mucosal cells via active transport. Once inside mucosal cells, ionic iron binds to the protein ferritin, creating iron-ferritin complexes that store iron until needed. When the body has enough iron, most of the stored iron is lost when worn-out epithelial cells slough off. When the body needs iron because, for example, it is lost during acute or chronic bleeding, there is increased uptake of iron from the intestine and accelerated release of iron into the bloodstream. Since women experience significant iron loss during menstruation, they have around four times as many iron transport proteins in their intestinal epithelial cells as do men.

Calcium—Blood levels of ionic calcium determine the absorption of dietary calcium. When blood levels of ionic calcium drop, parathyroid hormone (PTH) secreted by the parathyroid glands stimulates the release of calcium ions from bone matrices and increases the reabsorption of calcium by the kidneys. PTH also upregulates the activation of vitamin D in the kidney, which then facilitates intestinal calcium ion absorption.

Vitamin Absorption

The small intestine absorbs the vitamins that occur naturally in food and supplements. Fat-soluble vitamins (A, D, E, and K) are absorbed along with dietary lipids in micelles via simple diffusion. This is why you are advised to eat some fatty foods when you take fat-soluble vitamin supplements. Most water-soluble vitamins (including most B vitamins and vitamin C) also are absorbed by simple diffusion. An exception is vitamin B₁₂, which is a very large molecule. Intrinsic factor secreted in the stomach binds to vitamin B₁₂, preventing its digestion and creating a complex that binds to mucosal receptors in the terminal ileum, where it is taken up by endocytosis.

Water Absorption

Each day, about nine liters of fluid enter the small intestine. About 2.3 liters are ingested in foods and beverages, and the rest is from GI secretions. About 90 percent of this water is absorbed in the small intestine. Water absorption is driven by the concentration gradient of the water: The concentration of water is higher in chyme than it is in epithelial cells. Thus, water moves down its concentration gradient from the chyme into cells. As noted earlier, much of the remaining water is then absorbed in the colon.

24.1 Overview of Metabolic Reactions

barkerj1 — Wed, 06 Sep 2017 01:20:01 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the importance of carbohydrates, lipids and proteins in energy storage and energy availability
Describe the effects of a hypersecretion of glucocorticoids
Describe the effects of a hyposecretion of glucocorticoids

Metabolic processes are constantly taking place in the body. Metabolism is the sum of all of the chemical reactions that are involved in catabolism and anabolism. The reactions governing the breakdown of food to obtain energy are called catabolic reactions. Conversely, anabolic reactions use the energy produced by catabolic reactions to synthesize larger molecules from smaller ones, such as when the body forms proteins by stringing together amino acids. Both sets of reactions are critical to maintaining life.

Because catabolic reactions produce energy and anabolic reactions use energy, ideally, energy usage would balance the energy produced. If the net energy change is positive (catabolic reactions release more energy than the anabolic reactions use), then the body stores the excess energy by building fat molecules for long-term storage. On the other hand, if the net energy change is negative (catabolic reactions release less energy than anabolic reactions use), the body uses stored energy to compensate for the deficiency of energy released by catabolism.

Catabolic Reactions

Catabolic reactions break down large organic molecules into smaller molecules, releasing the energy contained in the chemical bonds. These energy releases (conversions) are not 100 percent efficient. The amount of energy released is less than the total amount contained in the molecule. Approximately 40 percent of energy yielded from catabolic reactions is directly transferred to the high-energy molecule adenosine triphosphate (ATP). ATP, the energy currency of cells, can be used immediately to power molecular machines that support cell, tissue, and organ function. This includes building new tissue and repairing damaged tissue. Some ATP can also be stored to fulfill future energy demands. The remaining 60 percent of the energy released from catabolic reactions is given off as heat, which tissues and body fluids absorb.

Structurally, ATP molecules consist of an adenine, a ribose, and three phosphate groups (Figure 1). The chemical bond between the second and third phosphate groups represents the greatest source of energy in a cell. It is the first bond that catabolic enzymes break when cells require energy to do work. The products of this reaction are a molecule of adenosine diphosphate (ADP) and a lone phosphate group (P_i). ATP, ADP, and P_i are constantly being cycled through reactions that build ATP and store energy, and reactions that break the phosphate-phosphate bonds in ATP to release energy.

[caption id="" align="aligncenter" width="550"] Figure 1. Structure of ATP Molecule. Adenosine triphosphate (ATP) is the energy molecule of the cell. During catabolic reactions, ATP is created and energy is stored until needed during anabolic reactions.[/caption]

The energy obtained from ATP drives all bodily functions, such as contracting muscles, maintaining the electrical potential of nerve cells, and absorbing food in the gastrointestinal tract. The metabolic reactions that produce ATP come from various sources (Figure 2).

[caption id="" align="aligncenter" width="520"] Figure 2. Sources of ATP. During catabolic reactions, proteins are broken down into amino acids, lipids are broken down into fatty acids, and polysaccharides are broken down into monosaccharides. These building blocks are then used for the synthesis of molecules in anabolic reactions.[/caption]

Of the four major macromolecular groups (carbohydrates, lipids, proteins, and nucleic acids) that are processed by digestion, carbohydrates are considered the most common source of energy to fuel the body. They take the form of either complex carbohydrates, polysaccharides like starch and glycogen, or simple sugars (monosaccharides) like glucose and fructose. Sugar catabolism breaks polysaccharides down into their individual monosaccharides. Among the monosaccharides, glucose is the most common fuel for ATP production in cells, and as such, there are a number of endocrine control mechanisms to regulate glucose concentration in the bloodstream. Excess glucose is either stored as an energy reserve in the liver and skeletal muscles as the complex polymer glycogen, or it is converted into fat (triglyceride) in adipose cells (adipocytes).

Among the lipids (fats), triglycerides are most often used for energy via a metabolic process called β-oxidation. About one-half of excess fat is stored in adipocytes that accumulate in the subcutaneous tissue under the skin, whereas the rest is stored in adipocytes in other tissues and organs.

Proteins, which are polymers, can be broken down into their monomers, individual amino acids. Amino acids can be used as building blocks of new proteins or broken down further for the production of ATP. When one is chronically starving, this use of amino acids for energy production can lead to a wasting away of the body, as more and more proteins are broken down. Nucleic acids are present in most of the foods you eat. During digestion, nucleic acids including DNA and various RNAs are broken down into their constituent nucleotides. These nucleotides are readily absorbed and transported throughout the body to be used by individual cells during nucleic acid metabolism.

Anabolic Reactions

In contrast to catabolic reactions, anabolic reactions involve the joining of smaller molecules into larger ones. Anabolic reactions combine monosaccharides to form polysaccharides, fatty acids to form triglycerides, amino acids to form proteins, and nucleotides to form nucleic acids. These processes require energy obtained from ATP molecules that were generated by catabolic reactions. Anabolic reactions, also called biosynthesis reactions, create new molecules that form new cells and tissues, and revitalize organs.

Hormonal Regulation of Metabolism

Catabolic and anabolic hormones in the body help regulate metabolic processes. Catabolic hormones stimulate the breakdown of molecules and the production of energy. These include cortisol, glucagon, adrenaline/epinephrine, and cytokines. All of these hormones are mobilized at specific times to meet the needs of the body. Anabolic hormones are required for the synthesis of molecules and include growth hormone, insulin-like growth factor, insulin, testosterone, and estrogen. Table 1 summarizes the function of each of the catabolic hormones and Table 2 summarizes the functions of the anabolic hormones.

Catabolic Hormones (Table 1)
Hormone	Function
Cortisol	Released from the adrenal gland in response to stress; its main role is to increase blood glucose levels by gluconeogenesis (breaking down fats and proteins)
Glucagon	Released from alpha cells in the pancreas either when starving or when the body needs to generate additional energy; it stimulates the breakdown of glycogen in the liver to increase blood glucose levels; its effect is the opposite of insulin; glucagon and insulin are a part of a negative-feedback system that stabilizes blood glucose levels
Adrenaline/epinephrine	Released in response to the activation of the sympathetic nervous system; increases heart rate and heart contractility, constricts blood vessels, is a bronchodilator that opens (dilates) the bronchi of the lungs to increase air volume in the lungs, and stimulates gluconeogenesis

Anabolic Hormones (Table 2)
Hormone	Function
Growth hormone (GH)	Synthesized and released from the pituitary gland; stimulates the growth of cells, tissues, and bones
Insulin-like growth factor (IGF)	Stimulates the growth of muscle and bone while also inhibiting cell death (apoptosis)
Insulin	Produced by the beta cells of the pancreas; plays an essential role in carbohydrate and fat metabolism, controls blood glucose levels, and promotes the uptake of glucose into body cells; causes cells in muscle, adipose tissue, and liver to take up glucose from the blood and store it in the liver and muscle as glucagon; its effect is the opposite of glucagon; glucagon and insulin are a part of a negative-feedback system that stabilizes blood glucose levels
Testosterone	Produced by the testes in males and the ovaries in females; stimulates an increase in muscle mass and strength as well as the growth and strengthening of bone
Estrogen	Produced primarily by the ovaries, it is also produced by the liver and adrenal glands; its anabolic functions include increasing metabolism and fat deposition

Metabolic Disorders: Cushing Syndrome and Addison’s Disease

As might be expected for a fundamental physiological process like metabolism, errors or malfunctions in metabolic processing lead to a pathophysiology or—if uncorrected—a disease state. Metabolic diseases are most commonly the result of malfunctioning proteins or enzymes that are critical to one or more metabolic pathways. Protein or enzyme malfunction can be the consequence of a genetic alteration or mutation. However, normally functioning proteins and enzymes can also have deleterious effects if their availability is not appropriately matched with metabolic need. For example, excessive production of the hormone cortisol (see Table 1) gives rise to Cushing syndrome. Clinically, Cushing syndrome is characterized by rapid weight gain, especially in the trunk and face region, depression, and anxiety. It is worth mentioning that tumors of the pituitary that produce adrenocorticotropic hormone (ACTH), which subsequently stimulates the adrenal cortex to release excessive cortisol, produce similar effects. This indirect mechanism of cortisol overproduction is referred to as Cushing disease.

Patients with Cushing syndrome can exhibit high blood glucose levels and are at an increased risk of becoming obese. They also show slow growth, accumulation of fat between the shoulders, weak muscles, bone pain (because cortisol causes proteins to be broken down to make glucose via gluconeogenesis), and fatigue. Other symptoms include excessive sweating (hyperhidrosis), capillary dilation, and thinning of the skin, which can lead to easy bruising. The treatments for Cushing syndrome are all focused on reducing excessive cortisol levels. Depending on the cause of the excess, treatment may be as simple as discontinuing the use of cortisol ointments. In cases of tumors, surgery is often used to remove the offending tumor. Where surgery is inappropriate, radiation therapy can be used to reduce the size of a tumor or ablate portions of the adrenal cortex. Finally, medications are available that can help to regulate the amounts of cortisol.

Insufficient cortisol production is equally problematic. Adrenal insufficiency, or Addison’s disease, is characterized by the reduced production of cortisol from the adrenal gland. It can result from malfunction of the adrenal glands—they do not produce enough cortisol—or it can be a consequence of decreased ACTH availability from the pituitary. Patients with Addison’s disease may have low blood pressure, paleness, extreme weakness, fatigue, slow or sluggish movements, lightheadedness, and salt cravings due to the loss of sodium and high blood potassium levels (hyperkalemia). Victims also may suffer from loss of appetite, chronic diarrhea, vomiting, mouth lesions, and patchy skin color. Diagnosis typically involves blood tests and imaging tests of the adrenal and pituitary glands. Treatment involves cortisol replacement therapy, which usually must be continued for life.

Oxidation-Reduction Reactions

The chemical reactions underlying metabolism involve the transfer of electrons from one compound to another by processes catalyzed by enzymes. The electrons in these reactions commonly come from hydrogen atoms, which consist of an electron and a proton. A molecule gives up a hydrogen atom, in the form of a hydrogen ion (H⁺) and an electron, breaking the molecule into smaller parts. The loss of an electron, or oxidation, releases a small amount of energy; both the electron and the energy are then passed to another molecule in the process of reduction, or the gaining of an electron. These two reactions always happen together in an oxidation-reduction reaction (also called a redox reaction)—when an electron is passed between molecules, the donor is oxidized and the recipient is reduced. Oxidation-reduction reactions often happen in a series, so that a molecule that is reduced is subsequently oxidized, passing on not only the electron it just received but also the energy it received. As the series of reactions progresses, energy accumulates that is used to combine P_i and ADP to form ATP, the high-energy molecule that the body uses for fuel.

Oxidation-reduction reactions are catalyzed by enzymes that trigger the removal of hydrogen atoms. Coenzymes work with enzymes and accept hydrogen atoms. The two most common coenzymes of oxidation-reduction reactions are nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). Their respective reduced coenzymes are NADH and FADH₂, which are energy-containing molecules used to transfer energy during the creation of ATP.

[caption id="attachment_3021" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of metabolism and nutrition.[/caption]

24.2 Carbohydrate Metabolism

barkerj1 — Wed, 06 Sep 2017 01:20:02 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the process of cellular respiration in general terms
Describe the process of glycolysis
Describe the formation of acetyl coenzyme A from pyruvic acid
Explain the role of the electron transport chain in cellular respiration
Describe the major steps in the generation of ATP by chemiosmosis
Describe the roles of ATP, NAD⁺, and FAD in energy metabolism in the cell
Summarize the ATP produced from the breakdown of a single glucose molecule
Describe the importance of oxygen gas in cellular respiration
Compare aerobic cellular respiration and lactic acid fermentation
Describe the importance of glucose in cellular respiration and ATP production

Carbohydrates are organic molecules composed of carbon, hydrogen, and oxygen atoms. The family of carbohydrates includes both simple and complex sugars. Glucose and fructose are examples of simple sugars, and starch, glycogen, and cellulose are all examples of complex sugars. The complex sugars are also called polysaccharides and are made of multiple monosaccharide molecules. Polysaccharides serve as energy storage (e.g., starch and glycogen) and as structural components (e.g., chitin in insects and cellulose in plants).

During digestion, carbohydrates are broken down into simple, soluble sugars that can be transported across the intestinal wall into the circulatory system to be transported throughout the body. Carbohydrate digestion begins in the mouth with the action of salivary amylase on starches and ends with monosaccharides being absorbed across the epithelium of the small intestine. Once the absorbed monosaccharides are transported to the tissues, the process of cellular respiration begins (Figure 1). This section will focus first on glycolysis, a process where the monosaccharide glucose is oxidized, releasing the energy stored in its bonds to produce ATP.

[caption id="" align="aligncenter" width="520"] Figure 1. Cellular Respiration. Cellular respiration oxidizes glucose molecules through glycolysis, the Krebs cycle, and oxidative phosphorylation to produce ATP.[/caption]

Glycolysis

Glucose is the body’s most readily available source of energy. After digestive processes break polysaccharides down into monosaccharides, including glucose, the monosaccharides are transported across the wall of the small intestine and into the circulatory system, which transports them to the liver. In the liver, hepatocytes either pass the glucose on through the circulatory system or store excess glucose as glycogen. Cells in the body take up the circulating glucose in response to insulin and, through a series of reactions called glycolysis, transfer some of the energy in glucose to ADP to form ATP (Figure 2). The last step in glycolysis produces the product pyruvate.

Glycolysis begins with the phosphorylation of glucose by hexokinase to form glucose-6-phosphate. This step uses one ATP, which is the donor of the phosphate group. Under the action of phosphofructokinase, glucose-6-phosphate is converted into fructose-6-phosphate. At this point, a second ATP donates its phosphate group, forming fructose-1,6-bisphosphate. This six-carbon sugar is split to form two phosphorylated three-carbon molecules, glyceraldehyde-3-phosphate and dihydroxyacetone phosphate, which are both converted into glyceraldehyde-3-phosphate. The glyceraldehyde-3-phosphate is further phosphorylated with groups donated by dihydrogen phosphate present in the cell to form the three-carbon molecule 1,3-bisphosphoglycerate. The energy of this reaction comes from the oxidation of (removal of electrons from) glyceraldehyde-3-phosphate. In a series of reactions leading to pyruvate, the two phosphate groups are then transferred from the molecule to which they are attached to two ADPs to form two ATPs by the process of substrate-level phosphorylation (direct phosphorylation). Thus, glycolysis uses two ATPs but generates four ATPs, yielding a net gain of two ATPs and two molecules of pyruvate. In the presence of oxygen, pyruvate continues on to the Krebs cycle (also called the citric acid cycle or tricarboxylic acid cycle (TCA), where additional energy is extracted and passed on.

[caption id="" align="aligncenter" width="520"] Figure 2. Glycolysis Overview. During the energy-consuming phase of glycolysis, two ATPs are consumed, transferring two phosphates to the glucose molecule. The glucose molecule then splits into two three-carbon compounds, each containing a phosphate. During the second phase, an additional phosphate is added to each of the three-carbon compounds. The energy for this endergonic reaction is provided by the removal (oxidation) of two electrons from each three-carbon compound. During the energy-releasing phase, the phosphates are removed from both three-carbon compounds and used to produce four ATP molecules.[/caption]

[caption id="" align="aligncenter" width="120"] Watch this video to learn about glycolysis.[/caption]

Glycolysis can be divided into two phases: energy consuming (also called chemical priming) and energy yielding. The first phase is the energy-consuming phase, so it requires two ATP molecules to start the reaction for each molecule of glucose. However, the end of the reaction produces four ATPs, resulting in a net gain of two ATP energy molecules.

Glycolysis can be expressed as the following equation:

Glucose + 2ATP + 2NAD⁺ + 4ADP + 2P_i → 2 Pyruvate + 4ATP + 2NADH + 2H⁺

This equation states that glucose, in combination with ATP (the energy source), NAD⁺ (a coenzyme that serves as an electron acceptor), and inorganic phosphate, breaks down into two pyruvate molecules, generating four ATP molecules—for a net yield of two ATP—and two energy-containing NADH coenzymes. The NADH that is produced in this process will be used later to produce ATP in the mitochondria. Importantly, by the end of this process, one glucose molecule generates two pyruvate molecules, two high-energy ATP molecules, and two electron-carrying NADH molecules.

The following discussions of glycolysis include the enzymes responsible for the reactions. When glucose enters a cell, the enzyme hexokinase (or glucokinase, in the liver) rapidly adds a phosphate to convert it into glucose-6-phosphate. A kinase is a type of enzyme that adds a phosphate molecule to a substrate (in this case, glucose, but it can be true of other molecules also). This conversion step requires one ATP and essentially traps the glucose in the cell, preventing it from passing back through the plasma membrane, thus allowing glycolysis to proceed. It also functions to maintain a concentration gradient with higher glucose levels in the blood than in the tissues. By establishing this concentration gradient, the glucose in the blood will be able to flow from an area of high concentration (the blood) into an area of low concentration (the tissues) to be either used or stored. Hexokinase is found in nearly every tissue in the body. Glucokinase, on the other hand, is expressed in tissues that are active when blood glucose levels are high, such as the liver. Hexokinase has a higher affinity for glucose than glucokinase and therefore is able to convert glucose at a faster rate than glucokinase. This is important when levels of glucose are very low in the body, as it allows glucose to travel preferentially to those tissues that require it more.

In the next step of the first phase of glycolysis, the enzyme glucose-6-phosphate isomerase converts glucose-6-phosphate into fructose-6-phosphate. Like glucose, fructose is also a six carbon-containing sugar. The enzyme phosphofructokinase-1 then adds one more phosphate to convert fructose-6-phosphate into fructose-1-6-bisphosphate, another six-carbon sugar, using another ATP molecule. Aldolase then breaks down this fructose-1-6-bisphosphate into two three-carbon molecules, glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. The triosephosphate isomerase enzyme then converts dihydroxyacetone phosphate into a second glyceraldehyde-3-phosphate molecule. Therefore, by the end of this chemical-priming or energy-consuming phase, one glucose molecule is broken down into two glyceraldehyde-3-phosphate molecules.

The second phase of glycolysis, the energy-yielding phase, creates the energy that is the product of glycolysis. Glyceraldehyde-3-phosphate dehydrogenase converts each three-carbon glyceraldehyde-3-phosphate produced during the energy-consuming phase into 1,3-bisphosphoglycerate. This reaction releases an electron that is then picked up by NAD⁺ to create an NADH molecule. NADH is a high-energy molecule, like ATP, but unlike ATP, it is not used as energy currency by the cell. Because there are two glyceraldehyde-3-phosphate molecules, two NADH molecules are synthesized during this step. Each 1,3-bisphosphoglycerate is subsequently dephosphorylated (i.e., a phosphate is removed) by phosphoglycerate kinase into 3-phosphoglycerate. Each phosphate released in this reaction can be added to one molecule of ADP to produce one ATP molecule, resulting in a gain of two ATP molecules.

The enzyme phosphoglycerate mutase then converts the 3-phosphoglycerate molecules into 2-phosphoglycerate. The enolase enzyme then acts upon the 2-phosphoglycerate molecules to convert them into phosphoenolpyruvate molecules. The last step of glycolysis involves the dephosphorylation of the two phosphoenolpyruvate molecules by pyruvate kinase to create two pyruvate molecules and two ATP molecules.

In summary, one glucose molecule breaks down into two pyruvate molecules, and creates two net ATP molecules (by substrate-level phosphorylation) and two NADH molecules by glycolysis. Therefore, glycolysis generates energy for the cell and creates pyruvate molecules that can be processed further through the aerobic Krebs cycle (also called the citric acid cycle or tricarboxylic acid cycle); converted into lactic acid or alcohol (in yeast) by fermentation; or used later for the synthesis of glucose through gluconeogenesis.

Anaerobic Conditions

When oxygen (O₂) is limited or absent, pyruvate enters an alternate, anaerobic pathway. In these reactions, pyruvate can be converted into lactic acid. In addition to generating an additional ATP, this pathway serves to keep the pyruvate concentration low so glycolysis continues, and it oxidizes NADH into the NAD⁺ needed by glycolysis. In this reaction, lactic acid replaces oxygen as the final electron acceptor. This lactic acid fermentation occurs in most cells of the body when oxygen is limited or mitochondria are absent or nonfunctional. For example, because erythrocytes (red blood cells) lack mitochondria, they must produce their ATP using this same fermentation pathway. This is an effective pathway of ATP production for short periods of time, ranging from seconds to a few minutes. The lactic acid produced diffuses into the plasma and is carried to the liver, where it is converted back into pyruvate or glucose via the Cori cycle. Similarly, when a person exercises, muscles use ATP faster than oxygen can be delivered to them. They depend on glycolysis and lactic acid production for rapid ATP production.

Aerobic Respiration

In the presence of oxygen, pyruvate can enter the Krebs cycle where additional energy is extracted as electrons are transferred from the pyruvate to the receptors NAD⁺, GDP, and FAD, with carbon dioxide being a “waste product” (Figure 3). The NADH and FADH₂ pass electrons on to the electron transport chain, which uses the transferred energy to produce ATP by oxidative phosphorylation. As the terminal step in the electron transport chain, oxygen is the terminal electron acceptor, combining with electrons and hydrogen ions to produce water inside the mitochondria.

[caption id="" align="aligncenter" width="550"] Figure 3. ATP production under aerobic versus anaerobic conditions. The process of lactic acid fermentation converts glucose into two lactate molecules either in the absence of oxygen or within erythrocytes that lack mitochondria. During aerobic respiration, glucose is oxidized into two pyruvate molecules.[/caption]

Krebs Cycle/Citric Acid Cycle/Tricarboxylic Acid Cycle

The pyruvate molecules generated during glycolysis are transported across the mitochondrial membrane into the inner mitochondrial matrix, where they are metabolized by enzymes in a pathway called the Krebs cycle (Figure 4). The Krebs cycle is also commonly called the citric acid cycle or the tricarboxylic acid (TCA) cycle. During the Krebs cycle, high-energy molecules, including ATP, NADH, and FADH₂, are created. NADH and FADH₂ then pass electrons through the electron transport chain in the mitochondria to generate more ATP molecules.

[caption id="" align="aligncenter" width="520"] Figure 4. Krebs Cycle. During the Krebs cycle, each pyruvate that is generated by glycolysis is converted into a two-carbon acetyl CoA molecule. The acetyl CoA is systematically processed through the cycle and produces high-energy NADH, FADH₂, and ATP molecules.[/caption]

The three-carbon pyruvate molecule generated during glycolysis moves from the cytoplasm into the mitochondrial matrix, where it is converted by the enzyme pyruvate dehydrogenase into a two-carbon acetyl coenzyme A (acetyl CoA) molecule. This reaction is an oxidative decarboxylation reaction. It converts the three-carbon pyruvate into a two-carbon acetyl CoA molecule, releasing carbon dioxide and transferring two electrons that combine with NAD⁺ to form NADH. Acetyl CoA enters the Krebs cycle by combining with a four-carbon molecule, oxaloacetate, to form the six-carbon molecule citrate, or citric acid, at the same time releasing the coenzyme A molecule.

The six-carbon citrate molecule is systematically converted to a five-carbon molecule and then a four-carbon molecule, ending with oxaloacetate, the beginning of the cycle. Along the way, each citrate molecule will produce one ATP, one FADH₂, and three NADH. The FADH₂ and NADH will enter the oxidative phosphorylation system located in the inner mitochondrial membrane. In addition, the Krebs cycle supplies the starting materials to process and break down proteins and fats.

To start the Krebs cycle, citrate synthase combines acetyl CoA and oxaloacetate to form a six-carbon citrate molecule; CoA is subsequently released and can combine with another pyruvate molecule to begin the cycle again. The aconitase enzyme converts citrate into isocitrate. In two successive steps of oxidative decarboxylation, two molecules of CO₂ and two NADH molecules are produced when isocitrate dehydrogenase converts isocitrate into the five-carbon α-ketoglutarate, which is then catalyzed and converted into the four-carbon succinyl CoA by α-ketoglutarate dehydrogenase. The enzyme succinyl CoA dehydrogenase then converts succinyl CoA into succinate and forms the high-energy molecule GTP, which transfers its energy to ADP to produce ATP by substrate-level phosphorylation. Succinate dehydrogenase then converts succinate into fumarate, forming a molecule of FADH₂. Fumarase then converts fumarate into malate, which malate dehydrogenase then converts back into oxaloacetate while reducing NAD⁺ to NADH. Oxaloacetate is then ready to combine with the next acetyl CoA to start the Krebs cycle again (see Figure 4). For each turn of the cycle, three NADH, one ATP (through GTP), and one FADH₂are created. Each carbon of pyruvate is converted into CO₂, which is released as a byproduct of oxidative (aerobic) respiration.

Oxidative Phosphorylation and the Electron Transport Chain

The electron transport chain (ETC) uses the NADH and FADH₂ produced by the Krebs cycle to generate ATP. Electrons from NADH and FADH₂ are transferred through protein complexes embedded in the inner mitochondrial membrane by a series of enzymatic reactions. The electron transport chain consists of a series of four enzyme complexes (Complex I – Complex IV) and two coenzymes (ubiquinone and Cytochrome c), which act as electron carriers and proton pumps used to transfer H⁺ ions into the space between the inner and outer mitochondrial membranes (Figure 5). The ETC couples the transfer of electrons between a donor (like NADH) and an electron acceptor (like O₂) with the transfer of protons (H⁺ ions) across the inner mitochondrial membrane, enabling the process of oxidative phosphorylation. In the presence of oxygen, energy is passed, stepwise, through the electron carriers to collect gradually the energy needed to attach a phosphate to ADP and produce ATP. The role of molecular oxygen, O₂, is as the terminal electron acceptor for the ETC. This means that once the electrons have passed through the entire ETC, they must be passed to another, separate molecule. These electrons, O₂, and H⁺ ions from the matrix combine to form new water molecules. This is the basis for your need to breathe in oxygen. Without oxygen, electron flow through the ETC ceases.

[caption id="" align="aligncenter" width="550"] Figure 5. Electron Transport Chain. The electron transport chain is a series of electron carriers and ion pumps that are used to pump H+ ions out of the inner mitochondrial matrix.[/caption]

The electrons released from NADH and FADH₂ are passed along the chain by each of the carriers, which are reduced when they receive the electron and oxidized when passing it on to the next carrier. Each of these reactions releases a small amount of energy, which is used to pump H⁺ ions across the inner membrane. The accumulation of these protons in the space between the membranes creates a proton gradient with respect to the mitochondrial matrix.

Also embedded in the inner mitochondrial membrane is an amazing protein pore complex called ATP synthase. Effectively, it is a turbine that is powered by the flow of H⁺ions across the inner membrane down a gradient and into the mitochondrial matrix. As the H⁺ions traverse the complex, the shaft of the complex rotates. This rotation enables other portions of ATP synthase to encourage ADP and P_i to create ATP. In accounting for the total number of ATP produced per glucose molecule through aerobic respiration, it is important to remember the following points:

A net of two ATP are produced through glycolysis (four produced and two consumed during the energy-consuming stage). However, these two ATP are used for transporting the NADH produced during glycolysis from the cytoplasm into the mitochondria. Therefore, the net production of ATP during glycolysis is zero.
In all phases after glycolysis, the number of ATP, NADH, and FADH₂ produced must be multiplied by two to reflect how each glucose molecule produces two pyruvate molecules.
In the ETC, about three ATP are produced for every oxidized NADH. However, only about two ATP are produced for every oxidized FADH₂. The electrons from FADH₂ produce less ATP, because they start at a lower point in the ETC (Complex II) compared to the electrons from NADH (Complex I) (see Figure 5).

Therefore, for every glucose molecule that enters aerobic respiration, a net total of 36 ATPs are produced (Figure 6).

[caption id="" align="aligncenter" width="450"] Figure 6. Carbohydrate Metabolism. Carbohydrate metabolism involves glycolysis, the Krebs cycle, and the electron transport chain.[/caption]

Gluconeogenesis

Gluconeogenesis is the synthesis of new glucose molecules from pyruvate, lactate, glycerol, or the amino acids alanine or glutamine. This process takes place primarily in the liver during periods of low glucose, that is, under conditions of fasting, starvation, and low carbohydrate diets. So, the question can be raised as to why the body would create something it has just spent a fair amount of effort to break down? Certain key organs, including the brain, can use only glucose as an energy source; therefore, it is essential that the body maintain a minimum blood glucose concentration. When the blood glucose concentration falls below that certain point, new glucose is synthesized by the liver to raise the blood concentration to normal.

Gluconeogenesis is not simply the reverse of glycolysis. There are some important differences (Figure 7). Pyruvate is a common starting material for gluconeogenesis. First, the pyruvate is converted into oxaloacetate. Oxaloacetate then serves as a substrate for the enzyme phosphoenolpyruvate carboxykinase (PEPCK), which transforms oxaloacetate into phosphoenolpyruvate (PEP). From this step, gluconeogenesis is nearly the reverse of glycolysis. PEP is converted back into 2-phosphoglycerate, which is converted into 3-phosphoglycerate. Then, 3-phosphoglycerate is converted into 1,3 bisphosphoglycerate and then into glyceraldehyde-3-phosphate. Two molecules of glyceraldehyde-3-phosphate then combine to form fructose-1-6-bisphosphate, which is converted into fructose 6-phosphate and then into glucose-6-phosphate. Finally, a series of reactions generates glucose itself. In gluconeogenesis (as compared to glycolysis), the enzyme hexokinase is replaced by glucose-6-phosphatase, and the enzyme phosphofructokinase-1 is replaced by fructose-1,6-bisphosphatase. This helps the cell to regulate glycolysis and gluconeogenesis independently of each other.

As will be discussed as part of lipolysis, fats can be broken down into glycerol, which can be phosphorylated to form dihydroxyacetone phosphate or DHAP. DHAP can either enter the glycolytic pathway or be used by the liver as a substrate for gluconeogenesis.

[caption id="" align="aligncenter" width="550"] Figure 8. Gluconeogenesis. Gluconeogenesis is the synthesis of glucose from pyruvate, lactate, glycerol, alanine, or glutamate.[/caption]

[caption id="attachment_1171" align="aligncenter" width="150"] Watch this CrashCourse video on ATP and cellular respiration.[/caption]

24.3 Lipid Metabolism

barkerj1 — Wed, 06 Sep 2017 01:20:03 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the control of the secretion of bile
Describe the control of the secretion of pancreatic juice
Describe the role of lipids in ATP production
Describe the role of ketone bodies in energy metabolism

Fats (or triglycerides) within the body are ingested as food or synthesized by adipocytes or hepatocytes from carbohydrate precursors (Figure 1). Lipid metabolism entails the oxidation of fatty acids to either generate energy or synthesize new lipids from smaller constituent molecules. Lipid metabolism is associated with carbohydrate metabolism, as products of glucose (such as acetyl CoA) can be converted into lipids.

[caption id="" align="aligncenter" width="450"] Figure 1. Triglyceride Broken Down into a Monoglyceride A triglyceride molecule (a) breaks down into a monoglyceride (b).[/caption]

Lipid metabolism begins in the intestine where ingested triglycerides are broken down into smaller chain fatty acids and subsequently into monoglyceride molecules (see Figure 1b) by pancreatic lipases, enzymes that break down fats after they are emulsified by bile salts. When food reaches the small intestine in the form of chyme, a digestive hormone called cholecystokinin (CCK) is released by intestinal cells in the intestinal mucosa. CCK stimulates the release of pancreatic lipase from the pancreas and stimulates the contraction of the gallbladder to release stored bile salts into the intestine. CCK also travels to the brain, where it can act as a hunger suppressant.

Together, the pancreatic lipases and bile salts break down triglycerides into free fatty acids. These fatty acids can be transported across the intestinal membrane. However, once they cross the membrane, they are recombined to again form triglyceride molecules. Within the intestinal cells, these triglycerides are packaged along with cholesterol molecules in phospholipid vesicles called chylomicrons (Figure 2). The chylomicrons enable fats and cholesterol to move within the aqueous environment of your lymphatic and circulatory systems. Chylomicrons leave the enterocytes by exocytosis and enter the lymphatic system via lacteals in the villi of the intestine. From the lymphatic system, the chylomicrons are transported to the circulatory system. Once in the circulation, they can either go to the liver or be stored in fat cells (adipocytes) that comprise adipose (fat) tissue found throughout the body.

[caption id="" align="aligncenter" width="380"] Figure 2. Chylomicrons. Chylomicrons contain triglycerides, cholesterol molecules, and other apolipoproteins (protein molecules). They function to carry these water-insoluble molecules from the intestine, through the lymphatic system, and into the bloodstream, which carries the lipids to adipose tissue for storage.[/caption]

Lipolysis

To obtain energy from fat, triglycerides must first be broken down by hydrolysis into their two principal components, fatty acids and glycerol. This process, called lipolysis, takes place in the cytoplasm. The resulting fatty acids are oxidized by β-oxidation into acetyl CoA, which is used by the Krebs cycle. The glycerol that is released from triglycerides after lipolysis directly enters the glycolysis pathway as DHAP. Because one triglyceride molecule yields three fatty acid molecules with as much as 16 or more carbons in each one, fat molecules yield more energy than carbohydrates and are an important source of energy for the human body. Triglycerides yield more than twice the energy per unit mass when compared to carbohydrates and proteins. Therefore, when glucose levels are low, triglycerides can be converted into acetyl CoA molecules and used to generate ATP through aerobic respiration.

The breakdown of fatty acids, called fatty acid oxidation or beta (β)-oxidation, begins in the cytoplasm, where fatty acids are converted into fatty acyl CoA molecules. This fatty acyl CoA combines with carnitine to create a fatty acyl carnitine molecule, which helps to transport the fatty acid across the mitochondrial membrane. Once inside the mitochondrial matrix, the fatty acyl carnitine molecule is converted back into fatty acyl CoA and then into acetyl CoA (Figure 3). The newly formed acetyl CoA enters the Krebs cycle and is used to produce ATP in the same way as acetyl CoA derived from pyruvate.

[caption id="" align="aligncenter" width="500"] Figure 3. Breakdown of Fatty Acids. During fatty acid oxidation, triglycerides can be broken down into acetyl CoA molecules and used for energy when glucose levels are low.[/caption]

Ketogenesis

If excessive acetyl CoA is created from the oxidation of fatty acids and the Krebs cycle is overloaded and cannot handle it, the acetyl CoA is diverted to create ketone bodies. These ketone bodies can serve as a fuel source if glucose levels are too low in the body. Ketones serve as fuel in times of prolonged starvation or when patients suffer from uncontrolled diabetes and cannot utilize most of the circulating glucose. In both cases, fat stores are liberated to generate energy through the Krebs cycle and will generate ketone bodies when too much acetyl CoA accumulates.

In this ketone synthesis reaction, excess acetyl CoA is converted into hydroxymethylglutaryl CoA (HMG CoA). HMG CoA is a precursor of cholesterol and is an intermediate that is subsequently converted into β-hydroxybutyrate, the primary ketone body in the blood (Figure 4).

[caption id="" align="aligncenter" width="580"] Figure 4. Ketogenesis. Excess acetyl CoA is diverted from the Krebs cycle to the ketogenesis pathway. This reaction occurs in the mitochondria of liver cells. The result is the production of β-hydroxybutyrate, the primary ketone body found in the blood.[/caption]

Ketone Body Oxidation

Organs that have classically been thought to be dependent solely on glucose, such as the brain, can actually use ketones as an alternative energy source. This keeps the brain functioning when glucose is limited. When ketones are produced faster than they can be used, they can be broken down into CO₂ and acetone. The acetone is removed by exhalation. One symptom of ketogenesis is that the patient’s breath smells sweet like alcohol. This effect provides one way of telling if a diabetic is properly controlling the disease. The carbon dioxide produced can acidify the blood, leading to diabetic ketoacidosis, a dangerous condition in diabetics.

Ketones oxidize to produce energy for the brain. beta (β)-hydroxybutyrate is oxidized to acetoacetate and NADH is released. An HS-CoA molecule is added to acetoacetate, forming acetoacetyl CoA. The carbon within the acetoacetyl CoA that is not bonded to the CoA then detaches, splitting the molecule in two. This carbon then attaches to another free HS-CoA, resulting in two acetyl CoA molecules. These two acetyl CoA molecules are then processed through the Krebs cycle to generate energy (Figure 5).

[caption id="" align="aligncenter" width="520"] Figure 5. Ketone Oxidation. When glucose is limited, ketone bodies can be oxidized to produce acetyl CoA to be used in the Krebs cycle to generate energy.[/caption]

Lipogenesis

When glucose levels are plentiful, the excess acetyl CoA generated by glycolysis can be converted into fatty acids, triglycerides, cholesterol, steroids, and bile salts. This process, called lipogenesis, creates lipids (fat) from the acetyl CoA and takes place in the cytoplasm of adipocytes (fat cells) and hepatocytes (liver cells). When you eat more glucose or carbohydrates than your body needs, your system uses acetyl CoA to turn the excess into fat. Although there are several metabolic sources of acetyl CoA, it is most commonly derived from glycolysis. Acetyl CoA availability is significant, because it initiates lipogenesis. Lipogenesis begins with acetyl CoA and advances by the subsequent addition of two carbon atoms from another acetyl CoA; this process is repeated until fatty acids are the appropriate length. Because this is a bond-creating anabolic process, ATP is consumed. However, the creation of triglycerides and lipids is an efficient way of storing the energy available in carbohydrates. Triglycerides and lipids, high-energy molecules, are stored in adipose tissue until they are needed.

Although lipogenesis occurs in the cytoplasm, the necessary acetyl CoA is created in the mitochondria and cannot be transported across the mitochondrial membrane. To solve this problem, pyruvate is converted into both oxaloacetate and acetyl CoA. Two different enzymes are required for these conversions. Oxaloacetate forms via the action of pyruvate carboxylase, whereas the action of pyruvate dehydrogenase creates acetyl CoA. Oxaloacetate and acetyl CoA combine to form citrate, which can cross the mitochondrial membrane and enter the cytoplasm. In the cytoplasm, citrate is converted back into oxaloacetate and acetyl CoA. Oxaloacetate is converted into malate and then into pyruvate. Pyruvate crosses back across the mitochondrial membrane to wait for the next cycle of lipogenesis. The acetyl CoA is converted into malonyl CoA that is used to synthesize fatty acids. Figure 6 summarizes the pathways of lipid metabolism.

[caption id="" align="aligncenter" width="550"] Figure 6. Lipid Metabolism. Lipids may follow one of several pathways during metabolism. Glycerol and fatty acids follow different pathways.[/caption]

24.4 Protein Metabolism

barkerj1 — Wed, 06 Sep 2017 01:20:03 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the hormonal control of digestive juice secretion
Describe the fate of amino acids that are metabolized for ATP production

Much of the body is made of protein, and these proteins take on a myriad of forms. They represent cell signaling receptors, signaling molecules, structural members, enzymes, intracellular trafficking components, extracellular matrix scaffolds, ion pumps, ion channels, oxygen and CO₂ transporters (hemoglobin). That is not even the complete list! There is protein in bones (collagen), muscles, and tendons; the hemoglobin that transports oxygen; and enzymes that catalyze all biochemical reactions. Protein is also used for growth and repair. Amid all these necessary functions, proteins also hold the potential to serve as a metabolic fuel source. Proteins are not stored for later use, so excess proteins must be converted into glucose or triglycerides, and used to supply energy or build energy reserves. Although the body can synthesize proteins from amino acids, food is an important source of those amino acids, especially because humans cannot synthesize all of the 20 amino acids used to build proteins.

The digestion of proteins begins in the stomach. When protein-rich foods enter the stomach, they are greeted by a mixture of the enzyme pepsin and hydrochloric acid (HCl; 0.5 percent). The latter produces an environmental pH of 1.5–3.5 that denatures proteins within food. Pepsin cuts proteins into smaller polypeptides and their constituent amino acids. When the food-gastric juice mixture (chyme) enters the small intestine, the pancreas releases sodium bicarbonate to neutralize the HCl. This helps to protect the lining of the intestine. The small intestine also releases digestive hormones, including secretin and CCK, which stimulate digestive processes to break down the proteins further. Secretin also stimulates the pancreas to release sodium bicarbonate. The pancreas releases most of the digestive enzymes, including the proteases trypsin, chymotrypsin, and elastase, which aid protein digestion. Together, all of these enzymes break complex proteins into smaller individual amino acids (Figure 1), which are then transported across the intestinal mucosa to be used to create new proteins, or to be converted into fats or acetyl CoA and used in the Krebs cycle.

[caption id="" align="aligncenter" width="500"] Figure 1. Digestive Enzymes and Hormones. Enzymes in the stomach and small intestine break down proteins into amino acids. HCl in the stomach aids in proteolysis, and hormones secreted by intestinal cells direct the digestive processes.[/caption]

In order to avoid breaking down the proteins that make up the pancreas and small intestine, pancreatic enzymes are released as inactive proenzymes that are only activated in the small intestine. In the pancreas, vesicles store trypsin and chymotrypsin as trypsinogen and chymotrypsinogen. Once released into the small intestine, an enzyme found in the wall of the small intestine, called enterokinase, binds to trypsinogen and converts it into its active form, trypsin. Trypsin then binds to chymotrypsinogen to convert it into the active chymotrypsin. Trypsin and chymotrypsin break down large proteins into smaller peptides, a process called proteolysis. These smaller peptides are catabolized into their constituent amino acids, which are transported across the apical surface of the intestinal mucosa in a process that is mediated by sodium-amino acid transporters. These transporters bind sodium and then bind the amino acid to transport it across the membrane. At the basal surface of the mucosal cells, the sodium and amino acid are released. The sodium can be reused in the transporter, whereas the amino acids are transferred into the bloodstream to be transported to the liver and cells throughout the body for protein synthesis.

Freely available amino acids are used to create proteins. If amino acids exist in excess, the body has no capacity or mechanism for their storage; thus, they are converted into glucose or ketones, or they are decomposed. Amino acid decomposition results in hydrocarbons and nitrogenous waste. However, high concentrations of nitrogen are toxic. The urea cycle processes nitrogen and facilitates its excretion from the body.

Urea Cycle

The urea cycle is a set of biochemical reactions that produces urea from ammonium ions in order to prevent a toxic level of ammonium in the body. It occurs primarily in the liver and, to a lesser extent, in the kidney. Prior to the urea cycle, ammonium ions are produced from the breakdown of amino acids. In these reactions, an amine group, or ammonium ion, from the amino acid is exchanged with a keto group on another molecule. This transamination event creates a molecule that is necessary for the Krebs cycle and an ammonium ion that enters into the urea cycle to be eliminated.

In the urea cycle, ammonium is combined with CO₂, resulting in urea and water. The urea is eliminated through the kidneys in the urine (Figure 2).

[caption id="" align="aligncenter" width="520"] Figure 2. Urea Cycle. Nitrogen is transaminated, creating ammonia and intermediates of the Krebs cycle. Ammonia is processed in the urea cycle to produce urea that is eliminated through the kidneys.[/caption]

Amino acids can also be used as a source of energy, especially in times of starvation. Because the processing of amino acids results in the creation of metabolic intermediates, including pyruvate, acetyl CoA, acetoacyl CoA, oxaloacetate, and α-ketoglutarate, amino acids can serve as a source of energy production through the Krebs cycle (Figure 3). Figure 4 summarizes the pathways of catabolism and anabolism for carbohydrates, lipids, and proteins.

[caption id="" align="aligncenter" width="550"] Figure 3. Energy from Amino Acids. Amino acids can be broken down into precursors for glycolysis or the Krebs cycle. Amino acids (in bold) can enter the cycle through more than one pathway.[/caption]

[caption id="attachment_1819" align="aligncenter" width="500"] Figure 4. Catabolic and Anabolic Pathways. Nutrients follow a complex pathway from ingestion through anabolism and catabolism to energy production.[/caption]

24.5 Metabolic States of the Body

barkerj1 — Wed, 06 Sep 2017 01:20:04 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the use of carbohydrates, lipids, and proteins during starvation conditions
Describe the relationship between gluconeogenesis, lipid metabolism, and protein catabolism

You eat periodically throughout the day; however, your organs, especially the brain, need a continuous supply of glucose. How does the body meet this constant demand for energy? Your body processes the food you eat both to use immediately and, importantly, to store as energy for later demands. If there were no method in place to store excess energy, you would need to eat constantly in order to meet energy demands. Distinct mechanisms are in place to facilitate energy storage, and to make stored energy available during times of fasting and starvation.

The Absorptive State

The absorptive state, or the fed state, occurs after a meal when your body is digesting the food and absorbing the nutrients (anabolism exceeds catabolism). Digestion begins the moment you put food into your mouth, as the food is broken down into its constituent parts to be absorbed through the intestine. The digestion of carbohydrates begins in the mouth, whereas the digestion of proteins and fats begins in the stomach and small intestine. The constituent parts of these carbohydrates, fats, and proteins are transported across the intestinal wall and enter the bloodstream (sugars and amino acids) or the lymphatic system (fats). From the intestines, these systems transport them to the liver, adipose tissue, or muscle cells that will process and use, or store, the energy.

Depending on the amounts and types of nutrients ingested, the absorptive state can linger for up to 4 hours. The ingestion of food and the rise of glucose concentrations in the bloodstream stimulate pancreatic beta cells to release insulin into the bloodstream, where it initiates the absorption of blood glucose by liver hepatocytes, and by adipose and muscle cells. Once inside these cells, glucose is immediately converted into glucose-6-phosphate. By doing this, a concentration gradient is established where glucose levels are higher in the blood than in the cells. This allows for glucose to continue moving from the blood to the cells where it is needed. Insulin also stimulates glycogenesis, the storage of glucose as glycogen, in the liver and muscle cells where it can be used for later energy needs of the body. Insulin also promotes the synthesis of protein in muscle. As you will see, muscle protein can be catabolized and used as fuel in times of starvation.

If energy is exerted shortly after eating, the dietary fats and sugars that were just ingested will be processed and used immediately for energy. If not, the excess glucose is stored as glycogen in the liver and muscle cells, or as fat in adipose tissue; excess dietary fat is also stored as triglycerides in adipose tissues.

Figure 1 summarizes the metabolic processes occurring in the body during the absorptive state.

[caption id="" align="aligncenter" width="560"] Figure 1. Absorptive State. During the absorptive state, the body digests food and absorbs the nutrients.[/caption]

The Postabsorptive State

The postabsorptive state, or the fasting state, occurs when the food has been digested, absorbed, and stored. You commonly fast overnight, but skipping meals during the day puts your body in the postabsorptive state as well. During this state, the body must rely initially on stored glycogen. Glucose levels in the blood begin to drop as it is absorbed and used by the cells. In response to the decrease in glucose, insulin levels also drop. Glycogen and triglyceride storage slows. However, due to the demands of the tissues and organs, blood glucose levels must be maintained in the normal range of 80–120 mg/dL. In response to a drop in blood glucose concentration, the hormone glucagon is released from the alpha cells of the pancreas. Glucagon acts upon the liver cells, where it inhibits glycogenesis and stimulates glycogenolysis, the breakdown of stored glycogen back into glucose. The glucose is released from the liver to be used by the peripheral tissues and the brain. As a result, blood glucose levels begin to rise. The stored glycogen in a well-fed human typically is sufficient to meet the energy needs of the body for several hours. Gluconeogenesis, the production of glucose from non-carbohydrates, will also begin in the liver to replace the glucose that has been used by the peripheral tissues.

After ingestion of food, fats and proteins are processed as described previously; however, the glucose processing changes a bit. The peripheral tissues preferentially absorb glucose. The liver, which normally absorbs and processes glucose, will not do so after a prolonged fast. The gluconeogenesis that has been ongoing in the liver will continue after fasting to replace the glycogen stores that were depleted in the liver. After these stores have been replenished, excess glucose that is absorbed by the liver will be converted into triglycerides and fatty acids for long-term storage. Figure 2 summarizes the metabolic processes occurring in the body during the postabsorptive state.

[caption id="" align="aligncenter" width="550"] Figure 2. Postabsorptive State. During the postabsorptive state, the body must rely on stored glycogen for energy.[/caption]

Starvation

When the body is deprived of nourishment for an extended period of time, it goes into “survival mode.” The first priority for survival is to provide enough glucose or fuel for the brain. The second priority is the conservation of amino acids for proteins. Therefore, when glucose is no longer available the body relies on ketone bodies to both satisfy the energy needs of the brain and other glucose-dependent organs, while maintaining proteins in the cells. Because glucose levels are very low during starvation, glycolysis will shut off in cells that can use alternative fuels. For example, muscles will switch from using glucose to fatty acids as fuel. As previously explained, fatty acids can be converted into acetyl CoA and processed through the Krebs cycle to make ATP. Pyruvate, lactate, and alanine from muscle cells are not converted into acetyl CoA and used in the Krebs cycle, but are exported to the liver to be used in the synthesis of glucose. As starvation continues, and more glucose is needed, glycerol from fatty acids can be liberated and used as a source for gluconeogenesis. After several days of starvation, ketone bodies become the major source of fuel for the heart and other organs. As starvation continues, fatty acids and triglyceride stores are oxidized to create these molecules. This prevents the continued breakdown of proteins that serve as carbon sources for gluconeogenesis. Once these lipid stores are fully depleted, proteins from muscles are released and broken down for glucose synthesis. Overall survival is dependent on the amount of fat and protein stored in the body.

24.7 Nutrition and Diet

barkerj1 — Wed, 06 Sep 2017 01:20:05 +0000

Learning Objectives

By the end of this section, you will be able to:

Explain the connection of metabolism to nutrition and homeostasis
Explain what is meant by a "basic food group"
Explain the nutritional value of each "food group"
Specify six essential nutritional factors and describe one dietary source for each group
Define "vitamin"
Describe the general functions of vitamins
Describe dietary sources of two fat soluble and two water soluble vitamins
Specify seven major minerals (macrominerals) required in human nutrition, specifying one function of each and good dietary sources for each

The carbohydrates, lipids, and proteins in the foods you eat are used for energy to power molecular, cellular, and organ system activities. Importantly, the energy is stored primarily as fats. The quantity and quality of food that is ingested, digested, and absorbed affects the amount of fat that is stored as excess calories. Diet—both what you eat and how much you eat—has a dramatic impact on your health. Eating too much or too little food can lead to serious medical issues, including cardiovascular disease, cancer, anorexia, and diabetes, among others. Combine an unhealthy diet with unhealthy environmental conditions, such as smoking, and the potential medical complications increase significantly.

Food and Metabolism

The amount of energy that is needed or ingested per day is measured in calories. The nutritional Calorie (C) is the amount of heat it takes to raise 1 kg (1000 g) of water by 1 °C. This is different from the calorie (c) used in the physical sciences, which is the amount of heat it takes to raise 1 g of water by 1 °C. When we refer to "calorie," we are referring to the nutritional Calorie.

On average, a person needs 1500 to 2000 calories per day to sustain (or carry out) daily activities. The total number of calories needed by one person is dependent on their body mass, age, height, gender, activity level, and the amount of exercise per day. If exercise is regular part of one’s day, more calories are required. As a rule, people underestimate the number of calories ingested and overestimate the amount they burn through exercise. This can lead to ingestion of too many calories per day. The accumulation of an extra 3500 calories adds one pound of weight. If an excess of 200 calories per day is ingested, one extra pound of body weight will be gained every 18 days. At that rate, an extra 20 pounds can be gained over the course of a year. Of course, this increase in calories could be offset by increased exercise. Running or jogging one mile burns almost 100 calories.

The type of food ingested also affects the body’s metabolic rate. Processing of carbohydrates requires less energy than processing of proteins. In fact, the breakdown of carbohydrates requires the least amount of energy, whereas the processing of proteins demands the most energy. In general, the amount of calories ingested and the amount of calories burned determines the overall weight. To lose weight, the number of calories burned per day must exceed the number ingested. Calories are in almost everything you ingest, so when considering calorie intake, beverages must also be considered.

To help provide guidelines regarding the types and quantities of food that should be eaten every day, Health Canada has published a simplified "Eat Well Plate" graphic to summarize the recommendations found in Canada's Food Guide (Figure 1). Such representations seek to put the recommended elements of a healthy meal into the context of a place setting of food. The accompanying websites canada.ca/foodguide gives clear recommendations regarding quantity and type of each food that you should consume each day, as well as identifying which foods belong in each category. The guidelines in general suggest you “Make half your plate fruits and vegetables.” The other half is grains and protein, with a slightly higher quantity of grains than protein. Dairy products are represented by a drink, but the quantity can be applied to other dairy products as well. All of these foodstuffs contain the energy-containing nutrients carbohydrates, lipids, and proteins in varying amounts, as well as various vitamins, minerals, and essential nutrients. Specifics vary with particular choices within each group, but in general grain products, vegetables and fruit contain higher amounts of carbohydrates than the other groups, whereas meat and dairy products contain higher amounts of protein and lipids.

[caption id="attachment_1113" align="aligncenter" width="232"] Figure 1. Health Canada's Eat Well Plate. Health Canada has developed food guidelines to help demonstrate how to maintain a healthy lifestyle.[/caption]

Essential nutrients

In addition to providing chemical energy, ingested foodstuffs must also provide any molecules that cannot be produced fast enough (or in some cases, at all) by the body to meet the body's needs. Such molecules are referred to as essential because they must be ingested to allow normal functioning of the human body.

There are two essential fatty acids that humans must ingest: linoleic acid (LA), an omega-6 fatty acid, and linolenic acid (ALA), an omega-3 fatty acid. These two fatty acids serve as precursor molecules that can be modified by the body, particularly in the liver, to produce other lipid molecules. However, they cannot be created from other molecules in the human body and so must be provided by consuming an external source. There are eight essential amino acids that humans must ingest from other sources: tryptophan, methionine, valine, threonine, phenylalanine, leucine, isoleucine, and lysine. An additional two - histidine and arginine - are essential for infants but not for adults. Any protein that contains in its primary structure any of these amino acids will not be made at all in their absence. All of the essential amino acids are found in animal product proteins (e.g. eggs, milk, fish, most meats), but almost no single plant source contains all of the essential amino acids. However, combinations of plants can be ingested together to provide them; for example, a combination of cereal grains (e.g. corn) and legumes (e.g. beans) can provide all eight essential amino acids. Although humans do produce it as a byproduct of cellular respiration, water is also an essential nutrient. We lose far more water through constant evaporation from our breath, mucous membranes, and sweat than is produced. Thus humans must ingest water regularly. Plant and animal cells consist largely of water, so a substantial amount of water can be obtained from (non-dehydrated) dietary sources. Nevertheless, humans living in all but the most comfortable of environments typically require access to a source of additional liquid water in addition to plant and animal sources. Excessive water loss (dehydration) can be fatal from a combination of an inability to sweat allowing a dangerous rise in body temperature and a dramatic drop in blood volume and increase in blood viscosity due to water loss from the blood plasma. Under extreme conditions (e.g. exercising strenuously in a hot environment) the lack of a reliable water sources can prove fatal within a few hours; an adult in comfortable surroundings could survive up to about a week without any water intake before succumbing. Generally the lack of other dietary nutrients in an otherwise health human would not prove fatal nearly as quickly. The other essential nutrients are the vitamins and minerals. Vitamins in general can be ingested directly or produced by modifying precursor molecules that can be ingested instead, but they are required and cannot be produced from other types of nutrients. Minerals are inorganic ions and as such cannot be 'produced' in the human body at all and must be ingested in an appropriate form.

Vitamins

Vitamins are organic compounds found in foods and are a necessary part of the biochemical reactions in the body. They are involved in a number of processes, including mineral and bone metabolism, and cell and tissue growth, and they act as cofactors for energy metabolism. The B vitamins play the largest role of any vitamins in metabolism (Table 3 and Table 4).

You get most of your vitamins through your diet, although some can be formed from the precursors absorbed during digestion. For example, the body synthesizes vitamin A from the β-carotene in orange vegetables like carrots and sweet potatoes. Vitamins are either fat-soluble or water-soluble. Fat-soluble vitamins A, D, E, and K, are absorbed through the intestinal tract with lipids in chylomicrons. Vitamin D is also synthesized in the skin through exposure to sunlight. Because they are carried in lipids, fat-soluble vitamins can accumulate in the lipids stored in the body. If excess vitamins are retained in the lipid stores in the body, hypervitaminosis can result.

Water-soluble vitamins, including the eight B vitamins and vitamin C, are absorbed with water in the gastrointestinal tract. These vitamins move easily through bodily fluids, which are water based, so they are not stored in the body. Excess water-soluble vitamins are excreted in the urine. Therefore, hypervitaminosis of water-soluble vitamins rarely occurs, except with an excess of vitamin supplements.

Fat-soluble Vitamins (Table 3)
Vitamin and alternative name	Sources	Recommended daily allowance	Function	Problems associated with deficiency
A retinal or β-carotene	Yellow and orange fruits and vegetables, dark green leafy vegetables, eggs, milk, liver	700–900 µg	Eye and bone development, immune function	Night blindness, epithelial changes, immune system deficiency
D cholecalciferol	Dairy products, egg yolks; also synthesized in the skin from exposure to sunlight	5–15 µg	Aids in calcium and phosphorus absorption, thereby promoting bone growth	Rickets, bone pain, muscle weakness, increased risk of death from cardiovascular disease, cognitive impairment, asthma in children, cancer
E tocopherols	Seeds, nuts, vegetable oils, avocados, wheat germ	15 mg	Antioxidant	Anemia
K phylloquinone	Dark green leafy vegetables, broccoli, Brussels sprouts, cabbage	90–120 µg	Blood clotting, bone health	Hemorrhagic disease of newborn in infants; uncommon in adults

Water-soluble Vitamins (Table 4)
Vitamin and alternative name	Sources	Recommended daily allowance	Function	Problems associated with deficiency
B₁ thiamine	Whole grains, enriched bread and cereals, milk, meat	1.1–1.2 mg	Carbohydrate metabolism	Beriberi, Wernicke-Korsikoff syndrome
B₂ riboflavin	Brewer’s yeast, almonds, milk, organ meats, legumes, enriched breads and cereals, broccoli, asparagus	1.1–1.3 mg	Synthesis of FAD for metabolism, production of red blood cells	Fatigue, slowed growth, digestive problems, light sensitivity, epithelial problems like cracks in the corners of the mouth
B₃ niacin	Meat, fish, poultry, enriched breads and cereals, peanuts	14–16 mg	Synthesis of NAD, nerve function, cholesterol production	Cracked, scaly skin; dementia; diarrhea; also known as pellagra
B₅ pantothenic acid	Meat, poultry, potatoes, oats, enriched breads and cereals, tomatoes	5 mg	Synthesis of coenzyme A in fatty acid metabolism	Rare: symptoms may include fatigue, insomnia, depression, irritability
B₆ pyridoxine	Potatoes, bananas, beans, seeds, nuts, meat, poultry, fish, eggs, dark green leafy vegetables, soy, organ meats	1.3–1.5 mg	Sodium and potassium balance, red blood cell synthesis, protein metabolism	Confusion, irritability, depression, mouth and tongue sores
B₇ biotin	Liver, fruits, meats	30 µg	Cell growth, metabolism of fatty acids, production of blood cells	Rare in developed countries; symptoms include dermatitis, hair loss, loss of muscular coordination
B₉ folic acid	Liver, legumes, dark green leafy vegetables, enriched breads and cereals, citrus fruits	400 µg	DNA/protein synthesis	Poor growth, gingivitis, appetite loss, shortness of breath, gastrointestinal problems, mental deficits
B₁₂ cyanocobalamin	Fish, meat, poultry, dairy products, eggs	2.4 µg	Fatty acid oxidation, nerve cell function, red blood cell production	Pernicious anemia, leading to nerve cell damage
C ascorbic acid	Citrus fruits, red berries, peppers, tomatoes, broccoli, dark green leafy vegetables	75–90 mg	Necessary to produce collagen for formation of connective tissue and teeth, and for wound healing	Dry hair, gingivitis, bleeding gums, dry and scaly skin, slow wound healing, easy bruising, compromised immunity; can lead to scurvy

Minerals

Minerals in food are inorganic ions or compounds that work with other nutrients to ensure the body functions properly. Minerals cannot be made in the body; they come from the diet. The amount of minerals in the body is small—only 4 percent of the total body mass—and most of that consists of the minerals that the body requires in moderate quantities: potassium, sodium, calcium, phosphorus, magnesium, and chloride.

The most common minerals in the body are calcium and phosphorous, both of which are stored in the skeleton and necessary for the hardening of bones. Most minerals are ionized, and their ionic forms are used in physiological processes throughout the body. Sodium and chloride ions are electrolytes in the blood and extracellular tissues, and iron ions are critical to the formation of hemoglobin. There are additional trace minerals that are still important to the body’s functions, but their required quantities are much lower.

Like vitamins, minerals can be consumed in toxic quantities (although it is rare). A healthy diet includes most of the minerals your body requires, so supplements and processed foods can add potentially toxic levels of minerals. Table 5 and Table 6 provide a summary of minerals and their function in the body.

Major Minerals (Table 5)
Mineral	Sources	Recommended daily allowance	Function	Problems associated with deficiency
Potassium	Meats, some fish, fruits, vegetables, legumes, dairy products	4700 mg	Nerve and muscle function; acts as an electrolyte	Hypokalemia: weakness, fatigue, muscle cramping, gastrointestinal problems, cardiac problems
Sodium	Table salt, milk, beets, celery, processed foods	2300 mg	Blood pressure, blood volume, muscle and nerve function	Rare
Calcium	Dairy products, dark green leafy vegetables, blackstrap molasses, nuts, brewer’s yeast, some fish	1000 mg	Bone structure and health; nerve and muscle functions, especially cardiac function	Slow growth, weak and brittle bones
Phosphorous	Meat, milk	700 mg	Bone formation, metabolism, ATP production	Rare
Magnesium	Whole grains, nuts, leafy green vegetables	310–420 mg	Enzyme activation, production of energy, regulation of other nutrients	Agitation, anxiety, sleep problems, nausea and vomiting, abnormal heart rhythms, low blood pressure, muscular problems
Chloride	Most foods, salt, vegetables, especially seaweed, tomatoes, lettuce, celery, olives	2300 mg	Balance of body fluids, digestion	Loss of appetite, muscle cramps

Trace Minerals (Table 6)
Mineral	Sources	Recommended daily allowance	Function	Problems associated with deficiency
Iron	Meat, poultry, fish, shellfish, legumes, nuts, seeds, whole grains, dark leafy green vegetables	8–18 mg	Transport of oxygen in blood, production of ATP	Anemia, weakness, fatigue
Zinc	Meat, fish, poultry, cheese, shellfish	8–11 mg	Immunity, reproduction, growth, blood clotting, insulin and thyroid function	Loss of appetite, poor growth, weight loss, skin problems, hair loss, vision problems, lack of taste or smell
Copper	Seafood, organ meats, nuts, legumes, chocolate, enriched breads and cereals, some fruits and vegetables	900 µg	Red blood cell production, nerve and immune system function, collagen formation, acts as an antioxidant	Anemia, low body temperature, bone fractures, low white blood cell concentration, irregular heartbeat, thyroid problems
Iodine	Fish, shellfish, garlic, lima beans, sesame seeds, soybeans, dark leafy green vegetables	150 µg	Thyroid function	Hypothyroidism: fatigue, weight gain, dry skin, temperature sensitivity
Sulfur	Eggs, meat, poultry, fish, legumes	None	Component of amino acids	Protein deficiency
Fluoride	Fluoridated water	3–4 mg	Maintenance of bone and tooth structure	Increased cavities, weak bones and teeth
Manganese	Nuts, seeds, whole grains, legumes	1.8–2.3 mg	Formation of connective tissue and bones, blood clotting, sex hormone development, metabolism, brain and nerve function	Infertility, bone malformation, weakness, seizures
Cobalt	Fish, nuts, leafy green vegetables, whole grains	None	Component of B₁₂	None
Selenium	Brewer’s yeast, wheat germ, liver, butter, fish, shellfish, whole grains	55 µg	Antioxidant, thyroid function, immune system function	Muscle pain
Chromium	Whole grains, lean meats, cheese, black pepper, thyme, brewer’s yeast	25–35 µg	Insulin function	High blood sugar, triglyceride, and cholesterol levels
Molybdenum	Legumes, whole grains, nuts	45 µg	Cofactor for enzymes	Rare

25.1 Physical Characteristics of Urine

barkerj1 — Wed, 06 Sep 2017 01:20:07 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the chemical composition of urine
Describe normal urine in terms of:
- Volume voided in a single day
- Variations in concentration of dissolved substances
- Variations in hydrogen ion concentration
Define:
- Anuria
- Oliguria
- Polyuria
- Dysuria
Define and identify the pathological conditions causing:
- Haematuria
- Glycosuria
- Pyuria
- Albuminuria
- Ketouria (acetonuria)
- Biliuria

The urinary system’s ability to filter the blood resides in about 2 to 3 million tufts of specialized capillaries—the glomeruli—distributed more or less equally between the two kidneys. Because the glomeruli filter the blood based mostly on particle size, large elements like blood cells, platelets, antibodies, and albumen are excluded. The glomerulus is the first part of the nephron, which then continues as a highly specialized tubular structure responsible for creating the final urine composition. All other solutes, such as ions, amino acids, vitamins, and wastes, are filtered to create a filtrate composition very similar to plasma. The glomeruli create about 200 liters (189 quarts) of this filtrate every day, yet you excrete less than two liters of waste you call urine.

Characteristics of the urine change, depending on influences such as water intake, exercise, environmental temperature, nutrient intake, and other factors (Table 1). Some of the characteristics such as color and odor are rough descriptors of your state of hydration. For example, if you exercise or work outside, and sweat a great deal, your urine will turn darker and produce a slight odor, even if you drink plenty of water. Athletes are often advised to consume water until their urine is clear. This is good advice; however, it takes time for the kidneys to process body fluids and store it in the bladder. Another way of looking at this is that the quality of the urine produced is an average over the time it takes to make that urine. Producing clear urine may take only a few minutes if you are drinking a lot of water or several hours if you are working outside and not drinking much.

Normal Urine Characteristics (Table 1)
Characteristic	Normal values
Color	Pale yellow to deep amber
Odor	Odorless
Volume	750–2000 mL/24 hour
pH	4.5–8.0
Specific gravity	1.003–1.032
Osmolarity	40–1350 mOsmol/kg
Urobilinogen	0.2–1.0 mg/100 mL
White blood cells	0–2 HPF (per high-power field of microscope)
Leukocyte esterase	None
Protein	None or trace
Bilirubin	<0.3 mg/100 mL
Ketones	None
Nitrites	None
Blood	None
Glucose	None

Urinalysis (urine analysis) often provides clues to renal disease. Normally, only traces of protein are found in urine, and when higher amounts are found, damage to the glomeruli is the likely basis. Unusually large quantities of urine may point to diseases like diabetes mellitus or hypothalamic tumors that cause diabetes insipidus. The color of urine is determined mostly by the breakdown products of red blood cell destruction (Figure 1). The “heme” of hemoglobin is converted by the liver into water-soluble forms that can be excreted into the bile and indirectly into the urine. This yellow pigment is urochrome. Urine color may also be affected by certain foods like beets, berries, and fava beans. A kidney stone or a cancer of the urinary system may produce sufficient bleeding to manifest as pink or even bright red urine. Diseases of the liver or obstructions of bile drainage from the liver impart a dark “tea” or “cola” hue to the urine. Dehydration produces darker, concentrated urine that may also possess the slight odor of ammonia. Most of the ammonia produced from protein breakdown is converted into urea by the liver, so ammonia is rarely detected in fresh urine. The strong ammonia odor you may detect in bathrooms or alleys is due to the breakdown of urea into ammonia by bacteria in the environment. About one in five people detect a distinctive odor in their urine after consuming asparagus; other foods such as onions, garlic, and fish can impart their own aromas! These food-caused odors are harmless.

[caption id="" align="aligncenter" width="230"] Figure 1. Urine Color.[/caption] Urine volume varies considerably. The normal range is one to two liters per day (Table 2). The kidneys must produce a minimum urine volume of about 500 mL/day to rid the body of wastes. Output below this level may be caused by severe dehydration or renal disease and is termed oliguria. The virtual absence of urine production is termed anuria. Excessive urine production is polyuria, which may be due to diabetes mellitus or diabetes insipidus. In diabetes mellitus, blood glucose levels exceed the number of available sodium-glucose transporters in the kidney, and glucose appears in the urine. The osmotic nature of glucose attracts water, leading to its loss in the urine. In the case of diabetes insipidus, insufficient pituitary antidiuretic hormone (ADH) release or insufficient numbers of ADH receptors in the collecting ducts means that too few water channels are inserted into the cell membranes that line the collecting ducts of the kidney. Insufficient numbers of water channels (aquaporins) reduce water absorption, resulting in high volumes of very dilute urine.

Urine Volumes (Table 2)
Volume condition	Volume	Causes
Normal	1–2 L/day
Polyuria	>2.5 L/day	Diabetes mellitus; diabetes insipidus; excess caffeine or alcohol; kidney disease; certain drugs, such as diuretics; sickle cell anemia; excessive water intake
Oliguria	300–500 mL/day	Dehydration; blood loss; diarrhea; cardiogenic shock; kidney disease; enlarged prostate
Anuria	<50 mL/day	Kidney failure; obstruction, such as kidney stone or tumor; enlarged prostate

The pH (hydrogen ion concentration) of the urine can vary more than 1000-fold, from a normal low of 4.5 to a maximum of 8.0. Diet can influence pH; meats lower the pH, whereas citrus fruits, vegetables, and dairy products raise the pH. Chronically high or low pH can lead to disorders, such as the development of kidney stones or osteomalacia.

Specific gravity is a measure of the quantity of solutes per unit volume of a solution and is traditionally easier to measure than osmolarity. Urine will always have a specific gravity greater than pure water (water = 1.0) due to the presence of solutes. Laboratories can now measure urine osmolarity directly, which is a more accurate indicator of urinary solutes than specific gravity. Remember that osmolarity is the number of osmoles or milliosmoles per liter of fluid (mOsmol/L). Urine osmolarity ranges from a low of 50–100 mOsmol/L to as high as 1200 mOsmol/L H₂O.

Cells are not normally found in the urine. The presence of leukocytes may indicate a urinary tract infection. Leukocyte esterase is released by leukocytes; if detected in the urine, it can be taken as indirect evidence of a urinary tract infection (UTI).

Protein does not normally leave the glomerular capillaries, so only trace amounts of protein should be found in the urine, approximately 10 mg/100 mL in a random sample. If excessive protein is detected in the urine, it usually means that the glomerulus is damaged and is allowing protein to “leak” into the filtrate.

Ketones are byproducts of fat metabolism. Finding ketones in the urine suggests that the body is using fat as an energy source in preference to glucose. In diabetes mellitus when there is not enough insulin (type I diabetes mellitus) or because of insulin resistance (type II diabetes mellitus), there is plenty of glucose, but without the action of insulin, the cells cannot take it up, so it remains in the bloodstream. Instead, the cells are forced to use fat as their energy source, and fat consumed at such a level produces excessive ketones as byproducts. These excess ketones will appear in the urine. Ketones may also appear if there is a severe deficiency of proteins or carbohydrates in the diet.

Nitrates (NO₃^–) occur normally in the urine. Gram-negative bacteria metabolize nitrate into nitrite (NO₂^–), and its presence in the urine is indirect evidence of infection.

There should be no blood found in the urine. It may sometimes appear in urine samples as a result of menstrual contamination, but this is not an abnormal condition. Now that you understand what the normal characteristics of urine are, the next section will introduce you to how you store and dispose of this waste product and how you make it.

[caption id="attachment_3023" align="aligncenter" width="150"] Watch this CrashCourse video to learn about the urinary system and the characteristics of urine.[/caption]

25.2 Gross Anatomy of Urine Transport

barkerj1 — Wed, 06 Sep 2017 01:20:07 +0000

Learning Objectives

By the end of this section, you will be able to:

Specify the location and function(s) as a part of the urinary system of the:
- Kidneys
- Ureters
- Urinary bladder
- Urethra
Describe the nervous control of micturition
Define and identify the pathological conditions causing cystitis

Rather than start with urine formation, this section will start with urine excretion. Urine is a fluid of variable composition that requires specialized structures to remove it from the body safely and efficiently. Blood is filtered, and the filtrate is transformed into urine at a relatively constant rate throughout the day. This processed liquid is stored until a convenient time for excretion. All structures involved in the transport and storage of the urine are large enough to be visible to the naked eye. This transport and storage system not only stores the waste, but it protects the tissues from damage due to the wide range of pH and osmolarity of the urine, prevents infection by foreign organisms, and for the male, provides reproductive functions.

Urethra

The urethra transports urine from the bladder to the outside of the body for disposal. The urethra is the only urologic organ that shows any significant anatomic difference between males and females; all other urine transport structures are identical (Figure 1).

[caption id="" align="aligncenter" width="560"] Figure 1. Female and Male Urethras. The urethra transports urine from the bladder to the outside of the body. This image shows (a) a female urethra and (b) a male urethra.[/caption]

The urethra in both males and females begins inferior and central to the two ureteral openings forming the three points of a triangular-shaped area at the base of the bladder called the trigone (Greek tri- = “triangle” and the root of the word “trigonometry”). The urethra tracks posterior and inferior to the pubic symphysis (see Figure 1a). In both males and females, the proximal urethra is lined by transitional epithelium, whereas the terminal portion is a nonkeratinized, stratified squamous epithelium. In the male, pseudostratified columnar epithelium lines the urethra between these two cell types. Voiding is regulated by an involuntary autonomic nervous system-controlled internal urinary sphincter, consisting of smooth muscle and voluntary skeletal muscle that forms the external urinary sphincter below it.

Female Urethra

The external urethral orifice is embedded in the anterior vaginal wall inferior to the clitoris, superior to the vaginal opening (introitus), and medial to the labia minora. Its short length, about 4 cm, is less of a barrier to fecal bacteria than the longer male urethra and the best explanation for the greater incidence of UTI in women. Voluntary control of the external urethral sphincter is a function of the pudendal nerve. It arises in the sacral region of the spinal cord, traveling via the S2–S4 nerves of the sacral plexus.

Male Urethra

The male urethra passes through the prostate gland immediately inferior to the bladder before passing below the pubic symphysis (see Figure 1b). The length of the male urethra varies between men but averages 20 cm in length. It is divided into four regions: the preprostatic urethra, the prostatic urethra, the membranous urethra, and the spongy or penile urethra. The preprostatic urethra is very short and incorporated into the bladder wall. The prostatic urethra passes through the prostate gland. During sexual intercourse, it receives sperm via the ejaculatory ducts and secretions from the seminal vesicles. Paired Cowper’s glands (bulbourethral glands) produce and secrete mucus into the urethra to buffer urethral pH during sexual stimulation. The mucus neutralizes the usually acidic environment and lubricates the urethra, decreasing the resistance to ejaculation. The membranous urethra passes through the deep muscles of the perineum, where it is invested by the overlying urethral sphincters. The spongy urethra exits at the tip (external urethral orifice) of the penis after passing through the corpus spongiosum. Mucous glands are found along much of the length of the urethra and protect the urethra from extremes of urine pH. Innervation is the same in both males and females.

Bladder

The urinary bladder collects urine from both ureters (Figure 2). The bladder lies anterior to the uterus in females, posterior to the pubic bone and anterior to the rectum. During late pregnancy, its capacity is reduced due to compression by the enlarging uterus, resulting in increased frequency of urination. In males, the anatomy is similar, minus the uterus, and with the addition of the prostate inferior to the bladder. The bladder is partially retroperitoneal (outside the peritoneal cavity) with its peritoneal-covered “dome” projecting into the abdomen when the bladder is distended with urine.

[caption id="" align="aligncenter" width="500"] Figure 2. Bladder. (a) Anterior cross section of the bladder. (b) The detrusor muscle of the bladder (source: monkey tissue) LM × 448. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)[/caption]

The bladder is a highly distensible organ comprised of irregular crisscrossing bands of smooth muscle collectively called the detrusor muscle. The interior surface is made of transitional cellular epithelium that is structurally suited for the large volume fluctuations of the bladder. When empty, it resembles columnar epithelia, but when stretched, it “transitions” (hence the name) to a squamous appearance (see Figure 2). Volumes in adults can range from nearly zero to 500–600 mL.

The detrusor muscle contracts with significant force in the young. The bladder’s strength diminishes with age, but voluntary contractions of abdominal skeletal muscles can increase intra-abdominal pressure to promote more forceful bladder emptying. Such voluntary contraction is also used in forceful defecation and childbirth.

Micturition Reflex

Micturition is a less-often used, but proper term for urination or voiding. It results from an interplay of involuntary and voluntary actions by the internal and external urethral sphincters. When bladder volume reaches about 150 mL, an urge to void is sensed but is easily overridden. Voluntary control of urination relies on consciously preventing relaxation of the external urethral sphincter to maintain urinary continence. As the bladder fills, subsequent urges become harder to ignore. Ultimately, voluntary constraint fails with resulting incontinence, which will occur as bladder volume approaches 300 to 400 mL.

Normal micturition is a result of stretch receptors in the bladder wall that transmit nerve impulses to the sacral region of the spinal cord to generate a spinal reflex. The resulting parasympathetic neural outflow causes contraction of the detrusor muscle and relaxation of the involuntary internal urethral sphincter. At the same time, the spinal cord inhibits somatic motor neurons, resulting in the relaxation of the skeletal muscle of the external urethral sphincter. The micturition reflex is active in infants but with maturity, children learn to override the reflex by asserting external sphincter control, thereby delaying voiding (potty training). This reflex may be preserved even in the face of spinal cord injury that results in paraplegia or quadriplegia. However, relaxation of the external sphincter may not be possible in all cases, and therefore, periodic catheterization may be necessary for bladder emptying.

Nerves involved in the control of urination include the hypogastric, pelvic, and pudendal (Figure 3). Voluntary micturition requires an intact spinal cord and functional pudendal nerve arising from the sacral micturition center. Since the external urinary sphincter is voluntary skeletal muscle, actions by cholinergic neurons maintain contraction (and thereby continence) during filling of the bladder. At the same time, sympathetic nervous activity via the hypogastric nerves suppresses contraction of the detrusor muscle. With further bladder stretch, afferent signals traveling over sacral pelvic nerves activate parasympathetic neurons. This activates efferent neurons to release acetylcholine at the neuromuscular junctions, producing detrusor contraction and bladder emptying.

[caption id="" align="aligncenter" width="425"] Figure 3. Nerves Innervating the Urinary System.[/caption]

Ureters

The kidneys and ureters are completely retroperitoneal, and the bladder has a peritoneal covering only over the dome. As urine is formed, it drains into the calyces of the kidney, which merge to form the funnel-shaped renal pelvis in the hilum of each kidney. The hilum narrows to become the ureter of each kidney. As urine passes through the ureter, it does not passively drain into the bladder but rather is propelled by waves of peristalsis. As the ureters enter the pelvis, they sweep laterally, hugging the pelvic walls. As they approach the bladder, they turn medially and pierce the bladder wall obliquely. This is important because it creates an one-way valve (a physiological sphincter rather than an anatomical sphincter) that allows urine into the bladder but prevents reflux of urine from the bladder back into the ureter. Children born lacking this oblique course of the ureter through the bladder wall are susceptible to “vesicoureteral reflux,” which dramatically increases their risk of serious UTI. Pregnancy also increases the likelihood of reflux and UTI.

The ureters are approximately 30 cm long. The inner mucosa is lined with transitional epithelium (Figure 4) and scattered goblet cells that secrete protective mucus. The muscular layer of the ureter consists of longitudinal and circular smooth muscles that create the peristaltic contractions to move the urine into the bladder without the aid of gravity. Finally, a loose adventitial layer composed of collagen and fat anchors the ureters between the parietal peritoneum and the posterior abdominal wall.

[caption id="" align="aligncenter" width="425"] Figure 4. Ureter. Peristaltic contractions help to move urine through the lumen with contributions from fluid pressure and gravity. LM × 128. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)[/caption]

Introduction

barkerj1 — Tue, 04 Apr 2017 22:17:03 +0000

Welcome to the Douglas College Anatomy & Physiology open textbook! This textbook is a project under development by our Biology faculty to ultimately provide students with all the factual information they need to succeed in the BIOL 1203 and BIOL 1209 courses at Douglas College in BC, Canada. Readers should be aware that the information herein is subject to change at any time as corrections, additions, or other important modifications are made. Only the most recent version will be considered to be complete and correct. The most recent version is accessible online at https://pressbooks.bccampus.ca/dcbiol12031209/, and the most recent version of the companion textbook (developed for Douglas College's BIOL 1103 and BIOL 1109 courses) is also accessible online at https://pressbooks.bccampus.ca/dcbiol11031109/. The material herein is drawn largely from the OpenStax Anatomy & Physiology textbook, also freely and perpetually available online at http://cnx.org/content/col11496/latest/. Chapter and section numbers have been left as they were in the version of the OpenStax A&P textbook from which they are drawn; some sections have been removed, and others have had some material added, to correspond with the curriculum used at Douglas College.

Preface

barkerj1 — Wed, 06 Sep 2017 01:16:53 +0000

Human Anatomy and Physiology II is designed for the second of two introductory human anatomy and physiology course offered at Douglas College. The textbook follows the scope and sequence of our own Human Anatomy and Physiology courses, and its coverage and organization were informed by the instructors who teach the course here at Douglas College.

About Douglas College

Douglas College is located in the province of British Columbia, Canada, hosting local, domestic, and international students. This textbook was adapted directly from the Human Anatomy & Physiology textbook originally created by OpenStax College to suit the needs of our own students and instructors, and will continue to be adapted and updated as those needs are recognized and change over time.

About Anatomy and Physiology II

Anatomy and Physiology II is designed for the second of two introductory human anatomy and physiology course offered at Douglas College. The text focuses on directly addressing the Course Objectives defined for BIOL 1203 and BIOL 1209 at Douglas College, covering the most important concepts and aiming to minimize distracting students with more minor details.

The development choices for this textbook were made with the guidance of hundreds of faculty who are deeply involved in teaching this course. These choices led to innovations in art, terminology, career orientation, practical applications, and multimedia-based learning, all with a goal of increasing relevance to students. We strove to make the discipline meaningful and memorable to students, so that they can draw from it a working knowledge that will enrich their future studies.

Cost

This textbook and its companion textbook Human Anatomy & Physiology I are available for free online, and in low-cost print editions from the Douglas College Bookstore.

Coverage and Scope

The units of our Human Anatomy and Physiology textbooks adhere to the scope and sequence followed by our courses at Douglas College.

Unit 1: Levels of Organization

Chapters 1–4 provide students with a basic understanding of human anatomy and physiology, including its language, the levels of organization, and the basics of chemistry and cell biology. These chapters provide a foundation for the further study of the body. They also focus particularly on how the body’s regions, important chemicals, and cells maintain homeostasis.

Chapter 1 An Introduction to the Human Body Chapter 2 The Chemical Level of Organization Chapter 3 The Cellular Level of Organization Chapter 4 The Tissue Level of Organization

Unit 2: Support and Movement

In Chapters 5–11, students explore the skin, the largest organ of the body, and examine the body’s skeletal and muscular systems, following a traditional sequence of topics. This unit is the first to walk students through specific systems of the body, and as it does so, it maintains a focus on homeostasis as well as those diseases and conditions that can disrupt it.

Chapter 5 The Integumentary System Chapter 6 Bone and Skeletal Tissue Chapter 7 The Axial Skeleton Chapter 8 The Appendicular Skeleton Chapter 9 Joints Chapter 10 Muscle Tissue Chapter 11 The Muscular System

Unit 3: Regulation, Integration, and Control

Chapters 12–17 help students answer questions about nervous and endocrine system control and regulation. In a break with the traditional sequence of topics, the special senses are integrated into the chapter on the somatic nervous system. The chapter on the neurological examination offers students a unique approach to understanding nervous system function using five simple but powerful diagnostic tests.

Chapter 12 Introduction to the Nervous System Chapter 13 The Anatomy of the Nervous System Chapter 14 The Somatic Nervous System Chapter 15 The Autonomic Nervous System Chapter 16 The Neurological Exam Chapter 17 The Endocrine System

Unit 4: Fluids and Transport

In Chapters 18–21, students examine the principal means of transport for materials needed to support the human body, regulate its internal environment, and provide protection. Chapter 18 Blood Chapter 19 The Cardiovascular System: The Heart Chapter 20 The Cardiovascular System: Blood Vessels and Circulation Chapter 21 The Lymphatic System and Immunity

Unit 5: Energy, Maintenance, and Environmental Exchange

In Chapters 22–26, students discover the interaction between body systems and the outside environment for the exchange of materials, the capture of energy, the release of waste, and the overall maintenance of the internal systems that regulate the exchange. The explanations and illustrations are particularly focused on how structure relates to function.

Chapter 22 The Respiratory System Chapter 23 The Digestive System Chapter 24 Nutrition and Metabolism Chapter 25 The Urinary System Chapter 26 Fluid, Electrolyte, and Acid–Base Balance

Unit 6: Human Development and the Continuity of Life

The closing chapters examine the male and female reproductive systems, describe the process of human development and the different stages of pregnancy, and end with a review of the mechanisms of inheritance.

Chapter 27 The Reproductive System Chapter 28 Development and Genetic Inheritance

Pedagogical Foundation and Features

Anatomy and Physiology is designed to promote scientific literacy. Throughout the text, you will find features that engage the students by taking selected topics a step further.

Homeostatic Imbalances discusses the effects and results of imbalances in the body.
Disorders showcases a disorder that is relevant to the body system at hand. This feature may focus on a specific disorder, or a set of related disorders.
Diseases showcases a disease that is relevant to the body system at hand.
Aging explores the effect aging has on a body’s system and specific disorders that manifest over time.
Career Connections presents information on the various careers often pursued by allied health students, such as medical technician, medical examiner, and neurophysiologist. Students are introduced to the educational requirements for and day-to-day responsibilities in these careers.
Everyday Connections tie anatomical and physiological concepts to emerging issues and discuss these in terms of everyday life. Topics include “Anabolic Steroids” and “The Effect of Second-Hand Tobacco Smoke.”
Interactive Links direct students to online exercises, simulations, animations, and videos to add a fuller context to core content and help improve understanding of the material. Many features include links to the University of Michigan’s interactive WebScopes, which allow students to zoom in on micrographs in the collection. These resources were vetted by reviewers and other subject matter experts to ensure that they are effective and accurate. We strongly urge students to explore these links, whether viewing a video or inputting data into a simulation, to gain the fullest experience and to learn how to search for information independently.

Dynamic, Learner-Centered Art

Our unique approach to visuals is designed to emphasize only the components most important in any given illustration. The art style is particularly aimed at focusing student learning through a powerful blend of traditional depictions and instructional innovations.

Much of the art in this book consists of black line illustrations. The strongest line is used to highlight the most important structures, and shading is used to show dimension and shape. Color is used sparingly to highlight and clarify the primary anatomical or functional point of the illustration. This technique is intended to draw students’ attention to the critical learning point in the illustration, without distraction from excessive gradients, shadows, and highlights. Full color is used when the structure or process requires it (for example, muscle diagrams and cardiovascular system illustrations).

[caption id="" align="aligncenter" width="300"] The Pharynx. By highlighting the most important portions of the illustration, the artwork helps students focus on the most important points, without overwhelming them.[/caption]

Micrographs

Micrograph magnifications have been calculated based on the objective provided with the image. If a micrograph was recorded at 40×, and the image was magnified an additional 2×, the final magnification of the micrograph is indicated as 80×.

Please note that, when viewing the textbook electronically, the micrograph magnification provided in the text does not take into account the size and magnification of the screen on your electronic device. There may be some variation.

[caption id="" align="aligncenter" width="500"] Sebaceous Glands. These glands secrete oils that lubricate and protect the skin. LM × 400. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

About Our Team

Senior Contributing Authors

Jennifer M. Barker	Douglas College

Contributing Authors

Sarah McKinnon	Douglas College

Special Thanks

The authors wish to thank all those who provided vital resources without which production of this textbook would not have been possible. First, we wish to thank OpenStax College in general and more specifically all the contributors to the Anatomy & Physiology textbook from which the majority of this textbook was derived. We also wish to thank BCcampus for financial and technical support throughout the adaptation of this textbook. Finally, we wish to thank the Douglas College Research and Scholarly Fund Adjudication Committee and the Douglas College Vice President's Academic Council for providing internal funding to allow the production and continued development of this work.

25.3 Gross Anatomy of the Kidney

barkerj1 — Wed, 06 Sep 2017 01:20:08 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the size, shape, and gross anatomy of the kidney
Describe the location of the renal cortex, renal medulla, and renal pelvis
Describe the blood supply of the kidney
Describe the blood supply of a nephron
Describe the structure of a nephron
Explain how the nephrons are arranged in the kidney
Define and idenfity the pathological conditions causing:
- Nephritis
- Pyelonephritis
- Glomerulonephritis
- Nephrosis

The kidneys lie on either side of the spine in the retroperitoneal space between the parietal peritoneum and the posterior abdominal wall, well protected by muscle, fat, and ribs. They are roughly the size of your fist, and the male kidney is typically a bit larger than the female kidney. The kidneys are well vascularized, receiving about 25 percent of the cardiac output at rest. [caption id="" align="aligncenter" width="120"] Watch this video to learn about the TED (Technology, Entertainment, Design) Conference held in March 2011.[/caption]

External Anatomy

The left kidney is located at about the T12 to L3 vertebrae, whereas the right is lower due to slight displacement by the liver. Upper portions of the kidneys are somewhat protected by the eleventh and twelfth ribs (Figure 1). Each kidney weighs about 125–175 g in males and 115–155 g in females. They are about 11–14 cm in length, 6 cm wide, and 4 cm thick, and are directly covered by a fibrous capsule composed of dense, irregular connective tissue that helps to hold their shape and protect them. This capsule is covered by a shock-absorbing layer of adipose tissue called the renal fat pad, which in turn is encompassed by a tough renal fascia. The fascia and, to a lesser extent, the overlying peritoneum serve to firmly anchor the kidneys to the posterior abdominal wall in a retroperitoneal position.

[caption id="" align="aligncenter" width="425"] Figure 1. Kidneys. The kidneys are slightly protected by the ribs and are surrounded by fat for protection (not shown).[/caption]

On the superior aspect of each kidney is the adrenal gland. The adrenal cortex directly influences renal function through the production of the hormone aldosterone to stimulate sodium reabsorption.

Internal Anatomy

A frontal section through the kidney reveals an outer region called the renal cortex and an inner region called the medulla (Figure 2). The renal columns are connective tissue extensions that radiate downward from the cortex through the medulla to separate the most characteristic features of the medulla, the renal pyramids and renal papillae. The papillae are bundles of collecting ducts that transport urine made by nephrons to the calyces of the kidney for excretion. The renal columns also serve to divide the kidney into 6–8 lobes and provide a supportive framework for vessels that enter and exit the cortex. The pyramids and renal columns taken together constitute the kidney lobes.

[caption id="" align="aligncenter" width="475"] Figure 2. Left Kidney.[/caption]

Renal Hilum

The renal hilum is the entry and exit site for structures servicing the kidneys: vessels, nerves, lymphatics, and ureters. The medial-facing hila are tucked into the sweeping convex outline of the cortex. Emerging from the hilum is the renal pelvis, which is formed from the major and minor calyxes in the kidney. The smooth muscle in the renal pelvis funnels urine via peristalsis into the ureter. The renal arteries form directly from the descending aorta, whereas the renal veins return cleansed blood directly to the inferior vena cava. The artery, vein, and renal pelvis are arranged in an anterior-to-posterior order.

Nephrons and Vessels

The renal artery first divides into segmental arteries, followed by further branching to form interlobar arteries that pass through the renal columns to reach the cortex (Figure 3). The interlobar arteries, in turn, branch into arcuate arteries, cortical radiate arteries, and then into afferent arterioles. The afferent arterioles service about 1.3 million nephrons in each kidney.

[caption id="" align="aligncenter" width="475"] Figure 3. Blood Flow in the Kidney.[/caption]

Nephrons are the “functional units” of the kidney; they cleanse the blood and balance the constituents of the circulation. The afferent arterioles form a tuft of high-pressure capillaries about 200 µm in diameter, the glomerulus. The rest of the nephron consists of a continuous sophisticated tubule whose proximal end surrounds the glomerulus in an intimate embrace—this is Bowman’s capsule. The glomerulus and Bowman’s capsule together form the renal corpuscle. As mentioned earlier, these glomerular capillaries filter the blood based on particle size. After passing through the renal corpuscle, the capillaries form a second arteriole, the efferent arteriole (Figure 4). These will next form a capillary network around the more distal portions of the nephron tubule, the peritubular capillaries and vasa recta, before returning to the venous system. As the glomerular filtrate progresses through the nephron, these capillary networks recover most of the solutes and water, and return them to the circulation. Since a capillary bed (the glomerulus) drains into a vessel that in turn forms a second capillary bed, the definition of a portal system is met. This is the only portal system in which an arteriole is found between the first and second capillary beds. (Portal systems also link the hypothalamus to the anterior pituitary, and the blood vessels of the digestive viscera to the liver.)

[caption id="" align="aligncenter" width="380"] Figure 4. Blood Flow in the Nephron. The two capillary beds are clearly shown in this figure. The efferent arteriole is the connecting vessel between the glomerulus and the peritubular capillaries and vasa recta.[/caption]

Cortex

In a dissected kidney, it is easy to identify the cortex; it appears lighter in color compared to the rest of the kidney. All of the renal corpuscles as well as both the proximal convoluted tubules (PCTs) and distal convoluted tubules are found here. Some nephrons have a short loop of Henle that does not dip beyond the cortex. These nephrons are called cortical nephrons. About 15 percent of nephrons have long loops of Henle that extend deep into the medulla and are called juxtamedullary nephrons.

25.4 Microscopic Anatomy of the Kidney

barkerj1 — Wed, 06 Sep 2017 01:20:09 +0000

Learning Objectives

By the end of this section, you will be able to:

Explain how urine is manufactured in a nephron
Describe the role in urine formation of the:
- Glomerulus
- Glomerular capsule
- Proximal convoluted tubule
- Loop of Henle
- Distal convoluted tubule
- Collecting duct
Describe the hormonal control of urine volume and composition

The renal structures that conduct the essential work of the kidney cannot be seen by the naked eye. Only a light or electron microscope can reveal these structures. Even then, serial sections and computer reconstruction are necessary to give us a comprehensive view of the functional anatomy of the nephron and its associated blood vessels.

Nephrons: The Functional Unit

Nephrons take a simple filtrate of the blood and modify it into urine. Many changes take place in the different parts of the nephron before urine is created for disposal. The term forming urine will be used hereafter to describe the filtrate as it is modified into true urine. The principle task of the nephron population is to balance the plasma to homeostatic set points and excrete potential toxins in the urine. They do this by accomplishing three principle functions—filtration, reabsorption, and secretion. They also have additional secondary functions that exert control in three areas: blood pressure (via production of renin), red blood cell production (via the hormone EPO), and calcium absorption (via conversion of calcidiol into calcitriol, the active form of vitamin D).

Renal Corpuscle

As discussed earlier, the renal corpuscle consists of a tuft of capillaries called the glomerulus that is largely surrounded by Bowman’s (glomerular) capsule. The glomerulus is a high-pressure capillary bed between afferent and efferent arterioles. Bowman’s capsule surrounds the glomerulus to form a lumen, and captures and directs this filtrate to the PCT. The outermost part of Bowman’s capsule, the parietal layer, is a simple squamous epithelium. It transitions onto the glomerular capillaries in an intimate embrace to form the visceral layer of the capsule. Here, the cells are not squamous, but uniquely shaped cells (podocytes) extending finger-like arms (pedicels) to cover the glomerular capillaries (Figure 1). These projections interdigitate to form filtration slits, leaving small gaps between the digits to form a sieve. As blood passes through the glomerulus, 10 to 20 percent of the plasma filters between these sieve-like fingers to be captured by Bowman’s capsule and funneled to the PCT. Where the fenestrae (windows) in the glomerular capillaries match the spaces between the podocyte “fingers,” the only thing separating the capillary lumen and the lumen of Bowman’s capsule is their shared basement membrane (Figure 2). These three features comprise what is known as the filtration membrane. This membrane permits very rapid movement of filtrate from capillary to capsule though pores that are only 70 nm in diameter.

[caption id="" align="aligncenter" width="480"] Figure 1. Podocytes. Podocytes interdigitate with structures called pedicels and filter substances in a way similar to fenestrations. In (a), the large cell body can be seen at the top right corner, with branches extending from the cell body. The smallest finger-like extensions are the pedicels. Pedicels on one podocyte always interdigitate with the pedicels of another podocyte. (b) This capillary has three podocytes wrapped around it.[/caption]

[caption id="" align="aligncenter" width="345"] Figure 2. Fenestrated Capillary. Fenestrations allow many substances to diffuse from the blood based primarily on size.[/caption]

The fenestrations prevent filtration of blood cells or large proteins, but allow most other constituents through. These substances cross readily if they are less than 4 nm in size and most pass freely up to 8 nm in size. An additional factor affecting the ability of substances to cross this barrier is their electric charge. The proteins associated with these pores are negatively charged, so they tend to repel negatively charged substances and allow positively charged substances to pass more readily. The basement membrane prevents filtration of medium-to-large proteins such as globulins. There are also mesangial cells in the filtration membrane that can contract to help regulate the rate of filtration of the glomerulus. Overall, filtration is regulated by fenestrations in capillary endothelial cells, podocytes with filtration slits, membrane charge, and the basement membrane between capillary cells. The result is the creation of a filtrate that does not contain cells or large proteins, and has a slight predominance of positively charged substances.

Lying just outside Bowman’s capsule and the glomerulus is the juxtaglomerular apparatus (JGA) (Figure 3). At the juncture where the afferent and efferent arterioles enter and leave Bowman’s capsule, the initial part of the distal convoluted tubule (DCT) comes into direct contact with the arterioles. The wall of the DCT at that point forms a part of the JGA known as the macula densa. This cluster of cuboidal epithelial cells monitors the fluid composition of fluid flowing through the DCT. In response to the concentration of Na⁺ in the fluid flowing past them, these cells release paracrine signals. They also have a single, nonmotile cilium that responds to the rate of fluid movement in the tubule. The paracrine signals released in response to changes in flow rate and Na⁺ concentration are adenosine triphosphate (ATP) and adenosine.

[caption id="" align="aligncenter" width="550"] Figure 3. Juxtaglomerular Apparatus and Glomerulus. (a) The JGA allows specialized cells to monitor the composition of the fluid in the DCT and adjust the glomerular filtration rate. (b) This micrograph shows the glomerulus and surrounding structures. LM × 1540. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

A second cell type in this apparatus is the juxtaglomerular cell. This is a modified, smooth muscle cell lining the afferent arteriole that can contract or relax in response to ATP or adenosine released by the macula densa. Such contraction and relaxation regulate blood flow to the glomerulus. If the osmolarity of the filtrate is too high (hyperosmotic), the juxtaglomerular cells will contract, decreasing the glomerular filtration rate (GFR) so less plasma is filtered, leading to less urine formation and greater retention of fluid. This will ultimately decrease blood osmolarity toward the physiologic norm. If the osmolarity of the filtrate is too low, the juxtaglomerular cells will relax, increasing the GFR and enhancing the loss of water to the urine, causing blood osmolarity to rise. In other words, when osmolarity goes up, filtration and urine formation decrease and water is retained. When osmolarity goes down, filtration and urine formation increase and water is lost by way of the urine. The net result of these opposing actions is to keep the rate of filtration relatively constant. A second function of the macula densa cells is to regulate renin release from the juxtaglomerular cells of the afferent arteriole (Figure 4). Active renin is a protein comprised of 304 amino acids that cleaves several amino acids from angiotensinogen to produce angiotensin I. Angiotensin I is not biologically active until converted to angiotensin II by angiotensin-converting enzyme (ACE) from the lungs. Angiotensin II is a systemic vasoconstrictor that helps to regulate blood pressure by increasing it. Angiotensin II also stimulates the release of the steroid hormone aldosterone from the adrenal cortex. Aldosterone stimulates Na⁺ reabsorption by the kidney, which also results in water retention and increased blood pressure.

[caption id="" align="aligncenter" width="600"] Figure 4. Conversion of Angiotensin I to Angiotensin II. The enzyme renin converts the pro-enzyme angiotensin I; the lung-derived enzyme ACE converts angiotensin I into active angiotensin II.[/caption]

Proximal Convoluted Tubule (PCT)

Filtered fluid collected by Bowman’s capsule enters into the PCT. It is called convoluted due to its tortuous path. Simple cuboidal cells form this tubule with prominent microvilli on the luminal surface, forming a brush border. These microvilli create a large surface area to maximize the absorption and secretion of solutes (Na⁺, Cl^–, glucose, etc.), the most essential function of this portion of the nephron. These cells actively transport ions across their membranes, so they possess a high concentration of mitochondria in order to produce sufficient ATP.

Loop of Henle

The descending and ascending portions of the loop of Henle (sometimes referred to as the nephron loop) are, of course, just continuations of the same tubule. They run adjacent and parallel to each other after having made a hairpin turn at the deepest point of their descent. The descending loop of Henle consists of an initial short, thick portion and long, thin portion, whereas the ascending loop consists of an initial short, thin portion followed by a long, thick portion. The descending thick portion consists of simple cuboidal epithelium similar to that of the PCT. The descending and ascending thin portions consists of simple squamous epithelium. As you will see later, these are important differences, since different portions of the loop have different permeabilities for solutes and water. The ascending thick portion consists of simple cuboidal epithelium similar to the DCT.

Distal Convoluted Tubule (DCT)

The DCT, like the PCT, is very tortuous and formed by simple cuboidal epithelium, but it is shorter than the PCT. These cells are not as active as those in the PCT; thus, there are fewer microvilli on the apical surface. However, these cells must also pump ions against their concentration gradient, so you will find of large numbers of mitochondria, although fewer than in the PCT.

Collecting Ducts

The collecting ducts are continuous with the nephron but not technically part of it. In fact, each duct collects filtrate from several nephrons for final modification. Collecting ducts merge as they descend deeper in the medulla to form about 30 terminal ducts, which empty at a papilla. They are lined with simple squamous epithelium with receptors for ADH. When stimulated by ADH, these cells will insert aquaporin channel proteins into their membranes, which as their name suggests, allow water to pass from the duct lumen through the cells and into the interstitial spaces to be recovered by the vasa recta. This process allows for the recovery of large amounts of water from the filtrate back into the blood. In the absence of ADH, these channels are not inserted, resulting in the excretion of water in the form of dilute urine. Most, if not all, cells of the body contain aquaporin molecules, whose channels are so small that only water can pass. At least 10 types of aquaporins are known in humans, and six of those are found in the kidney. The function of all aquaporins is to allow the movement of water across the lipid-rich, hydrophobic cell membrane (Figure 5).

[caption id="attachment_1836" align="aligncenter" width="500"] Figure 5. Aquaporin Water Channel. Positive charges inside the channel prevent the leakage of electrolytes across the cell membrane, while allowing water to move due to osmosis.[/caption]

25.5 Physiology of Urine Formation

barkerj1 — Wed, 06 Sep 2017 01:20:09 +0000

Learning Objectives

By the end of this section, you will be able to:

Briefly describe three methods used to augment kidney function

Having reviewed the anatomy and microanatomy of the urinary system, now is the time to focus on the physiology. You will discover that different parts of the nephron utilize specific processes to produce urine: filtration, reabsorption, and secretion. You will learn how each of these processes works and where they occur along the nephron and collecting ducts. The physiologic goal is to modify the composition of the plasma and, in doing so, produce the waste product urine. Failure of the renal anatomy and/or physiology can lead suddenly or gradually to renal failure. In this event, a number of symptoms, signs, or laboratory findings point to the diagnosis (Table 3). Renal failure is an ultimately fatal condition without medical intervention to replace the lost function. This can be accomplished by dialysis, where blood is pushed against a filtration membrane with a fluid on the other side, into which waste molecules from the blood plasma can diffuse. The fluid along with these waste products can then be removed from the body. The membrane may be an artificial, external membrane as in haemodialysis where a needle and tube is used to direct blood into a machine where it is filtered and then returned to the body. Alternatively, in peritoneal dialysis the peritoneal cavity is filled with dialysis fluid into which excess water and waste products can diffuse across the peritoneal membrane. In this case, the dialysis fluid is drained and replaced several times a day via a catheter. Finally, provided a suitable donor is found a kidney can be transplanted from a donor into a recipient; since one kidney is usually sufficient, this replacement kidney can come from a living donor.

Symptoms of Kidney Failure (Table 3)
Weakness
Lethargy
Shortness of breath
Widespread edema
Anemia
Metabolic acidosis
Metabolic alkalosis
Heart arrhythmias
Uremia (high urea level in the blood)
Loss of appetite
Fatigue
Excessive urination
Oliguria (too little urine output)

Glomerular Filtration Rate (GFR)

The volume of filtrate formed by both kidneys per minute is termed the glomerular filtration rate (GFR). The heart pumps about 5 L blood per min under resting conditions. Approximately 20 percent or one liter enters the kidneys to be filtered. On average, this liter results in the production of about 125 mL/min filtrate produced in men (range of 90 to 140 mL/min) and 105 mL/min filtrate produced in women (range of 80 to 125 mL/min). This amount equates to a volume of about 180 L/day in men and 150 L/day in women. Ninety-nine percent of this filtrate is returned to the circulation by reabsorption so that only about 1–2 liters of urine are produced per day (Table 4).

Calculating Urine Formation per Day (Table 4)
	Flow per minute (mL)	Calculation
Renal blood flow	1050	Cardiac output is about 5000 mL/minute, of which 21 percent flows through the kidney. 5000*0.21 = 1050 mL blood/min
Renal plasma flow	578	Renal plasma flow equals the blood flow per minute times the hematocrit. If a person has a hematocrit of 45, then the renal plasma flow is 55 percent. 1050*0.55 = 578 mL plasma/min
Glomerular filtration rate	110	The GFR is the amount of plasma entering Bowman’s capsule per minute. It is the renal plasma flow times the fraction that enters the renal capsule (19 percent). 578*0.19 = 110 mL filtrate/min
Urine	1296 ml/day	The filtrate not recovered by the kidney is the urine that will be eliminated. It is the GFR times the fraction of the filtrate that is not reabsorbed (0.8 percent). 110.008 = 0.9 mL urine /min Multiply urine/min times 60 minutes times 24 hours to get daily urine production. 0.960*24 = 1296 mL/day urine

GFR is influenced by the hydrostatic pressure and colloid osmotic pressure on either side of the capillary membrane of the glomerulus. Recall that filtration occurs as pressure forces fluid and solutes through a semipermeable barrier with the solute movement constrained by particle size. Hydrostatic pressure is the pressure produced by a fluid against a surface. If you have a fluid on both sides of a barrier, both fluids exert a pressure in opposing directions. Net fluid movement will be in the direction of the lower pressure. Osmosis is the movement of solvent (water) across a membrane that is impermeable to a solute in the solution. This creates a pressure, osmotic pressure, which will exist until the solute concentration is the same on both sides of a semipermeable membrane. As long as the concentration differs, water will move. Glomerular filtration occurs when glomerular hydrostatic pressure exceeds the luminal hydrostatic pressure of Bowman’s capsule. There is also an opposing force, the osmotic pressure, which is typically higher in the glomerular capillary.

To understand why this is so, look more closely at the microenvironment on either side of the filtration membrane. You will find osmotic pressure exerted by the solutes inside the lumen of the capillary as well as inside of Bowman’s capsule. Since the filtration membrane limits the size of particles crossing the membrane, the osmotic pressure inside the glomerular capillary is higher than the osmotic pressure in Bowman’s capsule. Recall that cells and the medium-to-large proteins cannot pass between the podocyte processes or through the fenestrations of the capillary endothelial cells. This means that red and white blood cells, platelets, albumins, and other proteins too large to pass through the filter remain in the capillary, creating an average colloid osmotic pressure of 30 mm Hg within the capillary. The absence of proteins in Bowman’s space (the lumen within Bowman’s capsule) results in an osmotic pressure near zero. Thus, the only pressure moving fluid across the capillary wall into the lumen of Bowman’s space is hydrostatic pressure. Hydrostatic (fluid) pressure is sufficient to push water through the membrane despite the osmotic pressure working against it. The sum of all of the influences, both osmotic and hydrostatic, results in a net filtration pressure (NFP) of about 10 mm Hg (Figure 1).

[caption id="" align="aligncenter" width="350"] Figure 1. Net Filtration Pressure. The NFP is the sum of osmotic and hydrostatic pressures.[/caption] A proper concentration of solutes in the blood is important in maintaining osmotic pressure both in the glomerulus and systemically. There are disorders in which too much protein passes through the filtration slits into the kidney filtrate. This excess protein in the filtrate leads to a deficiency of circulating plasma proteins. In turn, the presence of protein in the urine increases its osmolarity; this holds more water in the filtrate and results in an increase in urine volume. Because there is less circulating protein, principally albumin, the osmotic pressure of the blood falls. Less osmotic pressure pulling water into the capillaries tips the balance towards hydrostatic pressure, which tends to push it out of the capillaries. The net effect is that water is lost from the circulation to interstitial tissues and cells. This “plumps up” the tissues and cells, a condition termed systemic edema.

Net Filtration Pressure (NFP)

NFP determines filtration rates through the kidney. It is determined as follows:

NFP = Glomerular blood hydrostatic pressure (GBHP) – [capsular hydrostatic pressure (CHP) + blood colloid osmotic pressure (BCOP)] = 10 mm Hg

That is:

NFP = GBHP – [CHP + BCOP] = 10 mm Hg

Or:

NFP = 55 – [15 + 30] = 10 mm Hg As you can see, there is a low net pressure across the filtration membrane. Intuitively, you should realize that minor changes in osmolarity of the blood or changes in capillary blood pressure result in major changes in the amount of filtrate formed at any given point in time. The kidney is able to cope with a wide range of blood pressures. In large part, this is due to the autoregulatory nature of smooth muscle. When you stretch it, it contracts. Thus, when blood pressure goes up, smooth muscle in the afferent capillaries contracts to limit any increase in blood flow and filtration rate. When blood pressure drops, the same capillaries relax to maintain blood flow and filtration rate. The net result is a relatively steady flow of blood into the glomerulus and a relatively steady filtration rate in spite of significant systemic blood pressure changes. Mean arterial blood pressure is calculated by adding 1/3 of the difference between the systolic and diastolic pressures to the diastolic pressure. Therefore, if the blood pressure is 110/80, the difference between systolic and diastolic pressure is 30. One third of this is 10, which when added to the diastolic pressure of 80 gives a calculated mean arterial pressure of 90 mm Hg. Using arterial pressure for the "GBHP" in the formula for calculating net filtration pressure, if mean arterial pressure is above approximately 60 mm Hg, the pressure will be adequate to maintain glomerular filtration. Blood pressures below this level will impair renal function and cause systemic disorders that are severe enough to threaten survival. This condition is called shock.

Determination of the GFR is one of the tools used to assess the kidney’s excretory function. This is more than just an academic exercise. Since many drugs are excreted in the urine, a decline in renal function can lead to toxic accumulations. Additionally, administration of appropriate drug dosages for those drugs primarily excreted by the kidney requires an accurate assessment of GFR. GFR can be estimated closely by intravenous administration of inulin. Inulin is a plant polysaccharide that is neither reabsorbed nor secreted by the kidney. Its appearance in the urine is directly proportional to the rate at which it is filtered by the renal corpuscle. However, since measuring inulin clearance is cumbersome in the clinical setting, most often, the GFR is estimated by measuring naturally occurring creatinine, a protein-derived molecule produced by muscle metabolism that is not reabsorbed and only slightly secreted by the nephron.

[caption id="attachment_3025" align="aligncenter" width="150"] Watch this CrashCourse video to learn about the production of urine.[/caption]

25.6 Tubular Reabsorption and Tubular Secretion

barkerj1 — Wed, 06 Sep 2017 01:20:10 +0000

Learning Objectives

By the end of this section, you will be able to:

Compare the composition of glomerular filtrate and urine with respect to:
- Glucose
- Protein
- Salts (ions)
- Urea and uric acid
- Water

With up to 180 liters per day passing through the nephrons of the kidney, it is quite obvious that most of that fluid and its contents must be reabsorbed. That recovery occurs in the proximal convoluted tubule (PCT), loop of Henle, distal convoluted tubule (DCT), and the collecting ducts (Table 5 and Figure 1). Various portions of the nephron differ in their capacity to reabsorb water and specific solutes. While much of the reabsorption and secretion occur passively based on concentration gradients, the amount of water that is reabsorbed or lost is tightly regulated. This control is exerted directly by anti-diuretic hormone and aldosterone, and indirectly by renin. Most water is recovered in the PCT, loop of Henle, and DCT. About 10 percent (about 18 L) reaches the collecting ducts. The collecting ducts, under the influence of ADH, can recover almost all of the water passing through them, in cases of dehydration, or almost none of the water, in cases of over-hydration.

[caption id="" align="aligncenter" width="280"] Figure 1. Locations of Secretion and Reabsorption in the Nephron.[/caption]

Substances Secreted or Reabsorbed in the Nephron and Their Locations (Table 5)
Substance	PCT	Loop of Henle	DCT	Collecting ducts
Glucose	Almost 100 percent reabsorbed; secondary active transport with Na⁺
Oligopeptides, proteins, amino acids	Almost 100 percent reabsorbed; symport with Na⁺
Vitamins	Reabsorbed
Lactate	Reabsorbed
Creatinine	Secreted
Urea	50 percent reabsorbed by diffusion; also secreted	Secretion, diffusion in descending limb		Reabsorption in medullary collecting ducts; diffusion
Sodium	65 percent actively reabsorbed	25 percent reabsorbed in thick ascending limb; active transport	5 percent reabsorbed; active	5 percent reabsorbed, stimulated by aldosterone; active
Chloride	Reabsorbed, symport with Na⁺, diffusion	Reabsorbed in thin and thick ascending limb; diffusion in ascending limb	Reabsorbed; diffusion	Reabsorbed; symport
Water	67 percent reabsorbed osmotically with solutes	15 percent reabsorbed in descending limb; osmosis	8 percent reabsorbed if ADH; osmosis	Variable amounts reabsorbed, controlled by ADH, osmosis
Bicarbonate	80–90 percent symport reabsorption with Na⁺	Reabsorbed, symport with Na⁺ and antiport with Cl^–; in ascending limb		Reabsorbed antiport with Cl^–
H⁺	Secreted; diffusion		Secreted; active	Secreted; active
NH₄⁺	Secreted; diffusion		Secreted; diffusion	Secreted; diffusion
HCO₃^–	Reabsorbed; diffusion	Reabsorbed; diffusion in ascending limb	Reabsorbed; diffusion	Reabsorbed; antiport with Na⁺
Some drugs	Secreted		Secreted; active	Secreted; active
Potassium	65 percent reabsorbed; diffusion	20 percent reabsorbed in thick ascending limb; symport	Secreted; active	Secretion controlled by aldosterone; active
Calcium	Reabsorbed; diffusion	Reabsorbed in thick ascending limb; diffusion		Reabsorbed if parathyroid hormone present; active
Magnesium	Reabsorbed; diffusion	Reabsorbed in thick ascending limb; diffusion	Reabsorbed
Phosphate	85 percent reabsorbed, inhibited by parathyroid hormone, diffusion		Reabsorbed; diffusion

Mechanisms of Recovery

Mechanisms by which substances move across membranes for reabsorption or secretion include active transport, diffusion, facilitated diffusion, secondary active transport, and osmosis. These were discussed in an earlier chapter, and you may wish to review them.

Active transport utilizes energy, usually the energy found in a phosphate bond of ATP, to move a substance across a membrane from a low to a high concentration. It is very specific and must have an appropriately shaped receptor for the substance to be transported. An example would be the active transport of Na⁺ out of a cell and K⁺ into a cell by the Na⁺/K⁺ pump. Both ions are moved in opposite directions from a lower to a higher concentration.

Simple diffusion moves a substance from a higher to a lower concentration down its concentration gradient. It requires no energy and only needs to be soluble.

Facilitated diffusion is similar to diffusion in that it moves a substance down its concentration gradient. The difference is that it requires specific membrane receptors or channel proteins for movement. The movement of glucose and, in certain situations, Na⁺ ions, is an example of facilitated diffusion. In some cases of facilitated diffusion, two different substances share the same channel protein port; these mechanisms are described by the terms symport and antiport.

Symport mechanisms move two or more substances in the same direction at the same time, whereas antiport mechanisms move two or more substances in opposite directions across the cell membrane. Both mechanisms may utilize concentration gradients maintained by ATP pumps. This is a mechanism described by the term “secondary active transport.” For example, a Na⁺ ATPase pump on the basilar membrane of a cell may constantly pump Na⁺ out of a cell, maintaining a strong electrochemical gradient. On the opposite (apical) surface, a Na⁺/glucose symport protein channel assists both Na⁺ and glucose into the cell as Na⁺ moves down the concentration gradient created by the basilar Na⁺ ATPase pumps. The glucose molecule then diffuses across the basal membrane by facilitated diffusion into the interstitial space and from there into peritubular capillaries.

Most of the Ca⁺⁺, Na⁺, glucose, and amino acids must be reabsorbed by the nephron to maintain homeostatic plasma concentrations. Other substances, such as urea, K⁺, ammonia (NH₃₎, creatinine, and some drugs are secreted into the filtrate as waste products. Acid–base balance is maintained through actions of the lungs and kidneys: The lungs rid the body of H⁺, whereas the kidneys secrete or reabsorb H⁺ and HCO₃^– (Table 6). In the case of urea, about 50 percent is passively reabsorbed by the PCT. More is recovered by in the collecting ducts as needed. ADH induces the insertion of urea transporters and aquaporin channel proteins.

Substances Filtered and Reabsorbed by the Kidney per 24 Hours (Table 6)
Substance	Amount filtered (grams)	Amount reabsorbed (grams)	Amount in urine (grams)
Water	180 L	179 L	1 L
Proteins	10–20	10–20	0
Chlorine	630	625	5
Sodium	540	537	3
Bicarbonate	300	299.7	0.3
Glucose	180	180	0
Urea	53	28	25
Potassium	28	24	4
Uric acid	8.5	7.7	0.8
Creatinine	1.4	0	1.4

Reabsorption and Secretion in the PCT

The renal corpuscle filters the blood to create a filtrate that differs from blood mainly in the absence of cells and large proteins. From this point to the ends of the collecting ducts, the filtrate or forming urine is undergoing modification through secretion and reabsorption before true urine is produced. The first point at which the forming urine is modified is in the PCT. Here, some substances are reabsorbed, whereas others are secreted. Note the use of the term “reabsorbed.” All of these substances were “absorbed” in the digestive tract—99 percent of the water and most of the solutes filtered by the nephron must be reabsorbed. Water and substances that are reabsorbed are returned to the circulation by the peritubular and vasa recta capillaries. It is important to understand the difference between the glomerulus and the peritubular and vasa recta capillaries. The glomerulus has a relatively high pressure inside its capillaries and can sustain this by dilating the afferent arteriole while constricting the efferent arteriole. This assures adequate filtration pressure even as the systemic blood pressure varies. Movement of water into the peritubular capillaries and vasa recta will be influenced primarily by osmolarity and concentration gradients. Sodium is actively pumped out of the PCT into the interstitial spaces between cells and diffuses down its concentration gradient into the peritubular capillary. As it does so, water will follow passively to maintain an isotonic fluid environment inside the capillary. This is called obligatory water reabsorption, because water is “obliged” to follow the Na⁺ (Figure 2).

[caption id="" align="aligncenter" width="535"] Figure 2. Substances Reabsorbed and Secreted by the PCT.[/caption]

More substances move across the membranes of the PCT than any other portion of the nephron. Many of these substances (amino acids and glucose) use symport mechanisms for transport along with Na⁺. Antiport, active transport, diffusion, and facilitated diffusion are additional mechanisms by which substances are moved from one side of a membrane to the other. Recall that cells have two surfaces: apical and basal. The apical surface is the one facing the lumen or open space of a cavity or tube, in this case, the inside of the PCT. The basal surface of the cell faces the connective tissue base to which the cell attaches (basement membrane) or the cell membrane closer to the basement membrane if there is a stratified layer of cells. In the PCT, there is a single layer of simple cuboidal endothelial cells against the basement membrane. The numbers and particular types of pumps and channels vary between the apical and basilar surfaces (Table 7). A few of the substances that are transported with Na⁺ (symport mechanism) on the apical membrane include Cl^–, Ca⁺⁺, amino acids, glucose, and PO43−. Sodium is actively exchanged for K⁺ using ATP on the basal membrane. Most of the substances transported by a symport mechanism on the apical membrane are transported by facilitated diffusion on the basal membrane. At least three ions, K⁺, Ca⁺⁺, and Mg⁺⁺, diffuse laterally between adjacent cell membranes (transcellular).

Reabsorption of Major Solutes by the PCT (Table 7)
Basal membrane	Apical membrane
Active transport	Symport with Na⁺
Na⁺ (exchange for K⁺)	K⁺
Facilitated diffusion	Cl^–
K⁺	Ca⁺⁺
Cl^–	Mg⁺⁺
Ca⁺⁺	HCO₃^–
HCO₃^–	PO43−
PO43−	Amino acids
Amino acids	Glucose
Glucose	Fructose
Fructose	Galactose
Galactose	Lactate
Lactate	Succinate
Succinate	Citrate
Citrate	Diffusion between nephron cells
	K⁺
	Ca⁺⁺
	Mg⁺⁺

About 67 percent of the water, Na⁺, and K⁺ entering the nephron is reabsorbed in the PCT and returned to the circulation. Almost 100 percent of glucose, amino acids, and other organic substances such as vitamins are normally recovered here. Some glucose may appear in the urine if circulating glucose levels are high enough that all the glucose transporters in the PCT are saturated, so that their capacity to move glucose is exceeded (transport maximum, or T_m). In men, the maximum amount of glucose that can be recovered is about 375 mg/min, whereas in women, it is about 300 mg/min. This recovery rate translates to an arterial concentration of about 200 mg/dL. Though an exceptionally high sugar intake might cause sugar to appear briefly in the urine, the appearance of glycosuria usually points to type I or II diabetes mellitus. The transport of glucose from the lumen of the PCT to the interstitial space is similar to the way it is absorbed by the small intestine. Both glucose and Na⁺ bind simultaneously to the same symport proteins on the apical surface of the cell to be transported in the same direction, toward the interstitial space. Sodium moves down its electrochemical and concentration gradient into the cell and takes glucose with it. Na⁺ is then actively pumped out of the cell at the basal surface of the cell into the interstitial space. Glucose leaves the cell to enter the interstitial space by facilitated diffusion. The energy to move glucose comes from the Na⁺/K⁺ ATPase that pumps Na⁺ out of the cell on the basal surface. Fifty percent of Cl^–and variable quantities of Ca²⁺, Mg²⁺, and HPO₄²⁻ are also recovered in the PCT.

Recovery of bicarbonate (HCO₃^–) is vital to the maintenance of acid–base balance, since it is a very powerful and fast-acting buffer. An important enzyme is used to catalyze this mechanism: carbonic anhydrase (CA). This same enzyme and reaction is used in red blood cells in the transportation of CO₂, in the stomach to produce hydrochloric acid, and in the pancreas to produce HCO₃^– to buffer acidic chyme from the stomach. In the kidney, most of the CA is located within the cell, but a small amount is bound to the brush border of the membrane on the apical surface of the cell. In the lumen of the PCT, HCO₃^– combines with hydrogen ions to form carbonic acid (H₂CO₃). This is enzymatically catalyzed into CO₂ and water, which diffuse across the apical membrane into the cell. Water can move osmotically across the lipid bilayer membrane due to the presence of aquaporin water channels. Inside the cell, the reverse reaction occurs to produce bicarbonate ions (HCO₃^–). These bicarbonate ions are cotransported with Na⁺ across the basal membrane to the interstitial space around the PCT (Figure 3). At the same time this is occurring, a Na⁺/H⁺ antiporter excretes H⁺ into the lumen, while it recovers Na⁺. Note how the hydrogen ion is recycled so that bicarbonate can be recovered. Also, note that a Na⁺ gradient is created by the Na⁺/K⁺ pump.

HCO₃⁻+ H⁺↔ H₂CO₃↔ CO₂ + H₂O

The significant recovery of solutes from the PCT lumen to the interstitial space creates an osmotic gradient that promotes water recovery. As noted before, water moves through channels created by the aquaporin proteins. These proteins are found in all cells in varying amounts and help regulate water movement across membranes and through cells by creating a passageway across the hydrophobic lipid bilayer membrane. Changing the number of aquaporin proteins in membranes of the collecting ducts also helps to regulate the osmolarity of the blood. The movement of many positively charged ions also creates an electrochemical gradient. This charge promotes the movement of negative ions toward the interstitial spaces and the movement of positive ions toward the lumen.

[caption id="" align="aligncenter" width="400"] Figure 3. Reabsorption of Bicarbonate from the PCT.[/caption]

Reabsorption and Secretion in the Loop of Henle

The loop of Henle consists of two sections: thick and thin descending and thin and thick ascending sections. The loops of cortical nephrons do not extend into the renal medulla very far, if at all. Juxtamedullary nephrons have loops that extend variable distances, some very deep into the medulla. The descending and ascending portions of the loop are highly specialized to enable recovery of much of the Na⁺ and water that were filtered by the glomerulus. As the forming urine moves through the loop, the osmolarity will change from isosmotic with blood (about 278–300 mOsmol/kg) to both a very hypertonic solution of about 1200 mOsmol/kg and a very hypotonic solution of about 100 mOsmol/kg. These changes are accomplished by osmosis in the descending limb and active transport in the ascending limb. Solutes and water recovered from these loops are returned to the circulation by way of the vasa recta.

Descending Loop

The majority of the descending loop is comprised of simple squamous epithelial cells; to simplify the function of the loop, this discussion focuses on these cells. These membranes have permanent aquaporin channel proteins that allow unrestricted movement of water from the descending loop into the surrounding interstitium as osmolarity increases from about 300 mOsmol/kg to about 1200 mOsmol/kg. This increase results in reabsorption of up to 15 percent of the water entering the nephron. Modest amounts of urea, Na⁺, and other ions are also recovered here.

Most of the solutes that were filtered in the glomerulus have now been recovered along with a majority of water, about 82 percent. As the forming urine enters the ascending loop, major adjustments will be made to the concentration of solutes to create what you perceive as urine.

Ascending Loop

The ascending loop is made of very short thin and longer thick portions. Once again, to simplify the function, this section only considers the thick portion. The thick portion is lined with simple cuboidal epithelium without a brush border. It is completely impermeable to water due to the absence of aquaporin proteins, but ions, mainly Na⁺, are actively pumped out of the loop by large quantities of the Na^+/K⁺ ATPase pump. This has two significant effects: Removal of Na⁺ while retaining water leads to a hypotonic filtrate by the time it reaches the DCT; pumping Na⁺ into the interstitial space contributes to the hyperosmotic environment in the kidney medulla.

The Na^+/K⁺ ATPase pumps in the basal membrane create an electrochemical gradient, allowing reabsorption of Cl^– by Na⁺/Cl^– symporters in the apical membrane. At the same time that Na⁺ is actively pumped from the basal side of the cell into the interstitial fluid, Cl^– follows the Na⁺from the lumen into the interstitial fluid by a paracellular route between cells through leaky tight junctions. These are found between cells of the ascending loop, where they allow certain solutes to move according to their concentration gradient. Most of the K+ that enters the cell via symporters returns to the lumen (down its concentration gradient) through leaky channels in the apical membrane. Note the environment now created in the interstitial space: With the “back door exiting” K⁺, there is one Na⁺ and two Cl^– ions left in the interstitium surrounding the ascending loop. Therefore, in comparison to the lumen of the loop, the interstitial space is now a negatively charged environment. This negative charge attracts cations (Na⁺, K⁺, Ca²⁺, and Mg²⁺) from the lumen via a paracellular route to the interstitial space and vasa recta.

Countercurrent Multiplier System

The structure of the loop of Henle and associated vasa recta create a countercurrent multiplier system (Figure 4). The countercurrent term comes from the fact that the descending and ascending loops are next to each other and their fluid flows in opposite directions (countercurrent). The multiplier term is due to the action of solute pumps that increase (multiply) the concentrations of urea and Na⁺ deep in the medulla.

[caption id="" align="aligncenter" width="450"] Figure 4. Countercurrent Multiplier System.[/caption]

As discussed above, the ascending loop has many Na⁺ pumps that actively pump Na⁺ out of the forming urine into the interstitial spaces. In addition, collecting ducts have urea pumps that actively pump urea into the interstitial spaces. This results in the recovery of Na⁺ to the circulation via the vasa recta and creates a high osmolar environment in the depths of the medulla.

Ammonia (NH₃) is a toxic byproduct of protein metabolism. It is formed as amino acids are deaminated by liver hepatocytes. That means that the amine group, NH₂, is removed from amino acids as they are broken down. Most of the resulting ammonia is converted into urea by liver hepatocytes. Urea is not only less toxic but is utilized to aid in the recovery of water by the loop of Henle and collecting ducts. At the same time that water is freely diffusing out of the descending loop through aquaporin channels into the interstitial spaces of the medulla, urea freely diffuses into the lumen of the descending loop as it descends deeper into the medulla, much of it to be reabsorbed from the forming urine when it reaches the collecting duct. Thus, the movement of Na⁺ and urea into the interstitial spaces by these mechanisms creates the hyperosmotic environment of the medulla. The net result of this countercurrent multiplier system is to recover both water and Na⁺ in the circulation.

The amino acid glutamine can be deaminated by the kidney. As NH₂ from the amino acid is converted into NH₃ and pumped into the lumen of the PCT, Na⁺ and HCO₃^– are excreted into the interstitial fluid of the renal pyramid via a symport mechanism. When this process occurs in the cells of the PCT, the added benefit is a net loss of a hydrogen ion (complexed to ammonia to form the weak acid NH₄⁺) in the urine and a gain of a bicarbonate ion (HCO₃^–) in the blood. Ammonia and bicarbonate are exchanged in a one-to-one ratio. This exchange is yet another means by which the body can buffer and excrete acid. The presence of aquaporin channels in the descending loop allows prodigious quantities of water to leave the loop and enter the hyperosmolar interstitium of the pyramid, where it is returned to the circulation by the vasa recta. As the loop turns to become the ascending loop, there is an absence of aquaporin channels, so water cannot leave the loop. However, in the basal membrane of cells of the thick ascending loop, ATPase pumps actively remove Na⁺ from the cell. A Na⁺/K⁺/2Cl^–symporter in the apical membrane passively allows these ions to enter the cell cytoplasm from the lumen of the loop down a concentration gradient created by the pump. This mechanism works to dilute the fluid of the ascending loop ultimately to approximately 50–100 mOsmol/L.

At the transition from the DCT to the collecting duct, about 20 percent of the original water is still present and about 10 percent of the sodium. If no other mechanism for water reabsorption existed, about 20–25 liters of urine would be produced. Now consider what is happening in the adjacent capillaries, the vasa recta. They are recovering both solutes and water at a rate that preserves the countercurrent multiplier system. In general, blood flows slowly in capillaries to allow time for exchange of nutrients and wastes. In the vasa recta particularly, this rate of flow is important for two additional reasons. The flow must be slow to allow blood cells to lose and regain water without either crenating or bursting. Second, a rapid flow would remove too much Na⁺ and urea, destroying the osmolar gradient that is necessary for the recovery of solutes and water. Thus, by flowing slowly to preserve the countercurrent mechanism, as the vasa recta descend, Na⁺ and urea are freely able to enter the capillary, while water freely leaves; as they ascend, Na⁺ and urea are secreted into the surrounding medulla, while water reenters and is removed. [caption id="attachment_1336" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about reabsorption![/caption] Reabsorption and Secretion in the Distal Convoluted Tubule

Approximately 80 percent of filtered water has been recovered by the time the dilute forming urine enters the DCT. The DCT will recover another 10–15 percent before the forming urine enters the collecting ducts. Aldosterone increases the amount of Na⁺/K⁺ ATPase in the basal membrane of the DCT and collecting duct. The movement of Na⁺ out of the lumen of the collecting duct creates a negative charge that promotes the movement of Cl^–out of the lumen into the interstitial space by a paracellular route across tight junctions. Peritubular capillaries receive the solutes and water, returning them to the circulation.

Cells of the DCT also recover Ca⁺⁺ from the filtrate. Receptors for parathyroid hormone (PTH) are found in DCT cells and when bound to PTH, induce the insertion of calcium channels on their luminal surface. The channels enhance Ca⁺⁺ recovery from the forming urine. In addition, as Na⁺ is pumped out of the cell, the resulting electrochemical gradient attracts Ca⁺⁺ into the cell. Finally, calcitriol (1,25 dihydroxyvitamin D, the active form of vitamin D) is very important for calcium recovery. It induces the production of calcium-binding proteins that transport Ca⁺⁺ into the cell. These binding proteins are also important for the movement of calcium inside the cell and aid in exocytosis of calcium across the basolateral membrane. Any Ca⁺⁺ not reabsorbed at this point is lost in the urine.

Collecting Ducts and Recovery of Water

Solutes move across the membranes of the collecting ducts, which contain two distinct cell types, principal cells and intercalated cells. A principal cell possesses channels for the recovery or loss of sodium and potassium. An intercalated cell secretes or absorbs acid or bicarbonate. As in other portions of the nephron, there is an array of micromachines (pumps and channels) on display in the membranes of these cells.

Regulation of urine volume and osmolarity are major functions of the collecting ducts. By varying the amount of water that is recovered, the collecting ducts play a major role in maintaining the body’s normal osmolarity. If the blood becomes hyperosmotic, the collecting ducts recover more water to dilute the blood; if the blood becomes hyposmotic, the collecting ducts recover less of the water, leading to concentration of the blood. Another way of saying this is: If plasma osmolarity rises, more water is recovered and urine volume decreases; if plasma osmolarity decreases, less water is recovered and urine volume increases. This function is regulated by the posterior pituitary hormone ADH (vasopressin). With mild dehydration, plasma osmolarity rises slightly. This increase is detected by osmoreceptors in the hypothalamus, which stimulates the release of ADH from the posterior pituitary. If plasma osmolarity decreases slightly, the opposite occurs.

When stimulated by ADH, aquaporin channels are inserted into the apical membrane of principal cells, which line the collecting ducts. As the ducts descend through the medulla, the osmolarity surrounding them increases (due to the countercurrent mechanisms described above). If aquaporin water channels are present, water will be osmotically pulled from the collecting duct into the surrounding interstitial space and into the peritubular capillaries. Therefore, the final urine will be more concentrated. If less ADH is secreted, fewer aquaporin channels are inserted and less water is recovered, resulting in dilute urine. By altering the number of aquaporin channels, the volume of water recovered or lost is altered. This, in turn, regulates the blood osmolarity, blood pressure, and osmolarity of the urine.

As Na⁺ is pumped from the forming urine, water is passively recaptured for the circulation; this preservation of vascular volume is critically important for the maintenance of a normal blood pressure. Aldosterone is secreted by the adrenal cortex in response to angiotensin II stimulation. As an extremely potent vasoconstrictor, angiotensin II functions immediately to increase blood pressure. By also stimulating aldosterone production, it provides a longer-lasting mechanism to support blood pressure by maintaining vascular volume (water recovery).

In addition to receptors for ADH, principal cells have receptors for the steroid hormone aldosterone. While ADH is primarily involved in the regulation of water recovery, aldosterone regulates Na⁺ recovery. Aldosterone stimulates principal cells to manufacture luminal Na⁺ and K⁺ channels as well as Na⁺/K⁺ ATPase pumps on the basal membrane of the cells. When aldosterone output increases, more Na⁺ is recovered from the forming urine and water follows the Na⁺ passively. As the pump recovers Na⁺ for the body, it is also pumping K⁺ into the forming urine, since the pump moves K⁺ in the opposite direction. When aldosterone decreases, more Na⁺ remains in the forming urine and more K⁺ is recovered in the circulation. Symport channels move Na⁺ and Cl^–together. Still other channels in the principal cells secrete K⁺ into the collecting duct in direct proportion to the recovery of Na⁺.

Intercalated cells play significant roles in regulating blood pH. Intercalated cells reabsorb K⁺ and HCO₃^– while secreting H⁺. This function lowers the acidity of the plasma while increasing the acidity of the urine.

26.1 Body Fluids and Fluid Compartments

barkerj1 — Wed, 06 Sep 2017 01:20:12 +0000

Learning Objectives

By the end of this section, you will be able to:

Specify the three primary fluid compartments of the body
Describe the electrolyte composition of the three major fluid compartments in the body

The chemical reactions of life take place in aqueous solutions. The dissolved substances in a solution are called solutes. In the human body, solutes vary in different parts of the body, but may include proteins—including those that transport lipids, carbohydrates, and, very importantly, electrolytes. Often in medicine, a mineral dissociated from a salt that carries an electrical charge (an ion) is called and electrolyte. For instance, sodium ions (Na⁺) and chloride ions (Cl^-) are often referred to as electrolytes. In the body, water moves through semi-permeable membranes of cells and from one compartment of the body to another by a process called osmosis. Osmosis is basically the diffusion of water from regions of higher concentration to regions of lower concentration, along an osmotic gradient across a semi-permeable membrane. As a result, water will move into and out of cells and tissues, depending on the relative concentrations of the water and solutes found there. An appropriate balance of solutes inside and outside of cells must be maintained to ensure normal function.

Body Water Content

Human beings are mostly water, ranging from about 75 percent of body mass in infants to about 50–60 percent in adult men and women, to as low as 45 percent in old age. The percent of body water changes with development, because the proportions of the body given over to each organ and to muscles, fat, bone, and other tissues change from infancy to adulthood (Figure 1). Your brain and kidneys have the highest proportions of water, which composes 80–85 percent of their masses. In contrast, teeth have the lowest proportion of water, at 8–10 percent.

[caption id="" align="aligncenter" width="450"] Figure 1. Water Content of the Body’s Organs and Tissues. Water content varies in different body organs and tissues, from as little as 8 percent in the teeth to as much as 85 percent in the brain.[/caption]

Fluid Compartments

Body fluids can be discussed in terms of their specific fluid compartment, a location that is largely separate from another compartment by some form of a physical barrier. The intracellular fluid (ICF) compartment is the system that includes all fluid enclosed in cells by their plasma membranes. Extracellular fluid (ECF) surrounds all cells in the body. Extracellular fluid has two primary constituents: the fluid component of the blood (called plasma) and the interstitial fluid (IF) that surrounds all cells not in the blood (Figure 2).

[caption id="" align="aligncenter" width="380"] Figure 2. Fluid Compartments in the Human Body. The intracellular fluid (ICF) is the fluid within cells. The interstitial fluid (IF) is part of the extracellular fluid (ECF) between the cells. Blood plasma is the second part of the ECF. Materials travel between cells and the plasma in capillaries through the IF.[/caption]

Intracellular Fluid

The ICF lies within cells and is the principal component of the cytosol/cytoplasm. The ICF makes up about 60 percent of the total water in the human body, and in an average-size adult male, the ICF accounts for about 25 liters (seven gallons) of fluid (Figure 3). This fluid volume tends to be very stable, because the amount of water in living cells is closely regulated. If the amount of water inside a cell falls to a value that is too low, the cytosol becomes too concentrated with solutes to carry on normal cellular activities; if too much water enters a cell, the cell may burst and be destroyed.

[caption id="" align="aligncenter" width="380"] Figure 3. A Pie Graph Showing the Proportion of Total Body Fluid in Each of the Body’s Fluid Compartments. Most of the water in the body is intracellular fluid. The second largest volume is the interstitial fluid, which surrounds cells that are not blood cells.[/caption]

Extracellular Fluid

The ECF accounts for the other one-third of the body’s water content. Approximately 20 percent of the ECF is found in plasma. Plasma travels through the body in blood vessels and transports a range of materials, including blood cells, proteins (including clotting factors and antibodies), electrolytes, nutrients, gases, and wastes. Gases, nutrients, and waste materials travel between capillaries and cells through the IF. Cells are separated from the IF by a selectively permeable cell membrane that helps regulate the passage of materials between the IF and the interior of the cell. The body has other water-based ECF. These include the cerebrospinal fluid that bathes the brain and spinal cord, lymph, the synovial fluid in joints, the pleural fluid in the pleural cavities, the pericardial fluid in the cardiac sac, the peritoneal fluid in the peritoneal cavity, and the aqueous humor of the eye. Because these fluids are outside of cells, these fluids are also considered components of the ECF compartment.

Composition of Body Fluids

The compositions of the two components of the ECF—plasma and IF—are more similar to each other than either is to the ICF (Figure 4). Blood plasma has high concentrations of sodium, chloride, bicarbonate, and protein. The IF has high concentrations of sodium, chloride, and bicarbonate, but a relatively lower concentration of protein. In contrast, the ICF has elevated amounts of potassium, phosphate, magnesium, and protein. Overall, the ICF contains high concentrations of potassium and phosphate (HPO42−HPO42−), whereas both plasma and the ECF contain high concentrations of sodium and chloride.

[caption id="" align="aligncenter" width="380"] Figure 4. The Concentrations of Different Elements in Key Bodily Fluids. The graph shows the composition of the ICF, IF, and plasma. The compositions of plasma and IF are similar to one another but are quite different from the composition of the ICF.[/caption]

[caption id="" align="aligncenter" width="120"] Watch this video to learn more about body fluids, fluid compartments, and electrolytes.[/caption]

Most body fluids are neutral in charge. Thus, cations, or positively charged ions, and anions, or negatively charged ions, are balanced in fluids. As seen in the previous graph, sodium (Na⁺) ions and chloride (Cl^-) ions are concentrated in the ECF of the body, whereas potassium (K⁺) ions are concentrated inside cells. Although sodium and potassium can “leak” through “pores” into and out of cells, respectively, the high levels of potassium and low levels of sodium in the ICF are maintained by sodium-potassium pumps in the cell membranes. These pumps use the energy supplied by ATP to pump sodium out of the cell and potassium into the cell (Figure 5).

[caption id="" align="aligncenter" width="520"] Figure 5. The Sodium-Potassium Pump. The sodium-potassium pump is powered by ATP to transfer sodium out of the cytoplasm and into the ECF. The pump also transfers potassium out of the ECF and into the cytoplasm. (credit: modification of work by Mariana Ruiz Villarreal)[/caption]

Fluid Movement between Compartments

Hydrostatic pressure, the force exerted by a fluid against a wall, causes movement of fluid between compartments. The hydrostatic pressure of blood is the pressure exerted by blood against the walls of the blood vessels by the pumping action of the heart. In capillaries, hydrostatic pressure (also known as capillary blood pressure) is higher than the opposing “colloid osmotic pressure” in blood—a “constant” pressure primarily produced by circulating albumin—at the arteriolar end of the capillary (Figure 6). This pressure forces plasma and nutrients out of the capillaries and into surrounding tissues. Fluid and the cellular wastes in the tissues enter the capillaries at the venule end, where the hydrostatic pressure is less than the osmotic pressure in the vessel. Filtration pressure squeezes fluid from the plasma in the blood to the IF surrounding the tissue cells. The surplus fluid in the interstitial space that is not returned directly back to the capillaries is drained from tissues by the lymphatic system, and then re-enters the vascular system at the subclavian veins.

[caption id="" align="aligncenter" width="480"] Figure 6. Capillary Exchange. Net filtration occurs near the arterial end of the capillary since capillary hydrostatic pressure (CHP) is greater than blood colloidal osmotic pressure (BCOP). There is no net movement of fluid near the midpoint of the capillary since CHP = BCOP. Net reabsorption occurs near the venous end of the capillary since BCOP is greater than CHP.[/caption]

Hydrostatic pressure is especially important in governing the movement of water in the nephrons of the kidneys to ensure proper filtering of the blood to form urine. As hydrostatic pressure in the kidneys increases, the amount of water leaving the capillaries also increases, and more urine filtrate is formed. If hydrostatic pressure in the kidneys drops too low, as can happen in dehydration, the functions of the kidneys will be impaired, and less nitrogenous wastes will be removed from the bloodstream. Extreme dehydration can result in kidney failure. Fluid also moves between compartments along an osmotic gradient. Recall that an osmotic gradient is produced by the difference in concentration of all solutes on either side of a semi-permeable membrane. The magnitude of the osmotic gradient is proportional to the difference in the concentration of solutes on one side of the cell membrane to that on the other side. Water will move by osmosis from the side where its concentration is high (and the concentration of solute is low) to the side of the membrane where its concentration is low (and the concentration of solute is high). In the body, water moves by osmosis from plasma to the IF (and the reverse) and from the IF to the ICF (and the reverse). In the body, water moves constantly into and out of fluid compartments as conditions change in different parts of the body. For example, if you are sweating, you will lose water through your skin. Sweating depletes your tissues of water and increases the solute concentration in those tissues. As this happens, water diffuses from your blood into sweat glands and surrounding skin tissues that have become dehydrated because of the osmotic gradient. Additionally, as water leaves the blood, it is replaced by the water in other tissues throughout your body that are not dehydrated. If this continues, dehydration spreads throughout the body. When a dehydrated person drinks water and rehydrates, the water is redistributed by the same gradient, but in the opposite direction, replenishing water in all of the tissues.

Solute Movement between Compartments

The movement of some solutes between compartments is active, which consumes energy and is an active transport process, whereas the movement of other solutes is passive, which does not require energy. Active transport allows cells to move a specific substance against its concentration gradient through a membrane protein, requiring energy in the form of ATP. For example, the sodium-potassium pump employs active transport to pump sodium out of cells and potassium into cells, with both substances moving against their concentration gradients. Passive transport of a molecule or ion depends on its ability to pass through the membrane, as well as the existence of a concentration gradient that allows the molecules to diffuse from an area of higher concentration to an area of lower concentration. Some molecules, like gases, lipids, and water itself (which also utilizes water channels in the membrane called aquaporins), slip fairly easily through the cell membrane; others, including polar molecules like glucose, amino acids, and ions do not. Some of these molecules enter and leave cells using facilitated transport, whereby the molecules move down a concentration gradient through specific protein channels in the membrane. This process does not require energy. For example, glucose is transferred into cells by glucose transporters that use facilitated transport (Figure 7).

[caption id="" align="aligncenter" width="480"] Figure 7. Facilitated Diffusion. Glucose molecules use facilitated diffusion to move down a concentration gradient through the carrier protein channels in the membrane. (credit: modification of work by Mariana Ruiz Villarreal)[/caption]

26.2 Water Balance

barkerj1 — Wed, 06 Sep 2017 01:20:15 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the hormonal control of urine volume and composition

On a typical day, the average adult will take in about 2500 mL (almost 3 quarts) of aqueous fluids. Although most of the intake comes through the digestive tract, about 230 mL (8 ounces) per day is generated metabolically, in the last steps of aerobic respiration. Additionally, each day about the same volume (2500 mL) of water leaves the body by different routes; most of this lost water is removed as urine. The kidneys also can adjust blood volume though mechanisms that draw water out of the filtrate and urine. The kidneys can regulate water levels in the body; they conserve water if you are dehydrated, and they can make urine more dilute to expel excess water if necessary. Water is lost through the skin through evaporation from the skin surface without overt sweating and from air expelled from the lungs. This type of water loss is called insensible water loss because a person is usually unaware of it.

Regulation of Water Intake

Osmolality is the ratio of solutes in a solution to a volume of solvent in a solution. Plasma osmolality is thus the ratio of solutes to water in blood plasma. A person’s plasma osmolality value reflects his or her state of hydration. A healthy body maintains plasma osmolality within a narrow range, by employing several mechanisms that regulate both water intake and output.

Drinking water is considered voluntary. So how is water intake regulated by the body? Consider someone who is experiencing dehydration, a net loss of water that results in insufficient water in blood and other tissues. The water that leaves the body, as exhaled air, sweat, or urine, is ultimately extracted from blood plasma. As the blood becomes more concentrated, the thirst response—a sequence of physiological processes—is triggered (Figure 1). Osmoreceptors are sensory receptors in the thirst center in the hypothalamus that monitor the concentration of solutes (osmolality) of the blood. If blood osmolality increases above its ideal value, the hypothalamus transmits signals that result in a conscious awareness of thirst. The person should (and normally does) respond by drinking water. The hypothalamus of a dehydrated person also releases antidiuretic hormone (ADH) through the posterior pituitary gland. ADH signals the kidneys to recover water from urine, effectively diluting the blood plasma. To conserve water, the hypothalamus of a dehydrated person also sends signals via the sympathetic nervous system to the salivary glands in the mouth. The signals result in a decrease in watery, serous output (and an increase in stickier, thicker mucus output). These changes in secretions result in a “dry mouth” and the sensation of thirst.

[caption id="" align="aligncenter" width="380"] Figure 1. A Flowchart Showing the Thirst Response. The thirst response begins when osmoreceptors detect a decrease in water levels in the blood.[/caption]

Decreased blood volume resulting from water loss has two additional effects. First, baroreceptors, blood-pressure receptors in the arch of the aorta and the carotid arteries in the neck, detect a decrease in blood pressure that results from decreased blood volume. The heart is ultimately signaled to increase its rate and/or strength of contractions to compensate for the lowered blood pressure.

Second, the kidneys have a renin-angiotensin hormonal system that increases the production of the active form of the hormone angiotensin II, which helps stimulate thirst, but also stimulates the release of the hormone aldosterone from the adrenal glands. Aldosterone increases the reabsorption of sodium in the distal tubules of the nephrons in the kidneys, and water follows this reabsorbed sodium back into the blood.

If adequate fluids are not consumed, dehydration results and a person’s body contains too little water to function correctly. A person who repeatedly vomits or who has diarrhea may become dehydrated, and infants, because their body mass is so low, can become dangerously dehydrated very quickly. Endurance athletes such as distance runners often become dehydrated during long races. Dehydration can be a medical emergency, and a dehydrated person may lose consciousness, become comatose, or die, if his or her body is not rehydrated quickly.

Regulation of Water Output

Water loss from the body occurs predominantly through the renal system. A person produces an average of 1.5 liters (1.6 quarts) of urine per day. Although the volume of urine varies in response to hydration levels, there is a minimum volume of urine production required for proper bodily functions. The kidney excretes 100 to 1200 milliosmoles of solutes per day to rid the body of a variety of excess salts and other water-soluble chemical wastes, most notably creatinine, urea, and uric acid. Failure to produce the minimum volume of urine means that metabolic wastes cannot be effectively removed from the body, a situation that can impair organ function. The minimum level of urine production necessary to maintain normal function is about 0.47 liters (0.5 quarts) per day.

The kidneys also must make adjustments in the event of ingestion of too much fluid. Diuresis, which is the production of urine in excess of normal levels, begins about 30 minutes after drinking a large quantity of fluid. Diuresis reaches a peak after about 1 hour, and normal urine production is reestablished after about 3 hours.

Role of ADH

Antidiuretic hormone (ADH), also known as vasopressin, controls the amount of water reabsorbed from the collecting ducts and tubules in the kidney. This hormone is produced in the hypothalamus and is delivered to the posterior pituitary for storage and release (Figure 2). When the osmoreceptors in the hypothalamus detect an increase in the concentration of blood plasma, the hypothalamus signals the release of ADH from the posterior pituitary into the blood.

[caption id="" align="aligncenter" width="450"] Figure 2. Antidiuretic Hormone (ADH). ADH is produced in the hypothalamus and released by the posterior pituitary gland. It causes the kidneys to retain water, constricts arterioles in the peripheral circulation, and affects some social behaviors in mammals.[/caption]

ADH has two major effects. It constricts the arterioles in the peripheral circulation, which reduces the flow of blood to the extremities and thereby increases the blood supply to the core of the body. ADH also causes the epithelial cells that line the renal collecting tubules to move water channel proteins, called aquaporins, from the interior of the cells to the apical surface, where these proteins are inserted into the cell membrane (Figure 3). The result is an increase in the water permeability of these cells and, thus, a large increase in water passage from the urine through the walls of the collecting tubules, leading to more reabsorption of water into the bloodstream. When the blood plasma becomes less concentrated and the level of ADH decreases, aquaporins are removed from collecting tubule cell membranes, and the passage of water out of urine and into the blood decreases.

[caption id="" align="aligncenter" width="480"] Figure 3. Aquaporins. The binding of ADH to receptors on the cells of the collecting tubule results in aquaporins being inserted into the plasma membrane, shown in the lower cell. This dramatically increases the flow of water out of the tubule and into the bloodstream.[/caption]

A diuretic is a compound that increases urine output and therefore decreases water conservation by the body. Diuretics are used to treat hypertension, congestive heart failure, and fluid retention associated with menstruation. Alcohol acts as a diuretic by inhibiting the release of ADH. Additionally, caffeine, when consumed in high concentrations, acts as a diuretic.

26.3 Electrolyte Balance

barkerj1 — Wed, 06 Sep 2017 01:20:16 +0000

Learning Objectives

By the end of this section, you will be able to:

Specify four functions of ions in the body
Describe the hormonal control of urine volume and composition by aldosterone, renin, and angiotensin II

The body contains a large variety of ions, or electrolytes, which perform a variety of functions. Some ions assist in the transmission of electrical impulses along cell membranes in neurons and muscles. Other ions help to stabilize protein structures in enzymes. Still others aid in releasing hormones from endocrine glands. All of the ions in plasma contribute to the osmotic balance that controls the movement of water between cells and their environment.

Electrolytes in living systems include sodium, potassium, chloride, bicarbonate, calcium, phosphate, magnesium, copper, zinc, iron, manganese, molybdenum, copper, and chromium. In terms of body functioning, six electrolytes are most important: sodium, potassium, chloride, bicarbonate, calcium, and phosphate.

Roles of Electrolytes

These six ions aid in nerve excitability, endocrine secretion, membrane permeability, buffering body fluids, and controlling the movement of fluids between compartments. These ions enter the body through the digestive tract. More than 90 percent of the calcium and phosphate that enters the body is incorporated into bones and teeth, with bone serving as a mineral reserve for these ions. In the event that calcium and phosphate are needed for other functions, bone tissue can be broken down to supply the blood and other tissues with these minerals. Phosphate is a normal constituent of nucleic acids; hence, blood levels of phosphate will increase whenever nucleic acids are broken down.

Excretion of ions occurs mainly through the kidneys, with lesser amounts lost in sweat and in feces. Excessive sweating may cause a significant loss, especially of sodium and chloride. Severe vomiting or diarrhea will cause a loss of chloride and bicarbonate ions. Adjustments in respiratory and renal functions allow the body to regulate the levels of these ions in the ECF.

Table 1 lists the reference values for blood plasma, cerebrospinal fluid (CSF), and urine for the six ions addressed in this section. In a clinical setting, sodium, potassium, and chloride are typically analyzed in a routine urine sample. In contrast, calcium and phosphate analysis requires a collection of urine across a 24-hour period, because the output of these ions can vary considerably over the course of a day. Urine values reflect the rates of excretion of these ions. Bicarbonate is the one ion that is not normally excreted in urine; instead, it is conserved by the kidneys for use in the body’s buffering systems.

Electrolyte and Ion Reference Values (Table 1)
Name	Chemical symbol	Plasma	CSF	Urine
Sodium	Na⁺	136.00–146.00 (mM)	138.00–150.00 (mM)	40.00–220.00 (mM)
Potassium	K⁺	3.50–5.00 (mM)	0.35–3.5 (mM)	25.00–125.00 (mM)
Chloride	Cl^-	98.00–107.00 (mM)	118.00–132.00 (mM)	110.00–250.00 (mM)
Bicarbonate	HCO₃^-	22.00–29.00 (mM)	------	------
Calcium	Ca²⁺	2.15–2.55 (mmol/day)	------	Up to 7.49 (mmol/day)
Phosphate	HPO4²⁻ HPO4²⁻	0.81–1.45 (mmol/day)	------	12.90–42.00 (mmol/day)

Sodium

Sodium is the major cation of the extracellular fluid. It is responsible for one-half of the osmotic pressure gradient that exists between the interior of cells and their surrounding environment. People eating a typical Western diet, which is very high in NaCl, routinely take in 130 to 160 mmol/day of sodium, but humans require only 1 to 2 mmol/day. This excess sodium appears to be a major factor in hypertension (high blood pressure) in some people. Excretion of sodium is accomplished primarily by the kidneys. Sodium is freely filtered through the glomerular capillaries of the kidneys, and although much of the filtered sodium is reabsorbed in the proximal convoluted tubule, some remains in the filtrate and urine, and is normally excreted.

Hyponatremia is a lower-than-normal concentration of sodium, usually associated with excess water accumulation in the body, which dilutes the sodium. An absolute loss of sodium may be due to a decreased intake of the ion coupled with its continual excretion in the urine. An abnormal loss of sodium from the body can result from several conditions, including excessive sweating, vomiting, or diarrhea; the use of diuretics; excessive production of urine, which can occur in diabetes; and acidosis, either metabolic acidosis or diabetic ketoacidosis.

A relative decrease in blood sodium can occur because of an imbalance of sodium in one of the body’s other fluid compartments, like IF, or from a dilution of sodium due to water retention related to edema or congestive heart failure. At the cellular level, hyponatremia results in increased entry of water into cells by osmosis, because the concentration of solutes within the cell exceeds the concentration of solutes in the now-diluted ECF. The excess water causes swelling of the cells; the swelling of red blood cells—decreasing their oxygen-carrying efficiency and making them potentially too large to fit through capillaries—along with the swelling of neurons in the brain can result in brain damage or even death.

Hypernatremia is an abnormal increase of blood sodium. It can result from water loss from the blood, resulting in the hemoconcentration of all blood constituents. Hormonal imbalances involving anti-diuretic hormone or aldosterone may also result in higher-than-normal sodium values.

Potassium

Potassium is the major intracellular cation. It helps establish the resting membrane potential in neurons and muscle fibers after membrane depolarization and action potentials. In contrast to sodium, potassium has very little effect on osmotic pressure. The low levels of potassium in blood and CSF are due to the sodium-potassium pumps in cell membranes, which maintain the normal potassium concentration gradients between the ICF and ECF. The recommendation for daily intake/consumption of potassium is 4700 mg. Potassium is excreted, both actively and passively, through the renal tubules, especially the distal convoluted tubule and collecting ducts. Potassium participates in the exchange with sodium in the renal tubules under the influence of aldosterone, which also relies on basolateral sodium-potassium pumps.

Hypokalemia is an abnormally low potassium blood level. Similar to the situation with hyponatremia, hypokalemia can occur because of either an absolute reduction of potassium in the body or a relative reduction of potassium in the blood due to the redistribution of potassium. An absolute loss of potassium can arise from decreased intake, frequently related to starvation. It can also come about from vomiting, diarrhea, or alkalosis.

Some insulin-dependent diabetic patients experience a relative reduction of potassium in the blood from the redistribution of potassium. When insulin is administered and glucose is taken up by cells, potassium passes through the cell membrane along with glucose, decreasing the amount of potassium in the blood and IF, which can cause hyperpolarization of the cell membranes of neurons, reducing their responses to stimuli. Hyperkalemia, an elevated potassium blood level, also can impair the function of skeletal muscles, the nervous system, and the heart. Hyperkalemia can result from increased dietary intake of potassium. In such a situation, potassium from the blood ends up in the ECF in abnormally high concentrations. This can result in a partial depolarization (excitation) of the plasma membrane of skeletal muscle fibers, neurons, and cardiac cells of the heart, and can also lead to an inability of cells to repolarize. For the heart, this means that it won’t relax after a contraction, and will effectively “seize” and stop pumping blood, which is fatal within minutes. Because of such effects on the nervous system, a person with hyperkalemia may also exhibit mental confusion, numbness, and weakened respiratory muscles.

Chloride

Chloride is the predominant extracellular anion. Chloride is a major contributor to the osmotic pressure gradient between the ICF and ECF, and plays an important role in maintaining proper hydration. Chloride functions to balance cations in the ECF, maintaining the electrical neutrality of this fluid. The paths of secretion and reabsorption of chloride ions in the renal system follow the paths of sodium ions.

Hypochloremia, or lower-than-normal blood chloride levels, can occur because of defective renal tubular absorption. Vomiting, diarrhea, and metabolic acidosis can also lead to hypochloremia. Hyperchloremia, or higher-than-normal blood chloride levels, can occur due to dehydration, excessive intake of dietary salt (NaCl) or swallowing of sea water, aspirin intoxication, congestive heart failure, and the hereditary, chronic lung disease, cystic fibrosis. In people who have cystic fibrosis, chloride levels in sweat are two to five times those of normal levels, and analysis of sweat is often used in the diagnosis of the disease.

[caption id="" align="aligncenter" width="120"] Watch this video to see an explanation of the effect of seawater on humans. What effect does drinking seawater have on the body?[/caption]

Bicarbonate

Bicarbonate is the second most abundant anion in the blood. Its principal function is to maintain your body’s acid-base balance by being part of buffer systems. This role will be discussed in a different section.

Bicarbonate ions result from a chemical reaction that starts with carbon dioxide (CO₂) and water, two molecules that are produced at the end of aerobic metabolism. Only a small amount of CO₂ can be dissolved in body fluids. Thus, over 90 percent of the CO₂ is converted into bicarbonate ions, HCO₃^–, through the following reactions:

CO₂ + H₂O ↔ H₂CO₃↔ H₂CO₃^- + H⁺

The bidirectional arrows indicate that the reactions can go in either direction, depending on the concentrations of the reactants and products. Carbon dioxide is produced in large amounts in tissues that have a high metabolic rate. Carbon dioxide is converted into bicarbonate in the cytoplasm of red blood cells through the action of an enzyme called carbonic anhydrase. Bicarbonate is transported in the blood. Once in the lungs, the reactions reverse direction, and CO₂ is regenerated from bicarbonate to be exhaled as metabolic waste.

Calcium

About two pounds of calcium in your body are bound up in bone, which provides hardness to the bone and serves as a mineral reserve for calcium and its salts for the rest of the tissues. Teeth also have a high concentration of calcium within them. A little more than one-half of blood calcium is bound to proteins, leaving the rest in its ionized form. Calcium ions, Ca²⁺, are necessary for muscle contraction, enzyme activity, and blood coagulation. In addition, calcium helps to stabilize cell membranes and is essential for the release of neurotransmitters from neurons and of hormones from endocrine glands.

Calcium is absorbed through the intestines under the influence of activated vitamin D. A deficiency of vitamin D leads to a decrease in absorbed calcium and, eventually, a depletion of calcium stores from the skeletal system, potentially leading to rickets in children and osteomalacia in adults, contributing to osteoporosis.

Hypocalcemia, or abnormally low calcium blood levels, is seen in hypoparathyroidism, which may follow the removal of the thyroid gland, because the four nodules of the parathyroid gland are embedded in it. Hypercalcemia, or abnormally high calcium blood levels, is seen in primary hyperparathyroidism. Some malignancies may also result in hypercalcemia.

Phosphate

Phosphate is present in the body in three ionic forms: H₂PO₄⁻, HPO₄^2-, and PO₄³⁻. The most common form is HPO₄²⁻ HPO₄²⁻. Bone and teeth bind up 85 percent of the body’s phosphate as part of calcium-phosphate salts. Phosphate is found in phospholipids, such as those that make up the cell membrane, and in ATP, nucleotides, and buffers.

Hypophosphatemia, or abnormally low phosphate blood levels, occurs with heavy use of antacids, during alcohol withdrawal, and during malnourishment. In the face of phosphate depletion, the kidneys usually conserve phosphate, but during starvation, this conservation is impaired greatly. Hyperphosphatemia, or abnormally increased levels of phosphates in the blood, occurs if there is decreased renal function or in cases of acute lymphocytic leukemia. Additionally, because phosphate is a major constituent of the ICF, any significant destruction of cells can result in dumping of phosphate into the ECF.

Regulation of Sodium and Potassium

Sodium is reabsorbed from the renal filtrate, and potassium is excreted into the filtrate in the renal collecting tubule. The control of this exchange is governed principally by two hormones—aldosterone and angiotensin II.

Aldosterone

Recall that aldosterone increases the excretion of potassium and the reabsorption of sodium in the distal tubule. Aldosterone is released if blood levels of potassium increase, if blood levels of sodium severely decrease, or if blood pressure decreases. Its net effect is to conserve and increase water levels in the plasma by reducing the excretion of sodium, and thus water, from the kidneys. In a negative feedback loop, increased osmolality of the ECF (which follows aldosterone-stimulated sodium absorption) inhibits the release of the hormone (Figure 1).

[caption id="" align="aligncenter" width="250"] Figure 1. The Aldosterone Feedback Loop. Aldosterone, which is released by the adrenal gland, facilitates reabsorption of Na⁺ and thus the reabsorption of water.[/caption]

Angiotensin II

Angiotensin II causes vasoconstriction and an increase in systemic blood pressure. This action increases the glomerular filtration rate, resulting in more material filtered out of the glomerular capillaries and into Bowman’s capsule. Angiotensin II also signals an increase in the release of aldosterone from the adrenal cortex.

In the distal convoluted tubules and collecting ducts of the kidneys, aldosterone stimulates the synthesis and activation of the sodium-potassium pump (Figure 2). Sodium passes from the filtrate, into and through the cells of the tubules and ducts, into the ECF and then into capillaries. Water follows the sodium due to osmosis. Thus, aldosterone causes an increase in blood sodium levels and blood volume. Aldosterone’s effect on potassium is the reverse of that of sodium; under its influence, excess potassium is pumped into the renal filtrate for excretion from the body.

[caption id="" align="aligncenter" width="550"] Figure 2. The Renin-Angiotensin System. Angiotensin II stimulates the release of aldosterone from the adrenal cortex.[/caption]

Regulation of Calcium and Phosphate

Calcium and phosphate are both regulated through the actions of three hormones: parathyroid hormone (PTH), dihydroxyvitamin D (calcitriol), and calcitonin. All three are released or synthesized in response to the blood levels of calcium.

PTH is released from the parathyroid gland in response to a decrease in the concentration of blood calcium. The hormone activates osteoclasts to break down bone matrix and release inorganic calcium-phosphate salts. PTH also increases the gastrointestinal absorption of dietary calcium by converting vitamin D into dihydroxyvitamin D (calcitriol), an active form of vitamin D that intestinal epithelial cells require to absorb calcium.

PTH raises blood calcium levels by inhibiting the loss of calcium through the kidneys. PTH also increases the loss of phosphate through the kidneys.

Calcitonin is released from the thyroid gland in response to elevated blood levels of calcium. The hormone increases the activity of osteoblasts, which remove calcium from the blood and incorporate calcium into the bony matrix.

26.4 Acid-Base Balance

barkerj1 — Wed, 06 Sep 2017 01:20:21 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the sources of acids and bases in the body
Describe three mechanisms by which the body regulates its pH
Describe the carbonic acid-bicarbonate buffer system and specify two other chemical buffer systems

Proper physiological functioning depends on a very tight balance between the concentrations of acids and bases in the blood. Acid-balance balance is measured using the pH scale, as shown in Figure 1. A variety of buffering systems permits blood and other bodily fluids to maintain a narrow pH range, even in the face of perturbations. A buffer is a chemical system that prevents a radical change in fluid pH by dampening the change in hydrogen ion concentrations in the case of excess acid or base. Most commonly, the substance that absorbs the ions is either a weak acid, which takes up hydroxyl ions, or a weak base, which takes up hydrogen ions.

[caption id="" align="aligncenter" width="320"] Figure 1. The pH Scale. This chart shows where many common substances fall on the pH scale.[/caption]

Buffer Systems in the Body

The buffer systems in the human body are extremely efficient, and different systems work at different rates. It takes only seconds for the chemical buffers in the blood to make adjustments to pH. The respiratory tract can adjust the blood pH upward in minutes by exhaling CO₂ from the body. The renal system can also adjust blood pH through the excretion of hydrogen ions (H⁺) and the conservation of bicarbonate, but this process takes hours to days to have an effect.

The buffer systems functioning in blood plasma include plasma proteins, phosphate, and bicarbonate and carbonic acid buffers. The kidneys help control acid-base balance by excreting hydrogen ions and generating bicarbonate that helps maintain blood plasma pH within a normal range. Protein buffer systems work predominantly inside cells.

Protein Buffers in Blood Plasma and Cells

Nearly all proteins can function as buffers. Proteins are made up of amino acids, which contain positively charged amino groups and negatively charged carboxyl groups. The charged regions of these molecules can bind hydrogen and hydroxyl ions, and thus function as buffers. Buffering by proteins accounts for two-thirds of the buffering power of the blood and most of the buffering within cells.

Hemoglobin as a Buffer

Hemoglobin is the principal protein inside of red blood cells and accounts for one-third of the mass of the cell. During the conversion of CO₂ into bicarbonate, hydrogen ions liberated in the reaction are buffered by hemoglobin, which is reduced by the dissociation of oxygen. This buffering helps maintain normal pH. The process is reversed in the pulmonary capillaries to re-form CO₂, which then can diffuse into the air sacs to be exhaled into the atmosphere. This process is discussed in detail in the chapter on the respiratory system.

Phosphate Buffer

Phosphates are found in the blood in two forms: sodium dihydrogen phosphate (Na₂H₂PO₄⁻), which is a weak acid, and sodium monohydrogen phosphate (Na₂HPO₄^2-), which is a weak base. When Na₂HPO₄^2- comes into contact with a strong acid, such as HCl, the base picks up a second hydrogen ion to form the weak acid Na₂H₂PO₄⁻ and sodium chloride, NaCl. When Na₂HPO₄²⁻ (the weak acid) comes into contact with a strong base, such as sodium hydroxide (NaOH), the weak acid reverts back to the weak base and produces water. Acids and bases are still present, but they hold onto the ions.

HCl + Na₂HPO₄→ NaH₂PO₄ + NaCl

(strong acid) + (weak base) → (weak acid) + (salt)

NaOH + NaH₂PO₄→ Na₂HPO₄ + H₂O

(strong base) + (weak acid) → (weak base) + (water)

Bicarbonate-Carbonic Acid Buffer

The bicarbonate-carbonic acid buffer works in a fashion similar to phosphate buffers. The bicarbonate is regulated in the blood by sodium, as are the phosphate ions. When sodium bicarbonate (NaHCO₃), comes into contact with a strong acid, such as HCl, carbonic acid (H₂CO₃), which is a weak acid, and NaCl are formed. When carbonic acid comes into contact with a strong base, such as NaOH, bicarbonate and water are formed.

NaHCO₃ + HCl → H₂CO₃+NaCl

(sodium bicarbonate) + (strong acid) → (weak acid) + (salt)

H₂CO₃ + NaOH → HCO₃^- + H₂O

(weak acid) + (strong base) → (bicarbonate) + (water)

As with the phosphate buffer, a weak acid or weak base captures the free ions, and a significant change in pH is prevented. Bicarbonate ions and carbonic acid are present in the blood in a 20:1 ratio if the blood pH is within the normal range. With 20 times more bicarbonate than carbonic acid, this capture system is most efficient at buffering changes that would make the blood more acidic. This is useful because most of the body’s metabolic wastes, such as lactic acid and ketones, are acids. Carbonic acid levels in the blood are controlled by the expiration of CO₂ through the lungs. In red blood cells, carbonic anhydrase forces the dissociation of the acid, rendering the blood less acidic. Because of this acid dissociation, CO₂ is exhaled (see equations above). The level of bicarbonate in the blood is controlled through the renal system, where bicarbonate ions in the renal filtrate are conserved and passed back into the blood. However, the bicarbonate buffer is the primary buffering system of the IF surrounding the cells in tissues throughout the body.

Respiratory Regulation of Acid-Base Balance

The respiratory system contributes to the balance of acids and bases in the body by regulating the blood levels of carbonic acid (Figure 2). CO₂in the blood readily reacts with water to form carbonic acid, and the levels of CO₂and carbonic acid in the blood are in equilibrium. When the CO₂level in the blood rises (as it does when you hold your breath), the excess CO₂ reacts with water to form additional carbonic acid, lowering blood pH. Increasing the rate and/or depth of respiration (which you might feel the “urge” to do after holding your breath) allows you to exhale more CO₂. The loss of CO₂ from the body reduces blood levels of carbonic acid and thereby adjusts the pH upward, toward normal levels. As you might have surmised, this process also works in the opposite direction. Excessive deep and rapid breathing (as in hyperventilation) rids the blood of CO₂ and reduces the level of carbonic acid, making the blood too alkaline. This brief alkalosis can be remedied by rebreathing air that has been exhaled into a paper bag. Rebreathing exhaled air will rapidly bring blood pH down toward normal.

[caption id="" align="aligncenter" width="280"] Figure 2. Respiratory Regulation of Blood pH. The respiratory system can reduce blood pH by removing CO2 from the blood.[/caption]

The chemical reactions that regulate the levels of CO₂ and carbonic acid occur in the lungs when blood travels through the lung’s pulmonary capillaries. Minor adjustments in breathing are usually sufficient to adjust the pH of the blood by changing how much CO₂ is exhaled. In fact, doubling the respiratory rate for less than 1 minute, removing “extra” CO₂, would increase the blood pH by 0.2. This situation is common if you are exercising strenuously over a period of time. To keep up the necessary energy production, you would produce excess CO₂ (and lactic acid if exercising beyond your aerobic threshold). In order to balance the increased acid production, the respiration rate goes up to remove the CO₂. This helps to keep you from developing acidosis.

The body regulates the respiratory rate by the use of chemoreceptors, which primarily use CO₂ as a signal. Peripheral blood sensors are found in the walls of the aorta and carotid arteries. These sensors signal the brain to provide immediate adjustments to the respiratory rate if CO₂levels rise or fall. Yet other sensors are found in the brain itself. Changes in the pH of CSF affect the respiratory center in the medulla oblongata, which can directly modulate breathing rate to bring the pH back into the normal range.

Hypercapnia, or abnormally elevated blood levels of CO₂, occurs in any situation that impairs respiratory functions, including pneumonia and congestive heart failure. Reduced breathing (hypoventilation) due to drugs such as morphine, barbiturates, or ethanol (or even just holding one’s breath) can also result in hypercapnia. Hypocapnia, or abnormally low blood levels of CO₂, occurs with any cause of hyperventilation that drives off the CO₂, such as salicylate toxicity, elevated room temperatures, fever, or hysteria.

Renal Regulation of Acid-Base Balance

The renal regulation of the body’s acid-base balance addresses the metabolic component of the buffering system. Whereas the respiratory system (together with breathing centers in the brain) controls the blood levels of carbonic acid by controlling the exhalation of CO₂, the renal system controls the blood levels of bicarbonate. A decrease of blood bicarbonate can result from the inhibition of carbonic anhydrase by certain diuretics or from excessive bicarbonate loss due to diarrhea. Blood bicarbonate levels are also typically lower in people who have Addison’s disease (chronic adrenal insufficiency), in which aldosterone levels are reduced, and in people who have renal damage, such as chronic nephritis. Finally, low bicarbonate blood levels can result from elevated levels of ketones (common in unmanaged diabetes mellitus), which bind bicarbonate in the filtrate and prevent its conservation.

Bicarbonate ions, HCO₃^-, found in the filtrate, are essential to the bicarbonate buffer system, yet the cells of the tubule are not permeable to bicarbonate ions. The steps involved in supplying bicarbonate ions to the system are seen in Figure 3 and are summarized below:

Step 1: Sodium ions are reabsorbed from the filtrate in exchange for H⁺ by an antiport mechanism in the apical membranes of cells lining the renal tubule.
Step 2: The cells produce bicarbonate ions that can be shunted to peritubular capillaries.
Step 3: When CO₂ is available, the reaction is driven to the formation of carbonic acid, which dissociates to form a bicarbonate ion and a hydrogen ion.
Step 4: The bicarbonate ion passes into the peritubular capillaries and returns to the blood. The hydrogen ion is secreted into the filtrate, where it can become part of new water molecules and be reabsorbed as such, or removed in the urine.

[caption id="" align="aligncenter" width="550"] Figure 3. Conservation of Bicarbonate in the Kidney. Tubular cells are not permeable to bicarbonate; thus, bicarbonate is conserved rather than reabsorbed. Steps 1 and 2 of bicarbonate conservation are indicated.[/caption]

It is also possible that salts in the filtrate, such as sulfates, phosphates, or ammonia, will capture hydrogen ions. If this occurs, the hydrogen ions will not be available to combine with bicarbonate ions and produce CO₂. In such cases, bicarbonate ions are not conserved from the filtrate to the blood, which will also contribute to a pH imbalance and acidosis.

The hydrogen ions also compete with potassium to exchange with sodium in the renal tubules. If more potassium is present than normal, potassium, rather than the hydrogen ions, will be exchanged, and increased potassium enters the filtrate. When this occurs, fewer hydrogen ions in the filtrate participate in the conversion of bicarbonate into CO₂ and less bicarbonate is conserved. If there is less potassium, more hydrogen ions enter the filtrate to be exchanged with sodium and more bicarbonate is conserved.

Chloride ions are important in neutralizing positive ion charges in the body. If chloride is lost, the body uses bicarbonate ions in place of the lost chloride ions. Thus, lost chloride results in an increased reabsorption of bicarbonate by the renal system.

26.5 Disorders of Acid-Base Balance

barkerj1 — Wed, 06 Sep 2017 01:20:22 +0000

Learning Objectives

By the end of this section, you will be able to:

Define acidosis
Specify two general causes of acidosis
Define alkalosis
Specify two general causes of alkalosis

Normal arterial blood pH is restricted to a very narrow range of 7.35 to 7.45. A person who has a blood pH below 7.35 is considered to be in acidosis (actually, “physiological acidosis,” because blood is not truly acidic until its pH drops below 7), and a continuous blood pH below 7.0 can be fatal. Acidosis has several symptoms, including headache and confusion, and the individual can become lethargic and easily fatigued (Figure 1). A person who has a blood pH above 7.45 is considered to be in alkalosis, and a pH above 7.8 is fatal. Some symptoms of alkalosis include cognitive impairment (which can progress to unconsciousness), tingling or numbness in the extremities, muscle twitching and spasm, and nausea and vomiting. Both acidosis and alkalosis can be caused by either metabolic or respiratory disorders.

As discussed earlier in this chapter, the concentration of carbonic acid in the blood is dependent on the level of CO₂ in the body and the amount of CO₂ gas exhaled through the lungs. Thus, the respiratory contribution to acid-base balance is usually discussed in terms of CO₂ (rather than of carbonic acid). Remember that a molecule of carbonic acid is lost for every molecule of CO₂ exhaled, and a molecule of carbonic acid is formed for every molecule of CO₂ retained.

[caption id="" align="aligncenter" width="480"] Figure 1. Symptoms of Acidosis and Alkalosis. Symptoms of acidosis affect several organ systems. Both acidosis and alkalosis can be diagnosed using a blood test.[/caption]

Metabolic Acidosis: Primary Bicarbonate Deficiency

Metabolic acidosis occurs when the blood is too acidic (pH below 7.35) due to too little bicarbonate, a condition called primary bicarbonate deficiency. At the normal pH of 7.40, the ratio of bicarbonate to carbonic acid buffer is 20:1. If a person’s blood pH drops below 7.35, then he or she is in metabolic acidosis. The most common cause of metabolic acidosis is the presence of organic acids or excessive ketones in the blood. Table 2 lists some other causes of metabolic acidosis.

*Acid metabolites from ingested chemical.
Common Causes of Metabolic Acidosis and Blood Metabolites (Table 2)
Cause	Metabolite
Diarrhea	Bicarbonate
Uremia	Phosphoric, sulfuric, and lactic acids
Diabetic ketoacidosis	Increased ketones
Strenuous exercise	Lactic acid
Methanol	Formic acid*
Paraldehyde	β-Hydroxybutyric acid*
Isopropanol	Propionic acid*
Ethylene glycol	Glycolic acid, and some oxalic and formic acids*
Salicylate/aspirin	Sulfasalicylic acid (SSA)*

The first three of the eight causes of metabolic acidosis listed are medical (or unusual physiological) conditions. Strenuous exercise can cause temporary metabolic acidosis due to the production of lactic acid. The last five causes result from the ingestion of specific substances. The active form of aspirin is its metabolite, sulfasalicylic acid. An overdose of aspirin causes acidosis due to the acidity of this metabolite. Metabolic acidosis can also result from uremia, which is the retention of urea and uric acid. Metabolic acidosis can also arise from diabetic ketoacidosis, wherein an excess of ketones is present in the blood. Other causes of metabolic acidosis are a decrease in the excretion of hydrogen ions, which inhibits the conservation of bicarbonate ions, and excessive loss of bicarbonate ions through the gastrointestinal tract due to diarrhea.

Metabolic Alkalosis: Primary Bicarbonate Excess

Metabolic alkalosis is the opposite of metabolic acidosis. It occurs when the blood is too alkaline (pH above 7.45) due to too much bicarbonate (called primary bicarbonate excess). A transient excess of bicarbonate in the blood can follow ingestion of excessive amounts of bicarbonate, citrate, or antacids for conditions such as stomach acid reflux—known as heartburn. Cushing’s disease, which is the chronic hypersecretion of adrenocorticotrophic hormone (ACTH) by the anterior pituitary gland, can cause chronic metabolic alkalosis. The oversecretion of ACTH results in elevated aldosterone levels and an increased loss of potassium by urinary excretion. Other causes of metabolic alkalosis include the loss of hydrochloric acid from the stomach through vomiting, potassium depletion due to the use of diuretics for hypertension, and the excessive use of laxatives.

Respiratory Acidosis: Primary Carbonic Acid/CO₂ Excess

Respiratory acidosis occurs when the blood is overly acidic due to an excess of carbonic acid, resulting from too much CO₂ in the blood. Respiratory acidosis can result from anything that interferes with respiration, such as pneumonia, emphysema, or congestive heart failure.

Respiratory Alkalosis: Primary Carbonic Acid/CO₂Deficiency

Respiratory alkalosis occurs when the blood is overly alkaline due to a deficiency in carbonic acid and CO₂ levels in the blood. This condition usually occurs when too much CO₂ is exhaled from the lungs, as occurs in hyperventilation, which is breathing that is deeper or more frequent than normal. An elevated respiratory rate leading to hyperventilation can be due to extreme emotional upset or fear, fever, infections, hypoxia, or abnormally high levels of catecholamines, such as epinephrine and norepinephrine. Surprisingly, aspirin overdose—salicylate toxicity—can result in respiratory alkalosis as the body tries to compensate for initial acidosis.

Compensation Mechanisms

Various compensatory mechanisms exist to maintain blood pH within a narrow range, including buffers, respiration, and renal mechanisms. Although compensatory mechanisms usually work very well, when one of these mechanisms is not working properly (like kidney failure or respiratory disease), they have their limits. If the pH and bicarbonate to carbonic acid ratio are changed too drastically, the body may not be able to compensate. Moreover, extreme changes in pH can denature proteins. Extensive damage to proteins in this way can result in disruption of normal metabolic processes, serious tissue damage, and ultimately death.

Respiratory Compensation

Respiratory compensation for metabolic acidosis increases the respiratory rate to drive off CO₂ and readjust the bicarbonate to carbonic acid ratio to the 20:1 level. This adjustment can occur within minutes. Respiratory compensation for metabolic alkalosis is not as adept as its compensation for acidosis. The normal response of the respiratory system to elevated pH is to increase the amount of CO₂ in the blood by decreasing the respiratory rate to conserve CO₂. There is a limit to the decrease in respiration, however, that the body can tolerate. Hence, the respiratory route is less efficient at compensating for metabolic alkalosis than for acidosis.

Metabolic Compensation

Metabolic and renal compensation for respiratory diseases that can create acidosis revolves around the conservation of bicarbonate ions. In cases of respiratory acidosis, the kidney increases the conservation of bicarbonate and secretion of H⁺ through the exchange mechanism discussed earlier. These processes increase the concentration of bicarbonate in the blood, reestablishing the proper relative concentrations of bicarbonate and carbonic acid. In cases of respiratory alkalosis, the kidneys decrease the production of bicarbonate and reabsorb H⁺from the tubular fluid. These processes can be limited by the exchange of potassium by the renal cells, which use a K⁺-H⁺ exchange mechanism (antiporter).

Diagnosing Acidosis and Alkalosis

Lab tests for pH, CO₂ partial pressure (pCO₂),and HCO₃^–can identify acidosis and alkalosis, indicating whether the imbalance is respiratory or metabolic, and the extent to which compensatory mechanisms are working. The blood pH value, as shown in Table 3, indicates whether the blood is in acidosis, the normal range, or alkalosis. The pCO₂ and total HCO₃^– values aid in determining whether the condition is metabolic or respiratory, and whether the patient has been able to compensate for the problem. Table 3 lists the conditions and laboratory results that can be used to classify these conditions. Metabolic acid-base imbalances typically result from kidney disease, and the respiratory system usually responds to compensate.

Reference values (arterial): pH: 7.35–7.45; pCO₂: male: 35–48 mm Hg, female: 32–45 mm Hg; total venous bicarbonate: 22–29 mM. N denotes normal; ↑ denotes a rising or increased value; and ↓ denotes a falling or decreased value.
Types of Acidosis and Alkalosis (Table 3)
	pH	pCO₂	Total HCO₃^–
Metabolic acidosis	↓	N, then ↓	↓
Respiratory acidosis	↓	↑	N, then ↑
Metabolic alkalosis	↑	N, then↑	↑
Respiratory alkalosis	↑	↓	N, then ↓

Metabolic acidosis is problematic, as lower-than-normal amounts of bicarbonate are present in the blood. The pCO₂ would be normal at first, but if compensation has occurred, it would decrease as the body reestablishes the proper ratio of bicarbonate and carbonic acid/CO₂.

Respiratory acidosis is problematic, as excess CO₂is present in the blood. Bicarbonate levels would be normal at first, but if compensation has occurred, they would increase in an attempt to reestablish the proper ratio of bicarbonate and carbonic acid/CO₂.

Alkalosis is characterized by a higher-than-normal pH. Metabolic alkalosis is problematic, as elevated pH and excess bicarbonate are present. The pCO₂ would again be normal at first, but if compensation has occurred, it would increase as the body attempts to reestablish the proper ratios of bicarbonate and carbonic acid/CO₂.

Respiratory alkalosis is problematic, as CO₂deficiency is present in the bloodstream. The bicarbonate concentration would be normal at first. When renal compensation occurs, however, the bicarbonate concentration in blood decreases as the kidneys attempt to reestablish the proper ratios of bicarbonate and carbonic acid/CO₂by eliminating more bicarbonate to bring the pH into the physiological range.

27.1 Anatomy and Physiology of the Male Reproductive System

barkerj1 — Wed, 06 Sep 2017 01:20:23 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the location, structure, and function(s) of each of the components of the male reproductive system
Define the term "spermatogenesis"
Describe the role of follicle-stimulating hormone, luteinizing hormone, and testosterone in the male reproductive system
Describe the mechanism and stages of sperm release

[caption id="attachment_3027" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of the male reproductive system.[/caption]

Unique for its role in human reproduction, a gamete is a specialized sex cell carrying 23 chromosomes—one half the number in body cells. At fertilization, the chromosomes in one male gamete, called a sperm (or spermatozoon), combine with the chromosomes in one female gamete, called an oocyte. The function of the male reproductive system (Figure 1) is to produce sperm and transfer them to the female reproductive tract. The paired testes are a crucial component in this process, as they produce both sperm and androgens, the hormones that support male reproductive physiology. In humans, the most important male androgen is testosterone. Several accessory organs and ducts aid the process of sperm maturation and transport the sperm and other seminal components to the penis, which delivers sperm to the female reproductive tract. In this section, we examine each of these different structures, and discuss the process of sperm production and transport.

[caption id="" align="aligncenter" width="550"] Figure 1. Male Reproductive System. The structures of the male reproductive system include the testes, the epididymides, the penis, and the ducts and glands that produce and carry semen. Sperm exit the scrotum through the ductus deferens, which is bundled in the spermatic cord. The seminal vesicles and prostate gland add fluids to the sperm to create semen.[/caption]

Scrotum

The testes are located in a skin-covered, highly pigmented, muscular sack called the scrotum that extends from the body behind the penis (see Figure 1). This location is important in sperm production, which occurs within the testes, and proceeds more efficiently when the testes are kept 2 to 4°C below core body temperature.

The dartos muscle makes up the subcutaneous muscle layer of the scrotum (Figure 2). It continues internally to make up the scrotal septum, a wall that divides the scrotum into two compartments, each housing one testis. Descending from the internal oblique muscle of the abdominal wall are the two cremaster muscles, which cover each testis like a muscular net. By contracting simultaneously, the dartos and cremaster muscles can elevate the testes in cold weather (or water), moving the testes closer to the body and decreasing the surface area of the scrotum to retain heat. Alternatively, as the environmental temperature increases, the scrotum relaxes, moving the testes farther from the body core and increasing scrotal surface area, which promotes heat loss. Externally, the scrotum has a raised medial thickening on the surface called the raphae.

[caption id="" align="aligncenter" width="550"] Figure 2. The Scrotum and Testes. This anterior view shows the structures of the scrotum and testes.[/caption]

Testes

The testes (singular = testis) are the male gonads—that is, the male reproductive organs. They produce both sperm and androgens, such as testosterone, and are active throughout the reproductive lifespan of the male.

Paired ovals, the testes are each approximately 4 to 5 cm in length and are housed within the scrotum (see Figure 2). They are surrounded by two distinct layers of protective connective tissue (Figure 3). The outer tunica vaginalis is a serous membrane that has both a parietal and a thin visceral layer. Beneath the tunica vaginalis is the tunica albuginea, a tough, white, dense connective tissue layer covering the testis itself. Not only does the tunica albuginea cover the outside of the testis, it also invaginates to form septa that divide the testis into 300 to 400 structures called lobules. Within the lobules, sperm develop in structures called seminiferous tubules. During the seventh month of the developmental period of a male fetus, each testis moves through the abdominal musculature to descend into the scrotal cavity. This is called the “descent of the testis.” Cryptorchidism is the clinical term used when one or both of the testes fail to descend into the scrotum prior to birth. [caption id="" align="aligncenter" width="450"] Figure 3. Anatomy of the Testis. This sagittal view shows the seminiferous tubules, the site of sperm production. Formed sperm are transferred to the epididymis, where they mature. They leave the epididymis during an ejaculation via the ductus deferens.[/caption]

The tightly coiled seminiferous tubules form the bulk of each testis. They are composed of developing sperm cells surrounding a lumen, the hollow center of the tubule, where formed sperm are released into the duct system of the testis. Specifically, from the lumens of the seminiferous tubules, sperm move into the straight tubules (or tubuli recti), and from there into a fine meshwork of tubules called the rete testes. Sperm leave the rete testes, and the testis itself, through the 15 to 20 efferent ductules that cross the tunica albuginea.

Inside the seminiferous tubules are six different cell types. These include supporting cells called sustentacular cells, as well as five types of developing sperm cells called germ cells. Germ cell development progresses from the basement membrane—at the perimeter of the tubule—toward the lumen. Let’s look more closely at these cell types.

Sertoli Cells

Surrounding all stages of the developing sperm cells are elongate, branching Sertoli cells. Sertoli cells are a type of supporting cell called a sustentacular cell, or sustenocyte, that are typically found in epithelial tissue. Sertoli cells secrete signaling molecules that promote sperm production and can control whether germ cells live or die. They extend physically around the germ cells from the peripheral basement membrane of the seminiferous tubules to the lumen. Tight junctions between these sustentacular cells create the blood–testis barrier, which keeps bloodborne substances from reaching the germ cells and, at the same time, keeps surface antigens on developing germ cells from escaping into the bloodstream and prompting an autoimmune response.

Germ Cells

The least mature cells, the spermatogonia (singular = spermatogonium), line the basement membrane inside the tubule. Spermatogonia are the stem cells of the testis, which means that they are still able to differentiate into a variety of different cell types throughout adulthood. Spermatogonia divide to produce primary and secondary spermatocytes, then spermatids, which finally produce formed sperm. The process that begins with spermatogonia and concludes with the production of sperm is called spermatogenesis.

Spermatogenesis

As just noted, spermatogenesis occurs in the seminiferous tubules that form the bulk of each testis (see Figure 3). The process begins at puberty, after which time sperm are produced constantly throughout a man’s life. One production cycle, from spermatogonia through formed sperm, takes approximately 64 days. A new cycle starts approximately every 16 days, although this timing is not synchronous across the seminiferous tubules. Sperm counts—the total number of sperm a man produces—slowly decline after age 35, and some studies suggest that smoking can lower sperm counts irrespective of age.

The process of spermatogenesis begins with mitosis of the diploid spermatogonia (Figure 4). Because these cells are diploid (2n), they each have a complete copy of the father’s genetic material, or 46 chromosomes. However, mature gametes are haploid (1n), containing 23 chromosomes—meaning that daughter cells of spermatogonia must undergo a second cellular division through the process of meiosis. [caption id="" align="aligncenter" width="550"] Figure 4. Spermatogenesis. (a) Mitosis of a spermatogonial stem cell involves a single cell division that results in two identical, diploid daughter cells (spermatogonia to primary spermatocyte). Meiosis has two rounds of cell division: primary spermatocyte to secondary spermatocyte, and then secondary spermatocyte to spermatid. This produces four haploid daughter cells (spermatids). (b) In this electron micrograph of a cross-section of a seminiferous tubule from a rat, the lumen is the light-shaded area in the center of the image. The location of the primary spermatocytes is near the basement membrane, and the early spermatids are approaching the lumen (tissue source: rat). EM × 900. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Two identical diploid cells result from spermatogonia mitosis. One of these cells remains a spermatogonium, and the other becomes a primary spermatocyte, the next stage in the process of spermatogenesis. As in mitosis, DNA is replicated in a primary spermatocyte, and the cell undergoes cell division to produce two cells with identical chromosomes. Each of these is a secondary spermatocyte. Now a second round of cell division occurs in both of the secondary spermatocytes, separating the chromosome pairs. This second meiotic division results in a total of four cells with only half of the number of chromosomes. Each of these new cells is a spermatid. Although haploid, early spermatids look very similar to cells in the earlier stages of spermatogenesis, with a round shape, central nucleus, and large amount of cytoplasm. A process called spermiogenesis transforms these early spermatids, reducing the cytoplasm, and beginning the formation of the parts of a true sperm. The fifth stage of germ cell formation—spermatozoa, or formed sperm—is the end result of this process, which occurs in the portion of the tubule nearest the lumen. Eventually, the sperm are released into the lumen and are moved along a series of ducts in the testis toward a structure called the epididymis for the next step of sperm maturation.

Structure of Formed Sperm

Sperm are smaller than most cells in the body; in fact, the volume of a sperm cell is 85,000 times less than that of the female gamete. Approximately 100 to 300 million sperm are produced each day, whereas women typically ovulate only one oocyte per month as is true for most cells in the body, the structure of sperm cells speaks to their function. Sperm have a distinctive head, mid-piece, and tail region (Figure 5). The head of the sperm contains the extremely compact haploid nucleus with very little cytoplasm. These qualities contribute to the overall small size of the sperm (the head is only 5 μm long). A structure called the acrosome covers most of the head of the sperm cell as a “cap” that is filled with lysosomal enzymes important for preparing sperm to participate in fertilization. Tightly packed mitochondria fill the mid-piece of the sperm. ATP produced by these mitochondria will power the flagellum, which extends from the neck and the mid-piece through the tail of the sperm, enabling it to move the entire sperm cell. The central strand of the flagellum, the axial filament, is formed from one centriole inside the maturing sperm cell during the final stages of spermatogenesis. [caption id="" align="aligncenter" width="550"] Figure 5. Structure of Sperm. Sperm cells are divided into a head, containing DNA; a mid-piece, containing mitochondria; and a tail, providing motility. The acrosome is oval and somewhat flattened.[/caption]

Sperm Transport

To fertilize an egg, sperm must be moved from the seminiferous tubules in the testes, through the epididymis, and—later during ejaculation—along the length of the penis and out into the female reproductive tract.

Role of the Epididymis

From the lumen of the seminiferous tubules, the immotile sperm are surrounded by testicular fluid and moved to the epididymis (plural = epididymides), a coiled tube attached to the testis where newly formed sperm continue to mature (see Figure 3). Though the epididymis does not take up much room in its tightly coiled state, it would be approximately 6 m (20 feet) long if straightened. It takes an average of 12 days for sperm to move through the coils of the epididymis, with the shortest recorded transit time in humans being one day. Sperm enter the head of the epididymis and are moved along predominantly by the contraction of smooth muscles lining the epididymal tubes. As they are moved along the length of the epididymis, the sperm further mature and acquire the ability to move under their own power. Once inside the female reproductive tract, they will use this ability to move independently toward the unfertilized egg. The more mature sperm are then stored in the tail of the epididymis (the final section) until ejaculation occurs.

Duct System

During ejaculation, sperm exit the tail of the epididymis and are pushed by smooth muscle contraction to the ductus deferens (also called the vas deferens). The ductus deferens is a thick, muscular tube that is bundled together inside the scrotum with connective tissue, blood vessels, and nerves into a structure called the spermatic cord (see Figure 1 and Figure 2). Because the ductus deferens is physically accessible within the scrotum, surgical sterilization to interrupt sperm delivery can be performed by cutting and sealing a small section of the ductus (vas) deferens. This procedure is called a vasectomy, and it is an effective form of male birth control. Although it may be possible to reverse a vasectomy, clinicians consider the procedure permanent, and advise men to undergo it only if they are certain they no longer wish to father children.

From each epididymis, each ductus deferens extends superiorly into the abdominal cavity through the inguinal canal in the abdominal wall. From here, the ductus deferens continues posteriorly to the pelvic cavity, ending posterior to the bladder where it dilates in a region called the ampulla (meaning “flask”).

Sperm make up only 5 percent of the final volume of semen, the thick, milky fluid that the male ejaculates. The bulk of semen is produced by three critical accessory glands of the male reproductive system: the seminal vesicles, the prostate, and the bulbourethral glands.

Seminal Vesicles

As sperm pass through the ampulla of the ductus deferens at ejaculation, they mix with fluid from the associated seminal vesicle (see Figure 1). The paired seminal vesicles are glands that contribute approximately 60 percent of the semen volume. Seminal vesicle fluid contains large amounts of fructose, which is used by the sperm mitochondria to generate ATP to allow movement through the female reproductive tract.

The fluid, now containing both sperm and seminal vesicle secretions, next moves into the associated ejaculatory duct, a short structure formed from the ampulla of the ductus deferens and the duct of the seminal vesicle. The paired ejaculatory ducts transport the seminal fluid into the next structure, the prostate gland.

Prostate Gland

As shown in Figure 1, the centrally located prostate gland sits anterior to the rectum at the base of the bladder surrounding the prostatic urethra (the portion of the urethra that runs within the prostate). About the size of a walnut, the prostate is formed of both muscular and glandular tissues. It excretes an alkaline, milky fluid to the passing seminal fluid—now called semen—that is critical to first coagulate and then decoagulate the semen following ejaculation. The temporary thickening of semen helps retain it within the female reproductive tract, providing time for sperm to utilize the fructose provided by seminal vesicle secretions. When the semen regains its fluid state, sperm can then pass farther into the female reproductive tract.

The prostate normally doubles in size during puberty. At approximately age 25, it gradually begins to enlarge again. This enlargement does not usually cause problems; however, abnormal growth of the prostate, or benign prostatic hyperplasia (BPH), can cause constriction of the urethra as it passes through the middle of the prostate gland, leading to a number of lower urinary tract symptoms, such as a frequent and intense urge to urinate, a weak stream, and a sensation that the bladder has not emptied completely. By age 60, approximately 40 percent of men have some degree of BPH. By age 80, the number of affected individuals has jumped to as many as 80 percent. Treatments for BPH attempt to relieve the pressure on the urethra so that urine can flow more normally. Mild to moderate symptoms are treated with medication, whereas severe enlargement of the prostate is treated by surgery in which a portion of the prostate tissue is removed.

Another common disorder involving the prostate is prostate cancer. According to the Centers for Disease Control and Prevention (CDC), prostate cancer is the second most common cancer in men. However, some forms of prostate cancer grow very slowly and thus may not ever require treatment. Aggressive forms of prostate cancer, in contrast, involve metastasis to vulnerable organs like the lungs and brain. There is no link between BPH and prostate cancer, but the symptoms are similar. Prostate cancer is detected by a medical history, a blood test, and a rectal exam that allows physicians to palpate the prostate and check for unusual masses. If a mass is detected, the cancer diagnosis is confirmed by biopsy of the cells.

Bulbourethral Glands

The final addition to semen is made by two bulbourethral glands (or Cowper’s glands) that release a thick, salty fluid that lubricates the end of the urethra and the vagina, and helps to clean urine residues from the penile urethra. The fluid from these accessory glands is released after the male becomes sexually aroused, and shortly before the release of the semen. It is therefore sometimes called pre-ejaculate. It is important to note that, in addition to the lubricating proteins, it is possible for bulbourethral fluid to pick up sperm already present in the urethra, and therefore it may be able to cause pregnancy.

[caption id="" align="aligncenter" width="130"] Watch this video to explore the structures of the male reproductive system and the path of sperm, which starts in the testes and ends as the sperm leave the penis through the urethra.[/caption]

The Penis

The penis is the male organ of copulation (sexual intercourse). It is flaccid for non-sexual actions, such as urination, and turgid and rod-like with sexual arousal. When erect, the stiffness of the organ allows it to penetrate into the vagina and deposit semen into the female reproductive tract. [caption id="" align="aligncenter" width="550"] Figure 6. Cross-Sectional Anatomy of the Penis. Three columns of erectile tissue make up most of the volume of the penis.[/caption]

The shaft of the penis surrounds the urethra (Figure 6). The shaft is composed of three column-like chambers of erectile tissue that span the length of the shaft. Each of the two larger lateral chambers is called a corpus cavernosum (plural = corpora cavernosa). Together, these make up the bulk of the penis. The corpus spongiosum, which can be felt as a raised ridge on the erect penis, is a smaller chamber that surrounds the spongy, or penile, urethra. The end of the penis, called the glans penis, has a high concentration of nerve endings, resulting in very sensitive skin that influences the likelihood of ejaculation (see Figure 1). The skin from the shaft extends down over the glans and forms a collar called the prepuce (or foreskin). The foreskin also contains a dense concentration of nerve endings, and both lubricate and protect the sensitive skin of the glans penis. A surgical procedure called circumcision, often performed for religious or social reasons, removes the prepuce, typically within days of birth.

Both sexual arousal and REM sleep (during which dreaming occurs) can induce an erection. Penile erections are the result of vasocongestion, or engorgement of the tissues because of more arterial blood flowing into the penis than is leaving in the veins. During sexual arousal, nitric oxide (NO) is released from nerve endings near blood vessels within the corpora cavernosa and spongiosum. Release of NO activates a signaling pathway that results in relaxation of the smooth muscles that surround the penile arteries, causing them to dilate. This dilation increases the amount of blood that can enter the penis and induces the endothelial cells in the penile arterial walls to also secrete NO and perpetuate the vasodilation. The rapid increase in blood volume fills the erectile chambers, and the increased pressure of the filled chambers compresses the thin-walled penile venules, preventing venous drainage of the penis. The result of this increased blood flow to the penis and reduced blood return from the penis is erection. Depending on the flaccid dimensions of a penis, it can increase in size slightly or greatly during erection, with the average length of an erect penis measuring approximately 15 cm.

Testosterone

Testosterone, an androgen, is a steroid hormone produced by Leydig cells. The alternate term for Leydig cells, interstitial cells, reflects their location between the seminiferous tubules in the testes. In male embryos, testosterone is secreted by Leydig cells by the seventh week of development, with peak concentrations reached in the second trimester. This early release of testosterone results in the anatomical differentiation of the male sexual organs. In childhood, testosterone concentrations are low. They increase during puberty, activating characteristic physical changes and initiating spermatogenesis.

Functions of Testosterone

The continued presence of testosterone is necessary to keep the male reproductive system working properly, and Leydig cells produce approximately 6 to 7 mg of testosterone per day. Testicular steroidogenesis (the manufacture of androgens, including testosterone) results in testosterone concentrations that are 100 times higher in the testes than in the circulation. Maintaining these normal concentrations of testosterone promotes spermatogenesis, whereas low levels of testosterone can lead to infertility. In addition to intratesticular secretion, testosterone is also released into the systemic circulation and plays an important role in muscle development, bone growth, the development of secondary sex characteristics, and maintaining libido (sex drive) in both males and females. In females, the ovaries secrete small amounts of testosterone, although most is converted to estradiol. A small amount of testosterone is also secreted by the adrenal glands in both sexes.

Control of Testosterone

The regulation of testosterone concentrations throughout the body is critical for male reproductive function. The intricate interplay between the endocrine system and the reproductive system is shown in Figure 7. [caption id="" align="aligncenter" width="550"] Figure 7. Regulation of Testosterone Production. The hypothalamus and pituitary gland regulate the production of testosterone and the cells that assist in spermatogenesis. GnRH activates the anterior pituitary to produce LH and FSH, which in turn stimulate Leydig cells and Sertoli cells, respectively. The system is a negative feedback loop because the end products of the pathway, testosterone and inhibin, interact with the activity of GnRH to inhibit their own production.[/caption]

The regulation of Leydig cell production of testosterone begins outside of the testes. The hypothalamus and the pituitary gland in the brain integrate external and internal signals to control testosterone synthesis and secretion. The regulation begins in the hypothalamus. Pulsatile release of a hormone called gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the endocrine release of hormones from the pituitary gland. Binding of GnRH to its receptors on the anterior pituitary gland stimulates release of the two gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These two hormones are critical for reproductive function in both men and women. In men, FSH binds predominantly to the Sertoli cells within the seminiferous tubules to promote spermatogenesis. FSH also stimulates the Sertoli cells to produce hormones called inhibins, which function to inhibit FSH release from the pituitary, thus reducing testosterone secretion. These polypeptide hormones correlate directly with Sertoli cell function and sperm number; inhibin B can be used as a marker of spermatogenic activity. In men, LH binds to receptors on Leydig cells in the testes and upregulates the production of testosterone.

A negative feedback loop predominantly controls the synthesis and secretion of both FSH and LH. Low blood concentrations of testosterone stimulate the hypothalamic release of GnRH. GnRH then stimulates the anterior pituitary to secrete LH into the bloodstream. In the testis, LH binds to LH receptors on Leydig cells and stimulates the release of testosterone. When concentrations of testosterone in the blood reach a critical threshold, testosterone itself will bind to androgen receptors on both the hypothalamus and the anterior pituitary, inhibiting the synthesis and secretion of GnRH and LH, respectively. When the blood concentrations of testosterone once again decline, testosterone no longer interacts with the receptors to the same degree and GnRH and LH are once again secreted, stimulating more testosterone production. This same process occurs with FSH and inhibin to control spermatogenesis.

27.2 Anatomy and Physiology of the Female Reproductive System

barkerj1 — Wed, 06 Sep 2017 01:20:24 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the location, structure, and function(s) of each of the components of the female reproductive system
Describe the ovarian cycle, including the role of the hypothalamus and anterior pituitary gland in this cycle
Describe the stages in the uterine cycle, including the role of the hormones involved
Correlate the stages of the ovarian and uterine cycles
Explain the integrated hormonal regulation of the ovarian and uterine cycles
Describe the roles of the corpus luteum if pregnancy occurs

[caption id="attachment_3029" align="aligncenter" width="150"] Watch this CrashCourse video for an overview of the female reproductive system.[/caption] The female reproductive system functions to produce gametes and reproductive hormones, just like the male reproductive system; however, it also has the additional task of supporting the developing fetus and delivering it to the outside world. Unlike its male counterpart, the female reproductive system is located primarily inside the pelvic cavity (Figure 1). Recall that the ovaries are the female gonads. The gamete they produce is called an oocyte. We’ll discuss the production of oocytes in detail shortly. First, let’s look at some of the structures of the female reproductive system. [caption id="" align="aligncenter" width="555"] Figure 1. Female Reproductive System. The major organs of the female reproductive system are located inside the pelvic cavity.[/caption]

External Female Genitals

The external female reproductive structures are referred to collectively as the vulva (Figure 2). The mons pubis is a pad of fat that is located at the anterior, over the pubic bone. After puberty, it becomes covered in pubic hair. The labia majora (labia = “lips”; majora = “larger”) are folds of hair-covered skin that begin just posterior to the mons pubis. The thinner and more pigmented labia minora (labia = “lips”; minora = “smaller”) extend medial to the labia majora. Although they naturally vary in shape and size from woman to woman, the labia minora serve to protect the female urethra and the entrance to the female reproductive tract.

The superior, anterior portions of the labia minora come together to encircle the clitoris (or glans clitoris), an organ that originates from the same cells as the glans penis and has abundant nerves that make it important in sexual sensation and orgasm. The hymen is a thin membrane that sometimes partially covers the entrance to the vagina. An intact hymen cannot be used as an indication of “virginity”; even at birth, this is only a partial membrane, as menstrual fluid and other secretions must be able to exit the body, regardless of penile–vaginal intercourse. The vaginal opening is located between the opening of the urethra and the anus. It is flanked by outlets to the Bartholin’s glands (or greater vestibular glands). [caption id="" align="aligncenter" width="550"] Figure 2. The Vulva. The external female genitalia are referred to collectively as the vulva.[/caption]

Vagina

The vagina, shown at the bottom of Figure 1 and Figure 1, is a muscular canal (approximately 10 cm long) that serves as the entrance to the reproductive tract. It also serves as the exit from the uterus during menses and childbirth. The outer walls of the anterior and posterior vagina are formed into longitudinal columns, or ridges, and the superior portion of the vagina—called the fornix—meets the protruding uterine cervix. The walls of the vagina are lined with an outer, fibrous adventitia; a middle layer of smooth muscle; and an inner mucous membrane with transverse folds called rugae. Together, the middle and inner layers allow the expansion of the vagina to accommodate intercourse and childbirth. The thin, perforated hymen can partially surround the opening to the vaginal orifice. The hymen can be ruptured with strenuous physical exercise, penile–vaginal intercourse, and childbirth. The Bartholin’s glands and the lesser vestibular glands (located near the clitoris) secrete mucus, which keeps the vestibular area moist.

The vagina is home to a normal population of microorganisms that help to protect against infection by pathogenic bacteria, yeast, or other organisms that can enter the vagina. In a healthy woman, the most predominant type of vaginal bacteria is from the genus Lactobacillus. This family of beneficial bacterial flora secretes lactic acid, and thus protects the vagina by maintaining an acidic pH (below 4.5). Potential pathogens are less likely to survive in these acidic conditions. Lactic acid, in combination with other vaginal secretions, makes the vagina a self-cleansing organ. However, douching—or washing out the vagina with fluid—can disrupt the normal balance of healthy microorganisms, and actually increase a woman’s risk for infections and irritation. Indeed, the American College of Obstetricians and Gynecologists recommend that women do not douche, and that they allow the vagina to maintain its normal healthy population of protective microbial flora.

Ovaries

The ovaries are the female gonads (see Figure 1). Paired ovals, they are each about 2 to 3 cm in length, about the size of an almond. The ovaries are located within the pelvic cavity, and are supported by the mesovarium, an extension of the peritoneum that connects the ovaries to the broad ligament. Extending from the mesovarium itself is the suspensory ligament that contains the ovarian blood and lymph vessels. Finally, the ovary itself is attached to the uterus via the ovarian ligament.

The ovary comprises an outer covering of cuboidal epithelium called the ovarian surface epithelium that is superficial to a dense connective tissue covering called the tunica albuginea. Beneath the tunica albuginea is the cortex, or outer portion, of the organ. The cortex is composed of a tissue framework called the ovarian stroma that forms the bulk of the adult ovary. Oocytes develop within the outer layer of this stroma, each surrounded by supporting cells. This grouping of an oocyte and its supporting cells is called a follicle. The growth and development of ovarian follicles will be described shortly. Beneath the cortex lies the inner ovarian medulla, the site of blood vessels, lymph vessels, and the nerves of the ovary. You will learn more about the overall anatomy of the female reproductive system at the end of this section.

The Ovarian Cycle

The ovarian cycle is a set of predictable changes in a female’s oocytes and ovarian follicles. During a woman’s reproductive years, it is a roughly 28-day cycle that can be correlated with, but is not the same as, the menstrual cycle (discussed shortly). The cycle includes two interrelated processes: oogenesis (the production of female gametes) and folliculogenesis (the growth and development of ovarian follicles).

Oogenesis

Gametogenesis in females is called oogenesis. The process begins with the ovarian stem cells, or oogonia (Figure 3). Oogonia are formed during fetal development, and divide via mitosis, much like spermatogonia in the testis. Unlike spermatogonia, however, oogonia form primary oocytes in the fetal ovary prior to birth. These primary oocytes are then arrested in this stage of meiosis I, only to resume it years later, beginning at puberty and continuing until the woman is near menopause (the cessation of a woman’s reproductive functions). The number of primary oocytes present in the ovaries declines from one to two million in an infant, to approximately 400,000 at puberty, to zero by the end of menopause.

The initiation of ovulation—the release of an oocyte from the ovary—marks the transition from puberty into reproductive maturity for women. From then on, throughout a woman’s reproductive years, ovulation occurs approximately once every 28 days. Just prior to ovulation, a surge of luteinizing hormone triggers the resumption of meiosis in a primary oocyte. This initiates the transition from primary to secondary oocyte. However, as you can see in Figure 3, this cell division does not result in two identical cells. Instead, the cytoplasm is divided unequally, and one daughter cell is much larger than the other. This larger cell, the secondary oocyte, eventually leaves the ovary during ovulation. The smaller cell, called the first polar body, may or may not complete meiosis and produce second polar bodies; in either case, it eventually disintegrates. Therefore, even though oogenesis produces up to four cells, only one survives. [caption id="" align="aligncenter" width="550"] Figure 3. Oogenesis. The unequal cell division of oogenesis produces one to three polar bodies that later degrade, as well as a single haploid ovum, which is produced only if there is penetration of the secondary oocyte by a sperm cell.[/caption]

How does the diploid secondary oocyte become an ovum—the haploid female gamete? Meiosis of a secondary oocyte is completed only if a sperm succeeds in penetrating its barriers. Meiosis II then resumes, producing one haploid ovum that, at the instant of fertilization by a (haploid) sperm, becomes the first diploid cell of the new offspring (a zygote). Thus, the ovum can be thought of as a brief, transitional, haploid stage between the diploid oocyte and diploid zygote.

The larger amount of cytoplasm contained in the female gamete is used to supply the developing zygote with nutrients during the period between fertilization and implantation into the uterus. Interestingly, sperm contribute only DNA at fertilization —not cytoplasm. Therefore, the cytoplasm and all of the cytoplasmic organelles in the developing embryo are of maternal origin. This includes mitochondria, which contain their own DNA. Scientific research in the 1980s determined that mitochondrial DNA was maternally inherited, meaning that you can trace your mitochondrial DNA directly to your mother, her mother, and so on back through your female ancestors.

Mapping Human History with Mitochondrial DNA

When we talk about human DNA, we’re usually referring to nuclear DNA; that is, the DNA coiled into chromosomal bundles in the nucleus of our cells. We inherit half of our nuclear DNA from our father, and half from our mother. However, mitochondrial DNA (mtDNA) comes only from the mitochondria in the cytoplasm of the fat ovum we inherit from our mother. She received her mtDNA from her mother, who got it from her mother, and so on. Each of our cells contains approximately 1700 mitochondria, with each mitochondrion packed with mtDNA containing approximately 37 genes.

Mutations (changes) in mtDNA occur spontaneously in a somewhat organized pattern at regular intervals in human history. By analyzing these mutational relationships, researchers have been able to determine that we can all trace our ancestry back to one woman who lived in Africa about 200,000 years ago. Scientists have given this woman the biblical name Eve, although she is not, of course, the first Homo sapiens female. More precisely, she is our most recent common ancestor through matrilineal descent.

This doesn’t mean that everyone’s mtDNA today looks exactly like that of our ancestral Eve. Because of the spontaneous mutations in mtDNA that have occurred over the centuries, researchers can map different “branches” off of the “main trunk” of our mtDNA family tree. Your mtDNA might have a pattern of mutations that aligns more closely with one branch, and your neighbor’s may align with another branch. Still, all branches eventually lead back to Eve.

But what happened to the mtDNA of all of the other Homo sapiens females who were living at the time of Eve? Researchers explain that, over the centuries, their female descendants died childless or with only male children, and thus, their maternal line—and its mtDNA—ended.

Folliculogenesis

Again, ovarian follicles are oocytes and their supporting cells. They grow and develop in a process called folliculogenesis, which typically leads to ovulation of one follicle approximately every 28 days, along with death to multiple other follicles. The death of ovarian follicles is called atresia, and can occur at any point during follicular development. Recall that, a female infant at birth will have one to two million oocytes within her ovarian follicles, and that this number declines throughout life until menopause, when no follicles remain. As you’ll see next, follicles progress from primordial, to primary, to secondary and tertiary stages prior to ovulation—with the oocyte inside the follicle remaining as a primary oocyte until right before ovulation.

Folliculogenesis begins with follicles in a resting state. These small primordial follicles are present in newborn females and are the prevailing follicle type in the adult ovary (Figure 4). Primordial follicles have only a single flat layer of support cells, called granulosa cells, that surround the oocyte, and they can stay in this resting state for years—some until right before menopause.

After puberty, a few primordial follicles will respond to a recruitment signal each day, and will join a pool of immature growing follicles called primary follicles. Primary follicles start with a single layer of granulosa cells, but the granulosa cells then become active and transition from a flat or squamous shape to a rounded, cuboidal shape as they increase in size and proliferate. As the granulosa cells divide, the follicles—now called secondary follicles (see Figure 4)—increase in diameter, adding a new outer layer of connective tissue, blood vessels, and theca cells—cells that work with the granulosa cells to produce estrogens.

Within the growing secondary follicle, the primary oocyte now secretes a thin acellular membrane called the zona pellucida that will play a critical role in fertilization. A thick fluid, called follicular fluid, that has formed between the granulosa cells also begins to collect into one large pool, or antrum. Follicles in which the antrum has become large and fully formed are considered tertiary follicles (or antral follicles). Several follicles reach the tertiary stage at the same time, and most of these will undergo atresia. The one that does not die will continue to grow and develop until ovulation, when it will expel its secondary oocyte surrounded by several layers of granulosa cells from the ovary. Keep in mind that most follicles don’t make it to this point. In fact, roughly 99 percent of the follicles in the ovary will undergo atresia, which can occur at any stage of folliculogenesis. [caption id="" align="aligncenter" width="550"] Figure 4. Folliculogenesis. (a) The maturation of a follicle is shown in a clockwise direction proceeding from the primordial follicles. FSH stimulates the growth of a tertiary follicle, and LH stimulates the production of estrogen by granulosa and theca cells. Once the follicle is mature, it ruptures and releases the oocyte. Cells remaining in the follicle then develop into the corpus luteum. (b) In this electron micrograph of a secondary follicle, the oocyte, theca cells (thecae folliculi), and developing antrum are clearly visible. EM × 1100. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)[/caption]

Hormonal Control of the Ovarian Cycle

The process of development that we have just described, from primordial follicle to early tertiary follicle, takes approximately two months in humans. The final stages of development of a small cohort of tertiary follicles, ending with ovulation of a secondary oocyte, occur over a course of approximately 28 days. These changes are regulated by many of the same hormones that regulate the male reproductive system, including gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).

As in men, the hypothalamus produces GnRH, a hormone that signals the anterior pituitary gland to produce the gonadotropins FSH and LH (Figure 5). These gonadotropins leave the pituitary and travel through the bloodstream to the ovaries, where they bind to receptors on the granulosa and theca cells of the follicles. FSH stimulates the follicles to grow (hence its name of follicle-stimulating hormone), and the five or six tertiary follicles expand in diameter. The release of LH also stimulates the granulosa and theca cells of the follicles to produce the sex steroid hormone estradiol, a type of estrogen. This phase of the ovarian cycle, when the tertiary follicles are growing and secreting estrogen, is known as the follicular phase.

The more granulosa and theca cells a follicle has (that is, the larger and more developed it is), the more estrogen it will produce in response to LH stimulation. As a result of these large follicles producing large amounts of estrogen, systemic plasma estrogen concentrations increase. Following a classic negative feedback loop, the high concentrations of estrogen will stimulate the hypothalamus and pituitary to reduce the production of GnRH, LH, and FSH. Because the large tertiary follicles require FSH to grow and survive at this point, this decline in FSH caused by negative feedback leads most of them to die (atresia). Typically only one follicle, now called the dominant follicle, will survive this reduction in FSH, and this follicle will be the one that releases an oocyte. Scientists have studied many factors that lead to a particular follicle becoming dominant: size, the number of granulosa cells, and the number of FSH receptors on those granulosa cells all contribute to a follicle becoming the one surviving dominant follicle. [caption id="" align="aligncenter" width="550"] Figure 5. Hormonal Regulation of Ovulation. The hypothalamus and pituitary gland regulate the ovarian cycle and ovulation. GnRH activates the anterior pituitary to produce LH and FSH, which stimulate the production of estrogen and progesterone by the ovaries.[/caption]

When only the one dominant follicle remains in the ovary, it again begins to secrete estrogen. It produces more estrogen than all of the developing follicles did together before the negative feedback occurred. It produces so much estrogen that the normal negative feedback doesn’t occur. Instead, these extremely high concentrations of systemic plasma estrogen trigger a regulatory switch in the anterior pituitary that responds by secreting large amounts of LH and FSH into the bloodstream (see Figure 5). The positive feedback loop by which more estrogen triggers release of more LH and FSH only occurs at this point in the cycle.

It is this large burst of LH (called the LH surge) that leads to ovulation of the dominant follicle. The LH surge induces many changes in the dominant follicle, including stimulating the resumption of meiosis of the primary oocyte to a secondary oocyte. As noted earlier, the polar body that results from unequal cell division simply degrades. The LH surge also triggers proteases (enzymes that cleave proteins) to break down structural proteins in the ovary wall on the surface of the bulging dominant follicle. This degradation of the wall, combined with pressure from the large, fluid-filled antrum, results in the expulsion of the oocyte surrounded by granulosa cells into the peritoneal cavity. This release is ovulation.

In the next section, you will follow the ovulated oocyte as it travels toward the uterus, but there is one more important event that occurs in the ovarian cycle. The surge of LH also stimulates a change in the granulosa and theca cells that remain in the follicle after the oocyte has been ovulated. This change is called luteinization (recall that the full name of LH is luteinizing hormone), and it transforms the collapsed follicle into a new endocrine structure called the corpus luteum, a term meaning “yellowish body” (see Figure 4). Instead of estrogen, the luteinized granulosa and theca cells of the corpus luteum begin to produce large amounts of the sex steroid hormone progesterone, a hormone that is critical for the establishment and maintenance of pregnancy. Progesterone triggers negative feedback at the hypothalamus and pituitary, which keeps GnRH, LH, and FSH secretions low, so no new dominant follicles develop at this time.

The post-ovulatory phase of progesterone secretion is known as the luteal phase of the ovarian cycle. If pregnancy does not occur within 10 to 12 days, the corpus luteum will stop secreting progesterone and degrade into the corpus albicans, a nonfunctional “whitish body” that will disintegrate in the ovary over a period of several months. During this time of reduced progesterone secretion, FSH and LH are once again stimulated, and the follicular phase begins again with a new cohort of early tertiary follicles beginning to grow and secrete estrogen.

The Uterine Tubes

The uterine tubes (also called fallopian tubes or oviducts) serve as the conduit of the oocyte from the ovary to the uterus (Figure 6). Each of the two uterine tubes is close to, but not directly connected to, the ovary and divided into sections. The isthmus is the narrow medial end of each uterine tube that is connected to the uterus. The wide distal infundibulum flares out with slender, finger-like projections called fimbriae. The middle region of the tube, called the ampulla, is where fertilization often occurs. The uterine tubes also have three layers: an outer serosa, a middle smooth muscle layer, and an inner mucosal layer. In addition to its mucus-secreting cells, the inner mucosa contains ciliated cells that beat in the direction of the uterus, producing a current that will be critical to move the oocyte.

Following ovulation, the secondary oocyte surrounded by a few granulosa cells is released into the peritoneal cavity. The nearby uterine tube, either left or right, receives the oocyte. Unlike sperm, oocytes lack flagella, and therefore cannot move on their own. So how do they travel into the uterine tube and toward the uterus? High concentrations of estrogen that occur around the time of ovulation induce contractions of the smooth muscle along the length of the uterine tube. These contractions occur every 4 to 8 seconds, and the result is a coordinated movement that sweeps the surface of the ovary and the pelvic cavity. Current flowing toward the uterus is generated by coordinated beating of the cilia that line the outside and lumen of the length of the uterine tube. These cilia beat more strongly in response to the high estrogen concentrations that occur around the time of ovulation. As a result of these mechanisms, the oocyte–granulosa cell complex is pulled into the interior of the tube. Once inside, the muscular contractions and beating cilia move the oocyte slowly toward the uterus. When fertilization does occur, sperm typically meet the egg while it is still moving through the ampulla.

If the oocyte is successfully fertilized, the resulting zygote will begin to divide into two cells, then four, and so on, as it makes its way through the uterine tube and into the uterus. There, it will implant and continue to grow. If the egg is not fertilized, it will simply degrade—either in the uterine tube or in the uterus, where it may be shed with the next menstrual period. [caption id="" align="aligncenter" width="550"] Figure 6. Ovaries, Uterine Tubes, and Uterus. This anterior view shows the relationship of the ovaries, uterine tubes (oviducts), and uterus. Sperm enter through the vagina, and fertilization of an ovulated oocyte usually occurs in the distal uterine tube. From left to right, LM × 400, LM × 20. (Micrographs provided by the Regents of University of Michigan Medical School © 2012)[/caption]

The open-ended structure of the uterine tubes can have significant health consequences if bacteria or other contagions enter through the vagina and move through the uterus, into the tubes, and then into the pelvic cavity. If this is left unchecked, a bacterial infection (sepsis) could quickly become life-threatening. The spread of an infection in this manner is of special concern when unskilled practitioners perform abortions in non-sterile conditions. Sepsis is also associated with sexually transmitted bacterial infections, especially gonorrhea and chlamydia. These increase a woman’s risk for pelvic inflammatory disease (PID), infection of the uterine tubes or other reproductive organs. Even when resolved, PID can leave scar tissue in the tubes, leading to infertility.

The Uterus and Cervix

The uterus is the muscular organ that nourishes and supports the growing embryo (see Figure 6). Its average size is approximately 5 cm wide by 7 cm long (approximately 2 in by 3 in) when a female is not pregnant. It has three sections. The portion of the uterus superior to the opening of the uterine tubes is called the fundus. The middle section of the uterus is called the body of uterus (or corpus). The cervix is the narrow inferior portion of the uterus that projects into the vagina. The cervix produces mucus secretions that become thin and stringy under the influence of high systemic plasma estrogen concentrations, and these secretions can facilitate sperm movement through the reproductive tract.

Several ligaments maintain the position of the uterus within the abdominopelvic cavity. The broad ligament is a fold of peritoneum that serves as a primary support for the uterus, extending laterally from both sides of the uterus and attaching it to the pelvic wall. The round ligament attaches to the uterus near the uterine tubes, and extends to the labia majora. Finally, the uterosacral ligament stabilizes the uterus posteriorly by its connection from the cervix to the pelvic wall.

The wall of the uterus is made up of three layers. The most superficial layer is the serous membrane, or perimetrium, which consists of epithelial tissue that covers the exterior portion of the uterus. The middle layer, or myometrium, is a thick layer of smooth muscle responsible for uterine contractions. Most of the uterus is myometrial tissue, and the muscle fibers run horizontally, vertically, and diagonally, allowing the powerful contractions that occur during labor and the less powerful contractions (or cramps) that help to expel menstrual blood during a woman’s period. Anteriorly directed myometrial contractions also occur near the time of ovulation, and are thought to possibly facilitate the transport of sperm through the female reproductive tract.

The innermost layer of the uterus is called the endometrium. The endometrium contains a connective tissue lining, the lamina propria, which is covered by epithelial tissue that lines the lumen. Structurally, the endometrium consists of two layers: the stratum basalis and the stratum functionalis (the basal and functional layers). The stratum basalis layer is part of the lamina propria and is adjacent to the myometrium; this layer does not shed during menses. In contrast, the thicker stratum functionalis layer contains the glandular portion of the lamina propria and the endothelial tissue that lines the uterine lumen. It is the stratum functionalis that grows and thickens in response to increased levels of estrogen and progesterone. In the luteal phase of the menstrual cycle, special branches off of the uterine artery called spiral arteries supply the thickened stratum functionalis. This inner functional layer provides the proper site of implantation for the fertilized egg, and—should fertilization not occur—it is only the stratum functionalis layer of the endometrium that sheds during menstruation.

Recall that during the follicular phase of the ovarian cycle, the tertiary follicles are growing and secreting estrogen. At the same time, the stratum functionalis of the endometrium is thickening to prepare for a potential implantation. The post-ovulatory increase in progesterone, which characterizes the luteal phase, is key for maintaining a thick stratum functionalis. As long as a functional corpus luteum is present in the ovary, the endometrial lining is prepared for implantation. Indeed, if an embryo implants, signals are sent to the corpus luteum to continue secreting progesterone to maintain the endometrium, and thus maintain the pregnancy. If an embryo does not implant, no signal is sent to the corpus luteum and it degrades, ceasing progesterone production and ending the luteal phase. Without progesterone, the endometrium thins and, under the influence of prostaglandins, the spiral arteries of the endometrium constrict and rupture, preventing oxygenated blood from reaching the endometrial tissue. As a result, endometrial tissue dies and blood, pieces of the endometrial tissue, and white blood cells are shed through the vagina during menstruation, or the menses. The first menses after puberty, called menarche, can occur either before or after the first ovulation.

The Menstrual Cycle

Now that we have discussed the maturation of the cohort of tertiary follicles in the ovary, the build-up and then shedding of the endometrial lining in the uterus, and the function of the uterine tubes and vagina, we can put everything together to talk about the three phases of the menstrual cycle—the series of changes in which the uterine lining is shed, rebuilds, and prepares for implantation.

The timing of the menstrual cycle starts with the first day of menses, referred to as day one of a woman’s period. Cycle length is determined by counting the days between the onset of bleeding in two subsequent cycles. Because the average length of a woman’s menstrual cycle is 28 days, this is the time period used to identify the timing of events in the cycle. However, the length of the menstrual cycle varies among women, and even in the same woman from one cycle to the next, typically from 21 to 32 days.

Just as the hormones produced by the granulosa and theca cells of the ovary “drive” the follicular and luteal phases of the ovarian cycle, they also control the three distinct phases of the menstrual cycle. These are the menses phase, the proliferative phase, and the secretory phase.

Menses Phase

The menses phase of the menstrual cycle is the phase during which the lining is shed; that is, the days that the woman menstruates. Although it averages approximately five days, the menses phase can last from 2 to 7 days, or longer. As shown in Figure 7, the menses phase occurs during the early days of the follicular phase of the ovarian cycle, when progesterone, FSH, and LH levels are low. Recall that progesterone concentrations decline as a result of the degradation of the corpus luteum, marking the end of the luteal phase. This decline in progesterone triggers the shedding of the stratum functionalis of the endometrium. [caption id="" align="aligncenter" width="500"] Figure 7. Hormone Levels in Ovarian and Menstrual Cycles. The correlation of the hormone levels and their effects on the female reproductive system is shown in this timeline of the ovarian and menstrual cycles. The menstrual cycle begins at day one with the start of menses. Ovulation occurs around day 14 of a 28-day cycle, triggered by the LH surge.[/caption]

Proliferative Phase

Once menstrual flow ceases, the endometrium begins to proliferate again, marking the beginning of the proliferative phase of the menstrual cycle (see Figure 7). It occurs when the granulosa and theca cells of the tertiary follicles begin to produce increased amounts of estrogen. These rising estrogen concentrations stimulate the endometrial lining to rebuild.

Recall that the high estrogen concentrations will eventually lead to a decrease in FSH as a result of negative feedback, resulting in atresia of all but one of the developing tertiary follicles. The switch to positive feedback—which occurs with the elevated estrogen production from the dominant follicle—then stimulates the LH surge that will trigger ovulation. In a typical 28-day menstrual cycle, ovulation occurs on day 14. Ovulation marks the end of the proliferative phase as well as the end of the follicular phase.

Secretory Phase

In addition to prompting the LH surge, high estrogen levels increase the uterine tube contractions that facilitate the pick-up and transfer of the ovulated oocyte. High estrogen levels also slightly decrease the acidity of the vagina, making it more hospitable to sperm. In the ovary, the luteinization of the granulosa cells of the collapsed follicle forms the progesterone-producing corpus luteum, marking the beginning of the luteal phase of the ovarian cycle. In the uterus, progesterone from the corpus luteum begins the secretory phase of the menstrual cycle, in which the endometrial lining prepares for implantation (see Figure 7). Over the next 10 to 12 days, the endometrial glands secrete a fluid rich in glycogen. If fertilization has occurred, this fluid will nourish the ball of cells now developing from the zygote. At the same time, the spiral arteries develop to provide blood to the thickened stratum functionalis.

If no pregnancy occurs within approximately 10 to 12 days, the corpus luteum will degrade into the corpus albicans. Levels of both estrogen and progesterone will fall, and the endometrium will grow thinner. Prostaglandins will be secreted that cause constriction of the spiral arteries, reducing oxygen supply. The endometrial tissue will die, resulting in menses—or the first day of the next cycle.

Disorders of the… Feature

Female Reproductive System Research over many years has confirmed that cervical cancer is most often caused by a sexually transmitted infection with human papillomavirus (HPV). There are over 100 related viruses in the HPV family, and the characteristics of each strain determine the outcome of the infection. In all cases, the virus enters body cells and uses its own genetic material to take over the host cell’s metabolic machinery and produce more virus particles.

HPV infections are common in both men and women. Indeed, a recent study determined that 42.5 percent of females had HPV at the time of testing. These women ranged in age from 14 to 59 years and differed in race, ethnicity, and number of sexual partners. Of note, the prevalence of HPV infection was 53.8 percent among women aged 20 to 24 years, the age group with the highest infection rate.

HPV strains are classified as high or low risk according to their potential to cause cancer. Though most HPV infections do not cause disease, the disruption of normal cellular functions in the low-risk forms of HPV can cause the male or female human host to develop genital warts. Often, the body is able to clear an HPV infection by normal immune responses within 2 years. However, the more serious, high-risk infection by certain types of HPV can result in cancer of the cervix (Figure 8). Infection with either of the cancer-causing variants HPV 16 or HPV 18 has been linked to more than 70 percent of all cervical cancer diagnoses. Although even these high-risk HPV strains can be cleared from the body over time, infections persist in some individuals. If this happens, the HPV infection can influence the cells of the cervix to develop precancerous changes.

Risk factors for cervical cancer include having unprotected sex; having multiple sexual partners; a first sexual experience at a younger age, when the cells of the cervix are not fully mature; failure to receive the HPV vaccine; a compromised immune system; and smoking. The risk of developing cervical cancer is doubled with cigarette smoking. [caption id="" align="aligncenter" width="550"] Figure 8. Development of Cervical Cancer. In most cases, cells infected with the HPV virus heal on their own. In some cases, however, the virus continues to spread and becomes an invasive cancer.[/caption]

When the high-risk types of HPV enter a cell, two viral proteins are used to neutralize proteins that the host cells use as checkpoints in the cell cycle. The best studied of these proteins is p53. In a normal cell, p53 detects DNA damage in the cell’s genome and either halts the progression of the cell cycle—allowing time for DNA repair to occur—or initiates apoptosis. Both of these processes prevent the accumulation of mutations in a cell’s genome. High-risk HPV can neutralize p53, keeping the cell in a state in which fast growth is possible and impairing apoptosis, allowing mutations to accumulate in the cellular DNA.

The prevalence of cervical cancer in the United States is very low because of regular screening exams called pap smears. Pap smears sample cells of the cervix, allowing the detection of abnormal cells. If pre-cancerous cells are detected, there are several highly effective techniques that are currently in use to remove them before they pose a danger. However, women in developing countries often do not have access to regular pap smears. As a result, these women account for as many as 80 percent of the cases of cervical cancer worldwide.

In 2006, the first vaccine against the high-risk types of HPV was approved. There are now two HPV vaccines available: Gardasil^® and Cervarix^®. Whereas these vaccines were initially only targeted for women, because HPV is sexually transmitted, both men and women require vaccination for this approach to achieve its maximum efficacy. A recent study suggests that the HPV vaccine has cut the rates of HPV infection by the four targeted strains at least in half. Unfortunately, the high cost of manufacturing the vaccine is currently limiting access to many women worldwide.

The Breasts

Whereas the breasts are located far from the other female reproductive organs, they are considered accessory organs of the female reproductive system. The function of the breasts is to supply milk to an infant in a process called lactation. The external features of the breast include a nipple surrounded by a pigmented areola (Figure 9), whose coloration may deepen during pregnancy. The areola is typically circular and can vary in size from 25 to 100 mm in diameter. The areolar region is characterized by small, raised areolar glands that secrete lubricating fluid during lactation to protect the nipple from chafing. When a baby nurses, or draws milk from the breast, the entire areolar region is taken into the mouth.

Breast milk is produced by the mammary glands, which are modified sweat glands. The milk itself exits the breast through the nipple via 15 to 20 lactiferous ducts that open on the surface of the nipple. These lactiferous ducts each extend to a lactiferous sinus that connects to a glandular lobe within the breast itself that contains groups of milk-secreting cells in clusters called alveoli (see Figure 9). The clusters can change in size depending on the amount of milk in the alveolar lumen. Once milk is made in the alveoli, stimulated myoepithelial cells that surround the alveoli contract to push the milk to the lactiferous sinuses. From here, the baby can draw milk through the lactiferous ducts by suckling. The lobes themselves are surrounded by fat tissue, which determines the size of the breast; breast size differs between individuals and does not affect the amount of milk produced. Supporting the breasts are multiple bands of connective tissue called suspensory ligaments that connect the breast tissue to the dermis of the overlying skin. [caption id="" align="aligncenter" width="450"] Figure 9. Anatomy of the Breast. During lactation, milk moves from the alveoli through the lactiferous ducts to the nipple.[/caption]

During the normal hormonal fluctuations in the menstrual cycle, breast tissue responds to changing levels of estrogen and progesterone, which can lead to swelling and breast tenderness in some individuals, especially during the secretory phase. If pregnancy occurs, the increase in hormones leads to further development of the mammary tissue and enlargement of the breasts.

Hormonal Birth Control

Birth control pills take advantage of the negative feedback system that regulates the ovarian and menstrual cycles to stop ovulation and prevent pregnancy. Typically they work by providing a constant level of both estrogen and progesterone, which negatively feeds back onto the hypothalamus and pituitary, thus preventing the release of FSH and LH. Without FSH, the follicles do not mature, and without the LH surge, ovulation does not occur. Although the estrogen in birth control pills does stimulate some thickening of the endometrial wall, it is reduced compared with a normal cycle and is less likely to support implantation.

Some birth control pills contain 21 active pills containing hormones, and 7 inactive pills (placebos). The decline in hormones during the week that the woman takes the placebo pills triggers menses, although it is typically lighter than a normal menstrual flow because of the reduced endometrial thickening. Newer types of birth control pills have been developed that deliver low-dose estrogens and progesterone for the entire cycle (these are meant to be taken 365 days a year), and menses never occurs. While some women prefer to have the proof of a lack of pregnancy that a monthly period provides, menstruation every 28 days is not required for health reasons, and there are no reported adverse effects of not having a menstrual period in an otherwise healthy individual.

Because birth control pills function by providing constant estrogen and progesterone levels and disrupting negative feedback, skipping even just one or two pills at certain points of the cycle (or even being several hours late taking the pill) can lead to an increase in FSH and LH and result in ovulation. It is important, therefore, that the woman follow the directions on the birth control pill package to successfully prevent pregnancy.

28.1 Fertilization

barkerj1 — Wed, 06 Sep 2017 01:20:25 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the process of fertilization, specifying the site where it normally occurs, the general events that occur during fertilization, and the product of fertilization
Explain the phenomenon of multiple births in humans

Fertilization occurs when a sperm and an oocyte (egg) combine and their nuclei fuse. Because each of these reproductive cells is a haploid cell containing half of the genetic material needed to form a human being, their combination forms a diploid cell. This new single cell, called a zygote, contains all of the genetic material needed to form a human—half from the mother and half from the father.

Transit of Sperm

Fertilization is a numbers game. During ejaculation, hundreds of millions of sperm (spermatozoa) are released into the vagina. Almost immediately, millions of these sperm are overcome by the acidity of the vagina (approximately pH 3.8), and millions more may be blocked from entering the uterus by thick cervical mucus. Of those that do enter, thousands are destroyed by phagocytic uterine leukocytes. Thus, the race into the uterine tubes, which is the most typical site for sperm to encounter the oocyte, is reduced to a few thousand contenders. Their journey—thought to be facilitated by uterine contractions—usually takes from 30 minutes to 2 hours. If the sperm do not encounter an oocyte immediately, they can survive in the uterine tubes for another 3–5 days. Thus, fertilization can still occur if intercourse takes place a few days before ovulation. In comparison, an oocyte can survive independently for only approximately 24 hours following ovulation. Intercourse more than a day after ovulation will therefore usually not result in fertilization.

During the journey, fluids in the female reproductive tract prepare the sperm for fertilization through a process called capacitation, or priming. The fluids improve the motility of the spermatozoa. They also deplete cholesterol molecules embedded in the membrane of the head of the sperm, thinning the membrane in such a way that will help facilitate the release of the lysosomal (digestive) enzymes needed for the sperm to penetrate the oocyte’s exterior once contact is made. Sperm must undergo the process of capacitation in order to have the “capacity” to fertilize an oocyte. If they reach the oocyte before capacitation is complete, they will be unable to penetrate the oocyte’s thick outer layer of cells.

Contact Between Sperm and Oocyte

Upon ovulation, the oocyte released by the ovary is swept into—and along—the uterine tube. Fertilization must occur in the distal uterine tube because an unfertilized oocyte cannot survive the 72-hour journey to the uterus. As you will recall from your study of the oogenesis, this oocyte (specifically a secondary oocyte) is surrounded by two protective layers. The corona radiata is an outer layer of follicular (granulosa) cells that form around a developing oocyte in the ovary and remain with it upon ovulation. The underlying zona pellucida (pellucid = “transparent”) is a transparent, but thick, glycoprotein membrane that surrounds the cell’s plasma membrane.

As it is swept along the distal uterine tube, the oocyte encounters the surviving capacitated sperm, which stream toward it in response to chemical attractants released by the cells of the corona radiata. To reach the oocyte itself, the sperm must penetrate the two protective layers. The sperm first burrow through the cells of the corona radiata. Then, upon contact with the zona pellucida, the sperm bind to receptors in the zona pellucida. This initiates a process called the acrosomal reaction in which the enzyme-filled “cap” of the sperm, called the acrosome, releases its stored digestive enzymes. These enzymes clear a path through the zona pellucida that allows sperm to reach the oocyte. Finally, a single sperm makes contact with sperm-binding receptors on the oocyte’s plasma membrane (Figure 1). The plasma membrane of that sperm then fuses with the oocyte’s plasma membrane, and the head and mid-piece of the “winning” sperm enter the oocyte interior.

How do sperm penetrate the corona radiata? Some sperm undergo a spontaneous acrosomal reaction, which is an acrosomal reaction not triggered by contact with the zona pellucida. The digestive enzymes released by this reaction digest the extracellular matrix of the corona radiata. As you can see, the first sperm to reach the oocyte is never the one to fertilize it. Rather, hundreds of sperm cells must undergo the acrosomal reaction, each helping to degrade the corona radiata and zona pellucida until a path is created to allow one sperm to contact and fuse with the plasma membrane of the oocyte. If you consider the loss of millions of sperm between entry into the vagina and degradation of the zona pellucida, you can understand why a low sperm count can cause male infertility.

[caption id="" align="aligncenter" width="520"] Figure 1. Sperm and the Process of Fertilization. Before fertilization, hundreds of capacitated sperm must break through the surrounding corona radiata and zona pellucida so that one can contact and fuse with the oocyte plasma membrane.[/caption]

When the first sperm fuses with the oocyte, the oocyte deploys two mechanisms to prevent polyspermy, which is penetration by more than one sperm. This is critical because if more than one sperm were to fertilize the oocyte, the resulting zygote would be a triploid organism with three sets of chromosomes. This is incompatible with life.

The first mechanism is the fast block, which involves a near instantaneous change in sodium ion permeability upon binding of the first sperm, depolarizing the oocyte plasma membrane and preventing the fusion of additional sperm cells. The fast block sets in almost immediately and lasts for about a minute, during which time an influx of calcium ions following sperm penetration triggers the second mechanism, the slow block. In this process, referred to as the cortical reaction, cortical granules sitting immediately below the oocyte plasma membrane fuse with the membrane and release zonal inhibiting proteins and mucopolysaccharides into the space between the plasma membrane and the zona pellucida. Zonal inhibiting proteins cause the release of any other attached sperm and destroy the oocyte’s sperm receptors, thus preventing any more sperm from binding. The mucopolysaccharides then coat the nascent zygote in an impenetrable barrier that, together with hardened zona pellucida, is called a fertilization membrane.

The Zygote

Recall that at the point of fertilization, the oocyte has not yet completed meiosis; all secondary oocytes remain arrested in metaphase of meiosis II until fertilization. Only upon fertilization does the oocyte complete meiosis. The unneeded complement of genetic material that results is stored in a second polar body that is eventually ejected. At this moment, the oocyte has become an ovum, the female haploid gamete. The two haploid nuclei derived from the sperm and oocyte and contained within the egg are referred to as pronuclei. They decondense, expand, and replicate their DNA in preparation for mitosis. The pronuclei then migrate toward each other, their nuclear envelopes disintegrate, and the male- and female-derived genetic material intermingles. This step completes the process of fertilization and results in a single-celled diploid zygote with all the genetic instructions it needs to develop into a human.

Most of the time, a woman releases a single egg during an ovulation cycle. However, in approximately 1 percent of ovulation cycles, two eggs are released and both are fertilized. Two zygotes form, implant, and develop, resulting in the birth of dizygotic (or fraternal) twins. Because dizygotic twins develop from two eggs fertilized by two sperm, they are no more identical than siblings born at different times.

Much less commonly, a zygote can divide into two separate offspring during early development. This results in the birth of monozygotic (or identical) twins. Although the zygote can split as early as the two-cell stage, splitting occurs most commonly during the early blastocyst stage, with roughly 70–100 cells present. These two scenarios are distinct from each other, in that the twin embryos that separated at the two-cell stage will have individual placentas, whereas twin embryos that form from separation at the blastocyst stage will share a placenta and a chorionic cavity. [caption id="attachment_3031" align="aligncenter" width="150"] Watch this CrashCourse video to learn more about fertilization![/caption]

28.2 Embryonic Development

barkerj1 — Wed, 06 Sep 2017 01:20:26 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the early events following fertilization, including the production of the morula and blastocyst, and implantation
Describe the formation of the three primary germ layers, specifying the tissues and organs that arise from each
Describe the formation and function of the four extra-embryonic membranes
Describe the origins and function of the placenta and umbilical cord

Throughout this chapter, we will express embryonic and fetal ages in terms of weeks from fertilization, commonly called conception. The period of time required for full development of a fetus in utero is referred to as gestation (gestare = “to carry” or “to bear”). It can be subdivided into distinct gestational periods. The first 2 weeks of prenatal development are referred to as the pre-embryonic stage. A developing human is referred to as an embryo during weeks 3–8, and a fetus from the ninth week of gestation until birth. In this section, we’ll cover the pre-embryonic and embryonic stages of development, which are characterized by cell division, migration, and differentiation. By the end of the embryonic period, all of the organ systems are structured in rudimentary form, although the organs themselves are either nonfunctional or only semi-functional.

Pre-implantation Embryonic Development

Following fertilization, the zygote and its associated membranes, together referred to as the conceptus, continue to be projected toward the uterus by peristalsis and beating cilia. During its journey to the uterus, the zygote undergoes five or six rapid mitotic cell divisions. Although each cleavage results in more cells, it does not increase the total volume of the conceptus (Figure 1). Each daughter cell produced by cleavage is called a blastomere (blastos = “germ,” in the sense of a seed or sprout).

Approximately 3 days after fertilization, a 16-cell conceptus reaches the uterus. The cells that had been loosely grouped are now compacted and look more like a solid mass. The name given to this structure is the morula (morula = “little mulberry”). Once inside the uterus, the conceptus floats freely for several more days. It continues to divide, creating a ball of approximately 100 cells, and consuming nutritive endometrial secretions called uterine milk while the uterine lining thickens. The ball of now tightly bound cells starts to secrete fluid and organize themselves around a fluid-filled cavity, the blastocoel. At this developmental stage, the conceptus is referred to as a blastocyst. Within this structure, a group of cells forms into an inner cell mass, which is fated to become the embryo. The cells that form the outer shell are called trophoblasts (trophe = “to feed” or “to nourish”). These cells will develop into the chorionic sac and the fetal portion of the placenta (the organ of nutrient, waste, and gas exchange between mother and the developing offspring).

The inner mass of embryonic cells is totipotent during this stage, meaning that each cell has the potential to differentiate into any cell type in the human body. Totipotency lasts for only a few days before the cells’ fates are set as being the precursors to a specific lineage of cells.

[caption id="" align="aligncenter" width="380"] Figure 1. Pre-Embryonic Cleavages. Pre-embryonic cleavages make use of the abundant cytoplasm of the conceptus as the cells rapidly divide without changing the total volume.[/caption] As the blastocyst forms, the trophoblast excretes enzymes that begin to degrade the zona pellucida. In a process called “hatching,” the conceptus breaks free of the zona pellucida in preparation for implantation.

[caption id="" align="aligncenter" width="120"] View this time-lapse movie of a conceptus starting at day 3.[/caption]

Implantation

At the end of the first week, the blastocyst comes in contact with the uterine wall and adheres to it, embedding itself in the uterine lining via the trophoblast cells. Thus begins the process of implantation, which signals the end of the pre-embryonic stage of development (Figure 2). Implantation can be accompanied by minor bleeding. The blastocyst typically implants in the fundus of the uterus or on the posterior wall. However, if the endometrium is not fully developed and ready to receive the blastocyst, the blastocyst will detach and find a better spot. A significant percentage (50–75 percent) of blastocysts fail to implant; when this occurs, the blastocyst is shed with the endometrium during menses. The high rate of implantation failure is one reason why pregnancy typically requires several ovulation cycles to achieve.

[caption id="" align="aligncenter" width="480"] Figure 2. Pre-Embryonic Development. Ovulation, fertilization, pre-embryonic development, and implantation occur at specific locations within the female reproductive system in a time span of approximately 1 week.[/caption]

When implantation succeeds and the blastocyst adheres to the endometrium, the superficial cells of the trophoblast fuse with each other, forming the syncytiotrophoblast, a multinucleated body that digests endometrial cells to firmly secure the blastocyst to the uterine wall. In response, the uterine mucosa rebuilds itself and envelops the blastocyst (Figure 3). The trophoblast secretes human chorionic gonadotropin (hCG), a hormone that directs the corpus luteum to survive, enlarge, and continue producing progesterone and estrogen to suppress menses. These functions of hCG are necessary for creating an environment suitable for the developing embryo. As a result of this increased production, hCG accumulates in the maternal bloodstream and is excreted in the urine. Implantation is complete by the middle of the second week. Just a few days after implantation, the trophoblast has secreted enough hCG for an at-home urine pregnancy test to give a positive result.

[caption id="" align="aligncenter" width="520"] Figure 3. Implantation. During implantation, the trophoblast cells of the blastocyst adhere to the endometrium and digest endometrial cells until it is attached securely.[/caption]

Most of the time an embryo implants within the body of the uterus in a location that can support growth and development. However, in one to two percent of cases, the embryo implants either outside the uterus (an ectopic pregnancy) or in a region of uterus that can create complications for the pregnancy. If the embryo implants in the inferior portion of the uterus, the placenta can potentially grow over the opening of the cervix, a condition call placenta previa.

Disorder: Ectopic Pregnancies

In the vast majority of ectopic pregnancies, the embryo does not complete its journey to the uterus and implants in the uterine tube, referred to as a tubal pregnancy. However, there are also ovarian ectopic pregnancies (in which the egg never left the ovary) and abdominal ectopic pregnancies (in which an egg was “lost” to the abdominal cavity during the transfer from ovary to uterine tube, or in which an embryo from a tubal pregnancy re-implanted in the abdomen). Once in the abdominal cavity, an embryo can implant into any well-vascularized structure—the rectouterine cavity (Douglas’ pouch), the mesentery of the intestines, and the greater omentum are some common sites.

Tubal pregnancies can be caused by scar tissue within the tube following a sexually transmitted bacterial infection. The scar tissue impedes the progress of the embryo into the uterus—in some cases “snagging” the embryo and, in other cases, blocking the tube completely. Approximately one half of tubal pregnancies resolve spontaneously. Implantation in a uterine tube causes bleeding, which appears to stimulate smooth muscle contractions and expulsion of the embryo. In the remaining cases, medical or surgical intervention is necessary. If an ectopic pregnancy is detected early, the embryo’s development can be arrested by the administration of the cytotoxic drug methotrexate, which inhibits the metabolism of folic acid. If diagnosis is late and the uterine tube is already ruptured, surgical repair is essential.

Even if the embryo has successfully found its way to the uterus, it does not always implant in an optimal location (the fundus or the posterior wall of the uterus). Placenta previa can result if an embryo implants close to the internal os of the uterus (the internal opening of the cervix). As the fetus grows, the placenta can partially or completely cover the opening of the cervix (Figure 4). Although it occurs in only 0.5 percent of pregnancies, placenta previa is the leading cause of antepartum hemorrhage (profuse vaginal bleeding after week 24 of pregnancy but prior to childbirth).

[caption id="" align="aligncenter" width="380"] Figure 4. Placenta Previa. An embryo that implants too close to the opening of the cervix can lead to placenta previa, a condition in which the placenta partially or completely covers the cervix.[/caption]

Embryonic Membranes

During the second week of development, with the embryo implanted in the uterus, cells within the blastocyst start to organize into layers. Some grow to form the extra-embryonic membranes needed to support and protect the growing embryo: the amnion, the yolk sac, the allantois, and the chorion.

At the beginning of the second week, the cells of the inner cell mass form into a two-layered disc of embryonic cells, and a space—the amniotic cavity—opens up between it and the trophoblast (Figure 5). Cells from the upper layer of the disc (the epiblast) extend around the amniotic cavity, creating a membranous sac that forms into the amnion by the end of the second week. The amnion fills with amniotic fluid and eventually grows to surround the embryo. Early in development, amniotic fluid consists almost entirely of a filtrate of maternal plasma, but as the kidneys of the fetus begin to function at approximately the eighth week, they add urine to the volume of amniotic fluid. Floating within the amniotic fluid, the embryo—and later, the fetus—is protected from trauma and rapid temperature changes. It can move freely within the fluid and can prepare for swallowing and breathing out of the uterus.

[caption id="" align="aligncenter" width="380"] Figure 5. Development of the Embryonic Disc. Formation of the embryonic disc leaves spaces on either side that develop into the amniotic cavity and the yolk sac.[/caption]

On the ventral side of the embryonic disc, opposite the amnion, cells in the lower layer of the embryonic disk (the hypoblast) extend into the blastocyst cavity and form a yolk sac. The yolk sac supplies some nutrients absorbed from the trophoblast and also provides primitive blood circulation to the developing embryo for the second and third week of development. When the placenta takes over nourishing the embryo at approximately week 4, the yolk sac has been greatly reduced in size and its main function is to serve as the source of blood cells and germ cells (cells that will give rise to gametes). During week 3, a finger-like outpocketing of the yolk sac develops into the allantois, a primitive excretory duct of the embryo that will become part of the urinary bladder. Together, the stalks of the yolk sac and allantois establish the outer structure of the umbilical cord.

The last of the extra-embryonic membranes is the chorion, which is the one membrane that surrounds all others. The development of the chorion will be discussed in more detail shortly, as it relates to the growth and development of the placenta.

Embryogenesis

As the third week of development begins, the two-layered disc of cells becomes a three-layered disc through the process of gastrulation, during which the cells transition from totipotency to multipotency. The embryo, which takes the shape of an oval-shaped disc, forms an indentation called the primitive streak along the dorsal surface of the epiblast. A node at the caudal or “tail” end of the primitive streak emits growth factors that direct cells to multiply and migrate. Cells migrate toward and through the primitive streak and then move laterally to create two new layers of cells. The first layer is the endoderm, a sheet of cells that displaces the hypoblast and lies adjacent to the yolk sac. The second layer of cells fills in as the middle layer, or mesoderm. The cells of the epiblast that remain (not having migrated through the primitive streak) become the ectoderm (Figure 6).

[caption id="" align="aligncenter" width="480"] Figure 6. Germ Layers. Formation of the three primary germ layers occurs during the first 2 weeks of development. The embryo at this stage is only a few millimeters in length.[/caption]

Each of these germ layers will develop into specific structures in the embryo. Whereas the ectoderm and endoderm form tightly connected epithelial sheets, the mesodermal cells are less organized and exist as a loosely connected cell community. The ectoderm gives rise to cell lineages that differentiate to become the central and peripheral nervous systems, sensory organs, epidermis, hair, and nails. Mesodermal cells ultimately become the skeleton, muscles, connective tissue, heart, blood vessels, and kidneys. The endoderm goes on to form the epithelial lining of the gastrointestinal tract, liver, and pancreas, as well as the lungs (Figure 7).

[caption id="" align="aligncenter" width="320"] Figure 7. Fates of Germ Layers in Embryo. Following gastrulation of the embryo in the third week, embryonic cells of the ectoderm, mesoderm, and endoderm begin to migrate and differentiate into the cell lineages that will give rise to mature organs and organ systems in the infant.[/caption]

Development of the Placenta

During the first several weeks of development, the cells of the endometrium—referred to as decidual cells—nourish the nascent embryo. During prenatal weeks 4–12, the developing placenta gradually takes over the role of feeding the embryo, and the decidual cells are no longer needed. The mature placenta is composed of tissues derived from the embryo, as well as maternal tissues of the endometrium. The placenta connects to the conceptus via the umbilical cord, which carries deoxygenated blood and wastes from the fetus through two umbilical arteries; nutrients and oxygen are carried from the mother to the fetus through the single umbilical vein. The umbilical cord is surrounded by the amnion, and the spaces within the cord around the blood vessels are filled with Wharton’s jelly, a mucous connective tissue.

The maternal portion of the placenta develops from the deepest layer of the endometrium, the decidua basalis. To form the embryonic portion of the placenta, the syncytiotrophoblast and the underlying cells of the trophoblast (cytotrophoblast cells) begin to proliferate along with a layer of extraembryonic mesoderm cells. These form the chorionic membrane, which envelops the entire conceptus as the chorion. The chorionic membrane forms finger-like structures called chorionic villi that burrow into the endometrium like tree roots, making up the fetal portion of the placenta. The cytotrophoblast cells perforate the chorionic villi, burrow farther into the endometrium, and remodel maternal blood vessels to augment maternal blood flow surrounding the villi. Meanwhile, fetal mesenchymal cells derived from the mesoderm fill the villi and differentiate into blood vessels, including the three umbilical blood vessels that connect the embryo to the developing placenta (Figure 8).

[caption id="" align="aligncenter" width="520"] Figure 8. Cross-Section of the Placenta. In the placenta, maternal and fetal blood components are conducted through the surface of the chorionic villi, but maternal and fetal bloodstreams never mix directly.[/caption]

The placenta develops throughout the embryonic period and during the first several weeks of the fetal period; placentation is complete by weeks 14–16. As a fully developed organ, the placenta provides nutrition and excretion, respiration, and endocrine function (Table 1 and Figure 9). It receives blood from the fetus through the umbilical arteries. Capillaries in the chorionic villi filter fetal wastes out of the blood and return clean, oxygenated blood to the fetus through the umbilical vein. Nutrients and oxygen are transferred from maternal blood surrounding the villi through the capillaries and into the fetal bloodstream. Some substances move across the placenta by simple diffusion. Oxygen, carbon dioxide, and any other lipid-soluble substances take this route. Other substances move across by facilitated diffusion. This includes water-soluble glucose. The fetus has a high demand for amino acids and iron, and those substances are moved across the placenta by active transport.

Maternal and fetal blood does not commingle because blood cells cannot move across the placenta. This separation prevents the mother’s cytotoxic T cells from reaching and subsequently destroying the fetus, which bears “non-self” antigens. Further, it ensures the fetal red blood cells do not enter the mother’s circulation and trigger antibody development (if they carry “non-self” antigens)—at least until the final stages of pregnancy or birth. This is the reason that, even in the absence of preventive treatment, an Rh⁻ mother doesn’t develop antibodies that could cause hemolytic disease in her first Rh⁺ fetus.

Although blood cells are not exchanged, the chorionic villi provide ample surface area for the two-way exchange of substances between maternal and fetal blood. The rate of exchange increases throughout gestation as the villi become thinner and increasingly branched. The placenta is permeable to lipid-soluble fetotoxic substances: alcohol, nicotine, barbiturates, antibiotics, certain pathogens, and many other substances that can be dangerous or fatal to the developing embryo or fetus. For these reasons, pregnant women should avoid fetotoxic substances. Alcohol consumption by pregnant women, for example, can result in a range of abnormalities referred to as fetal alcohol spectrum disorders (FASD). These include organ and facial malformations, as well as cognitive and behavioral disorders.

Functions of the Placenta (Table 1)
Nutrition and digestion	Respiration	Endocrine function
Mediates diffusion of maternal glucose, amino acids, fatty acids, vitamins, and minerals Stores nutrients during early pregnancy to accommodate increased fetal demand later in pregnancy Excretes and filters fetal nitrogenous wastes into maternal blood	Mediates maternal-to-fetal oxygen transport and fetal-to-maternal carbon dioxide transport	Secretes several hormones, including hCG, estrogens, and progesterone, to maintain the pregnancy and stimulate maternal and fetal development Mediates the transmission of maternal hormones into fetal blood and vice versa

[caption id="" align="aligncenter" width="320"] Figure 9. Placenta. This post-expulsion placenta and umbilical cord (white) are viewed from the fetal side.[/caption]

Organogenesis

Following gastrulation, rudiments of the central nervous system develop from the ectoderm in the process of neurulation (Figure 10). Specialized neuroectodermal tissues along the length of the embryo thicken into the neural plate. During the fourth week, tissues on either side of the plate fold upward into a neural fold. The two folds converge to form the neural tube. The tube lies atop a rod-shaped, mesoderm-derived notochord, which eventually becomes the nucleus pulposus of intervertebral discs. Block-like structures called somites form on either side of the tube, eventually differentiating into the axial skeleton, skeletal muscle, and dermis. During the fourth and fifth weeks, the anterior neural tube dilates and subdivides to form vesicles that will become the brain structures.

Folate, one of the B vitamins, is important to the healthy development of the neural tube. A deficiency of maternal folate in the first weeks of pregnancy can result in neural tube defects, including spina bifida—a birth defect in which spinal tissue protrudes through the newborn’s vertebral column, which has failed to completely close. A more severe neural tube defect is anencephaly, a partial or complete absence of brain tissue.

[caption id="" align="aligncenter" width="500"] Figure 10. Neurulation. The embryonic process of neurulation establishes the rudiments of the future central nervous system and skeleton.[/caption]

The embryo, which begins as a flat sheet of cells, begins to acquire a cylindrical shape through the process of embryonic folding (Figure 11). The embryo folds laterally and again at either end, forming a C-shape with distinct head and tail ends. The embryo envelops a portion of the yolk sac, which protrudes with the umbilical cord from what will become the abdomen. The folding essentially creates a tube, called the primitive gut, that is lined by the endoderm. The amniotic sac, which was sitting on top of the flat embryo, envelops the embryo as it folds.

[caption id="" align="aligncenter" width="520"] Figure 11. Embryonic Folding. Embryonic folding converts a flat sheet of cells into a hollow, tube-like structure.[/caption]

Within the first 8 weeks of gestation, a developing embryo establishes the rudimentary structures of all of its organs and tissues from the ectoderm, mesoderm, and endoderm. This process is called organogenesis.

Like the central nervous system, the heart also begins its development in the embryo as a tube-like structure, connected via capillaries to the chorionic villi. Cells of the primitive tube-shaped heart are capable of electrical conduction and contraction. The heart begins beating in the beginning of the fourth week, although it does not actually pump embryonic blood until a week later, when the oversized liver has begun producing red blood cells. (This is a temporary responsibility of the embryonic liver that the bone marrow will assume during fetal development.) During weeks 4–5, the eye pits form, limb buds become apparent, and the rudiments of the pulmonary system are formed.

During the sixth week, uncontrolled fetal limb movements begin to occur. The gastrointestinal system develops too rapidly for the embryonic abdomen to accommodate it, and the intestines temporarily loop into the umbilical cord. Paddle-shaped hands and feet develop fingers and toes by the process of apoptosis (programmed cell death), which causes the tissues between the fingers to disintegrate. By week 7, the facial structure is more complex and includes nostrils, outer ears, and lenses (Figure 12). By the eighth week, the head is nearly as large as the rest of the embryo’s body, and all major brain structures are in place. The external genitalia are apparent, but at this point, male and female embryos are indistinguishable. Bone begins to replace cartilage in the embryonic skeleton through the process of ossification. By the end of the embryonic period, the embryo is approximately 3 cm (1.2 in) from crown to rump and weighs approximately 8 g (0.25 oz).

[caption id="" align="aligncenter" width="320"] Figure 12. Embryo at 7 Weeks. An embryo at the end of 7 weeks of development is only 10 mm in length, but its developing eyes, limb buds, and tail are already visible. (This embryo was derived from an ectopic pregnancy.) (credit: Ed Uthman)[/caption] [caption id="attachment_3033" align="aligncenter" width="150"] Watch this CrashCourse video to learn about the stages of embryonic development![/caption]

28.3 Fetal Development

barkerj1 — Wed, 06 Sep 2017 01:20:26 +0000

Learning Objectives

By the end of this section, you will be able to:

Define the terms "embryo" and "fetus"

As you will recall, a developing human is called a fetus from the ninth week of gestation until birth. This 30-week period of development is marked by continued cell growth and differentiation, which fully develop the structures and functions of the immature organ systems formed during the embryonic period. The completion of fetal development results in a newborn who, although still immature in many ways, is capable of survival outside the womb.

Sexual Differentiation

Sexual differentiation does not begin until the fetal period, during weeks 9–12. Embryonic males and females, though genetically distinguishable, are morphologically identical (Figure 1). Bipotential gonads, or gonads that can develop into male or female sexual organs, are connected to a central cavity called the cloaca via Müllerian ducts and Wolffian ducts. (The cloaca is an extension of the primitive gut.) Several events lead to sexual differentiation during this period.

During male fetal development, the bipotential gonads become the testes and associated epididymis. The Müllerian ducts degenerate. The Wolffian ducts become the vas deferens, and the cloaca becomes the urethra and rectum.

During female fetal development, the bipotential gonads develop into ovaries. The Wolffian ducts degenerate. The Müllerian ducts become the uterine tubes and uterus, and the cloaca divides and develops into a vagina, a urethra, and a rectum.

[caption id="" align="aligncenter" width="350"] Figure 1. Sexual Differentiation. Differentiation of the male and female reproductive systems does not occur until the fetal period of development.[/caption]

The Fetal Circulatory System

During prenatal development, the fetal circulatory system is integrated with the placenta via the umbilical cord so that the fetus receives both oxygen and nutrients from the placenta. However, after childbirth, the umbilical cord is severed, and the newborn’s circulatory system must be reconfigured. When the heart first forms in the embryo, it exists as two parallel tubes derived from mesoderm and lined with endothelium, which then fuse together. As the embryo develops into a fetus, the tube-shaped heart folds and further differentiates into the four chambers present in a mature heart. Unlike a mature cardiovascular system, however, the fetal cardiovascular system also includes circulatory shortcuts, or shunts. A shunt is an anatomical (or sometimes surgical) diversion that allows blood flow to bypass immature organs such as the lungs and liver until childbirth.

The placenta provides the fetus with necessary oxygen and nutrients via the umbilical vein. (Remember that veins carry blood toward the heart. In this case, the blood flowing to the fetal heart is oxygenated because it comes from the placenta. The respiratory system is immature and cannot yet oxygenate blood on its own.) From the umbilical vein, the oxygenated blood flows toward the inferior vena cava, all but bypassing the immature liver, via the ductus venosus shunt (Figure 2). The liver receives just a trickle of blood, which is all that it needs in its immature, semifunctional state. Blood flows from the inferior vena cava to the right atrium, mixing with fetal venous blood along the way.

Although the fetal liver is semifunctional, the fetal lungs are nonfunctional. The fetal circulation therefore bypasses the lungs by shifting some of the blood through the foramen ovale, a shunt that directly connects the right and left atria and avoids the pulmonary trunk altogether. Most of the rest of the blood is pumped to the right ventricle, and from there, into the pulmonary trunk, which splits into pulmonary arteries. However, a shunt within the pulmonary artery, the ductus arteriosus, diverts a portion of this blood into the aorta. This ensures that only a small volume of oxygenated blood passes through the immature pulmonary circuit, which has only minor metabolic requirements. Blood vessels of uninflated lungs have high resistance to flow, a condition that encourages blood to flow to the aorta, which presents much lower resistance. The oxygenated blood moves through the foramen ovale into the left atrium, where it mixes with the now deoxygenated blood returning from the pulmonary circuit. This blood then moves into the left ventricle, where it is pumped into the aorta. Some of this blood moves through the coronary arteries into the myocardium, and some moves through the carotid arteries to the brain.

The descending aorta carries partially oxygenated and partially deoxygenated blood into the lower regions of the body. It eventually passes into the umbilical arteries through branches of the internal iliac arteries. The deoxygenated blood collects waste as it circulates through the fetal body and returns to the umbilical cord. Thus, the two umbilical arteries carry blood low in oxygen and high in carbon dioxide and fetal wastes. This blood is filtered through the placenta, where wastes diffuse into the maternal circulation. Oxygen and nutrients from the mother diffuse into the placenta and from there into the fetal blood, and the process repeats.

[caption id="" align="aligncenter" width="525"] Figure 2. Fetal Circulatory System. The fetal circulatory system includes three shunts to divert blood from undeveloped and partially functioning organs, as well as blood supply to and from the placenta.[/caption]

Other Organ Systems

During weeks 9–12 of fetal development, the brain continues to expand, the body elongates, and ossification continues. Fetal movements are frequent during this period, but are jerky and not well-controlled. The bone marrow begins to take over the process of erythrocyte production—a task that the liver performed during the embryonic period. The liver now secretes bile. The fetus circulates amniotic fluid by swallowing it and producing urine. The eyes are well-developed by this stage, but the eyelids are fused shut. The fingers and toes begin to develop nails. By the end of week 12, the fetus measures approximately 9 cm (3.5 in) from crown to rump.

Weeks 13–16 are marked by sensory organ development. The eyes move closer together; blinking motions begin, although the eyes remain sealed shut. The lips exhibit sucking motions. The ears move upward and lie flatter against the head. The scalp begins to grow hair. The excretory system is also developing: the kidneys are well-formed, and meconium, or fetal feces, begins to accumulate in the intestines. Meconium consists of ingested amniotic fluid, cellular debris, mucus, and bile.

During approximately weeks 16–20, as the fetus grows and limb movements become more powerful, the mother may begin to feel quickening, or fetal movements. However, space restrictions limit these movements and typically force the growing fetus into the “fetal position,” with the arms crossed and the legs bent at the knees. Sebaceous glands coat the skin with a waxy, protective substance called vernix caseosa that protects and moisturizes the skin and may provide lubrication during childbirth. A silky hair called lanugo also covers the skin during weeks 17–20, but it is shed as the fetus continues to grow. Extremely premature infants sometimes exhibit residual lanugo.

Developmental weeks 21–30 are characterized by rapid weight gain, which is important for maintaining a stable body temperature after birth. The bone marrow completely takes over erythrocyte synthesis, and the axons of the spinal cord begin to be myelinated, or coated in the electrically insulating glial cell sheaths that are necessary for efficient nervous system functioning. (The process of myelination is not completed until adolescence.) During this period, the fetus grows eyelashes. The eyelids are no longer fused and can be opened and closed. The lungs begin producing surfactant, a substance that reduces surface tension in the lungs and assists proper lung expansion after birth. Inadequate surfactant production in premature newborns may result in respiratory distress syndrome, and as a result, the newborn may require surfactant replacement therapy, supplemental oxygen, or maintenance in a continuous positive airway pressure (CPAP) chamber during their first days or weeks of life. In male fetuses, the testes descend into the scrotum near the end of this period. The fetus at 30 weeks measures 28 cm (11 in) from crown to rump and exhibits the approximate body proportions of a full-term newborn, but still is much leaner.

The fetus continues to lay down subcutaneous fat from week 31 until birth. The added fat fills out the hypodermis, and the skin transitions from red and wrinkled to soft and pink. Lanugo is shed, and the nails grow to the tips of the fingers and toes. Immediately before birth, the average crown-to-rump length is 35.5–40.5 cm (14–16 in), and the fetus weighs approximately 2.5–4 kg (5.5–8.8 lbs). Once born, the newborn is no longer confined to the fetal position, so subsequent measurements are made from head-to-toe instead of from crown-to-rump. At birth, the average length is approximately 51 cm (20 in).

28.4 Maternal Changes During Pregnancy, Labor, and Birth

barkerj1 — Wed, 06 Sep 2017 01:20:27 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the physiological basis of the human chorionic gonadotropin (hCG) test
Describe the roles of the following hormones in pregnancy:
- Estrogen
- Progesterone
- Prolactin
- Oxytocin
Describe the roles of the following hormones in labour:
- Estrogen
- Progesterone
- Prolactin
- Oxytocin
Describe the hormonal changes which induce labour
Describe the three stages of labour

A full-term pregnancy lasts approximately 270 days (approximately 38.5 weeks) from conception to birth. Because it is easier to remember the first day of the last menstrual period (LMP) than to estimate the date of conception, obstetricians set the due date as 284 days (approximately 40.5 weeks) from the LMP. This assumes that conception occurred on day 14 of the woman’s cycle, which is usually a good approximation. The 40 weeks of an average pregnancy are usually discussed in terms of three trimesters, each approximately 13 weeks. During the second and third trimesters, the pre-pregnancy uterus—about the size of a fist—grows dramatically to contain the fetus, causing a number of anatomical changes in the mother (Figure 1).

[caption id="" align="aligncenter" width="300"] Figure 1. Size of Uterus throughout Pregnancy. The uterus grows throughout pregnancy to accommodate the fetus.[/caption]

Effects of Hormones

Virtually all of the effects of pregnancy can be attributed in some way to the influence of hormones—particularly estrogens, progesterone, and human chorionic gonadotropin (hCG). During weeks 7–12 from the LMP, the pregnancy hormones are primarily generated by the corpus luteum. Progesterone secreted by the corpus luteum stimulates the production of decidual cells of the endometrium that nourish the blastocyst before placentation. As the placenta develops and the corpus luteum degenerates during weeks 12–17, the placenta gradually takes over as the endocrine organ of pregnancy.

The placenta converts weak androgens secreted by the maternal and fetal adrenal glands to estrogens, which are necessary for pregnancy to progress. Estrogen levels climb throughout the pregnancy, increasing 30-fold by childbirth. Estrogens have the following actions:

They suppress FSH and LH production, effectively preventing ovulation. (This function is the biological basis of hormonal birth control pills.)
They induce the growth of fetal tissues and are necessary for the maturation of the fetal lungs and liver.
They promote fetal viability by regulating progesterone production and triggering fetal synthesis of cortisol, which helps with the maturation of the lungs, liver, and endocrine organs such as the thyroid gland and adrenal gland.
They stimulate maternal tissue growth, leading to uterine enlargement and mammary duct expansion and branching.

Relaxin, another hormone secreted by the corpus luteum and then by the placenta, helps prepare the mother’s body for childbirth. It increases the elasticity of the symphysis pubis joint and pelvic ligaments, making room for the growing fetus and allowing expansion of the pelvic outlet for childbirth. Relaxin also helps dilate the cervix during labor.

The placenta takes over the synthesis and secretion of progesterone throughout pregnancy as the corpus luteum degenerates. Like estrogen, progesterone suppresses FSH and LH. It also inhibits uterine contractions, protecting the fetus from preterm birth. This hormone decreases in late gestation, allowing uterine contractions to intensify and eventually progress to true labor. The placenta also produces hCG. In addition to promoting survival of the corpus luteum, hCG stimulates the male fetal gonads to secrete testosterone, which is essential for the development of the male reproductive system.

The anterior pituitary enlarges and ramps up its hormone production during pregnancy, raising the levels of thyrotropin, prolactin, and adrenocorticotropic hormone (ACTH). Thyrotropin, in conjunction with placental hormones, increases the production of thyroid hormone, which raises the maternal metabolic rate. This can markedly augment a pregnant woman’s appetite and cause hot flashes. Prolactin stimulates enlargement of the mammary glands in preparation for milk production. ACTH stimulates maternal cortisol secretion, which contributes to fetal protein synthesis. In addition to the pituitary hormones, increased parathyroid levels mobilize calcium from maternal bones for fetal use.

Weight Gain

The second and third trimesters of pregnancy are associated with dramatic changes in maternal anatomy and physiology. The most obvious anatomical sign of pregnancy is the dramatic enlargement of the abdominal region, coupled with maternal weight gain. This weight results from the growing fetus as well as the enlarged uterus, amniotic fluid, and placenta. Additional breast tissue and dramatically increased blood volume also contribute to weight gain (Table 2). Surprisingly, fat storage accounts for only approximately 2.3 kg (5 lbs) in a normal pregnancy and serves as a reserve for the increased metabolic demand of breastfeeding.

During the first trimester, the mother does not need to consume additional calories to maintain a healthy pregnancy. However, a weight gain of approximately 0.45 kg (1 lb) per month is common. During the second and third trimesters, the mother’s appetite increases, but it is only necessary for her to consume an additional 300 calories per day to support the growing fetus. Most women gain approximately 0.45 kg (1 lb) per week.

Contributors to Weight Gain During Pregnancy (Table 2)
Component	Weight (kg)	Weight (lb)
Fetus	3.2–3.6	7–8
Placenta and fetal membranes	0.9–1.8	2–4
Amniotic fluid	0.9–1.4	2–3
Breast tissue	0.9–1.4	2–3
Blood	1.4	4
Fat	0.9–4.1	3–9
Uterus	0.9–2.3	2–5
Total	10–16.3	22–36

Changes in Organ Systems During Pregnancy

As the woman’s body adapts to pregnancy, characteristic physiologic changes occur. These changes can sometimes prompt symptoms often referred to collectively as the common discomforts of pregnancy.

Digestive and Urinary System Changes

Nausea and vomiting, sometimes triggered by an increased sensitivity to odors, are common during the first few weeks to months of pregnancy. This phenomenon is often referred to as “morning sickness,” although the nausea may persist all day. The source of pregnancy nausea is thought to be the increased circulation of pregnancy-related hormones, specifically circulating estrogen, progesterone, and hCG. Decreased intestinal peristalsis may also contribute to nausea. By about week 12 of pregnancy, nausea typically subsides.

A common gastrointestinal complaint during the later stages of pregnancy is gastric reflux, or heartburn, which results from the upward, constrictive pressure of the growing uterus on the stomach. The same decreased peristalsis that may contribute to nausea in early pregnancy is also thought to be responsible for pregnancy-related constipation as pregnancy progresses.

The downward pressure of the uterus also compresses the urinary bladder, leading to frequent urination. The problem is exacerbated by increased urine production. In addition, the maternal urinary system processes both maternal and fetal wastes, further increasing the total volume of urine.

Circulatory System Changes

Blood volume increases substantially during pregnancy, so that by childbirth, it exceeds its preconception volume by 30 percent, or approximately 1–2 liters. The greater blood volume helps to manage the demands of fetal nourishment and fetal waste removal. In conjunction with increased blood volume, the pulse and blood pressure also rise moderately during pregnancy. As the fetus grows, the uterus compresses underlying pelvic blood vessels, hampering venous return from the legs and pelvic region. As a result, many pregnant women develop varicose veins or hemorrhoids.

Respiratory System Changes

During the second half of pregnancy, the respiratory minute volume (volume of gas inhaled or exhaled by the lungs per minute) increases by 50 percent to compensate for the oxygen demands of the fetus and the increased maternal metabolic rate. The growing uterus exerts upward pressure on the diaphragm, decreasing the volume of each inspiration and potentially causing shortness of breath, or dyspnea. During the last several weeks of pregnancy, the pelvis becomes more elastic, and the fetus descends lower in a process called lightening. This typically ameliorates dyspnea.

The respiratory mucosa swell in response to increased blood flow during pregnancy, leading to nasal congestion and nose bleeds, particularly when the weather is cold and dry. Humidifier use and increased fluid intake are often recommended to counteract congestion.

Integumentary System Changes

The dermis stretches extensively to accommodate the growing uterus, breast tissue, and fat deposits on the thighs and hips. Torn connective tissue beneath the dermis can cause striae (stretch marks) on the abdomen, which appear as red or purple marks during pregnancy that fade to a silvery white color in the months after childbirth.

An increase in melanocyte-stimulating hormone, in conjunction with estrogens, darkens the areolae and creates a line of pigment from the umbilicus to the pubis called the linea nigra (Figure 2). Melanin production during pregnancy may also darken or discolor skin on the face to create a chloasma, or “mask of pregnancy.”

[caption id="" align="aligncenter" width="225"] Figure 2. Linea Nigra. The linea nigra, a dark medial line running from the umbilicus to the pubis, forms during pregnancy and persists for a few weeks following childbirth. The linea nigra shown here corresponds to a pregnancy that is 22 weeks along.[/caption]

Physiology of Labor

Childbirth, or parturition, typically occurs within a week of a woman’s due date, unless the woman is pregnant with more than one fetus, which usually causes her to go into labor early. As a pregnancy progresses into its final weeks, several physiological changes occur in response to hormones that trigger labor.

First, recall that progesterone inhibits uterine contractions throughout the first several months of pregnancy. As the pregnancy enters its seventh month, progesterone levels plateau and then drop. Estrogen levels, however, continue to rise in the maternal circulation (Figure 3). The increasing ratio of estrogen to progesterone makes the myometrium (the uterine smooth muscle) more sensitive to stimuli that promote contractions (because progesterone no longer inhibits them). Moreover, in the eighth month of pregnancy, fetal cortisol rises, which boosts estrogen secretion by the placenta and further overpowers the uterine-calming effects of progesterone. Some women may feel the result of the decreasing levels of progesterone in late pregnancy as weak and irregular peristaltic Braxton Hicks contractions, also called false labor. These contractions can often be relieved with rest or hydration.

[caption id="" align="aligncenter" width="400"] Figure 3. Hormones Initiating Labor. A positive feedback loop of hormones works to initiate labor.[/caption] A common sign that labor will begin shortly is the so-called “bloody show.” During pregnancy, a plug of mucus accumulates in the cervical canal, blocking the entrance to the uterus. Approximately 1–2 days prior to the onset of true labor, this plug loosens and is expelled, along with a small amount of blood.

Meanwhile, the posterior pituitary has been boosting its secretion of oxytocin, a hormone that stimulates the contractions of labor. At the same time, the myometrium increases its sensitivity to oxytocin by expressing more receptors for this hormone. As labor nears, oxytocin begins to stimulate stronger, more painful uterine contractions, which—in a positive feedback loop—stimulate the secretion of prostaglandins from fetal membranes. Like oxytocin, prostaglandins also enhance uterine contractile strength. The fetal pituitary also secretes oxytocin, which increases prostaglandins even further. Given the importance of oxytocin and prostaglandins to the initiation and maintenance of labor, it is not surprising that, when a pregnancy is not progressing to labor and needs to be induced, a pharmaceutical version of these compounds (called pitocin) is administered by intravenous drip.

Finally, stretching of the myometrium and cervix by a full-term fetus in the vertex (head-down) position is regarded as a stimulant to uterine contractions. The sum of these changes initiates the regular contractions known as true labor, which become more powerful and more frequent with time. The pain of labor is attributed to myometrial hypoxia during uterine contractions.

Stages of Childbirth

The process of childbirth can be divided into three stages: cervical dilation, expulsion of the newborn, and afterbirth (Figure 4).

Cervical Dilation

For vaginal birth to occur, the cervix must dilate fully to 10 cm in diameter—wide enough to deliver the newborn’s head. The dilation stage is the longest stage of labor and typically takes 6–12 hours. However, it varies widely and may take minutes, hours, or days, depending in part on whether the mother has given birth before; in each subsequent labor, this stage tends to be shorter.

[caption id="" align="aligncenter" width="420"] Figure 4. Stages of Childbirth. The stages of childbirth include Stage 1, early cervical dilation; Stage 2, full dilation and expulsion of the newborn; and Stage 3, delivery of the placenta and associated fetal membranes. (The position of the newborn’s shoulder is described relative to the mother.)[/caption]

True labor progresses in a positive feedback loop in which uterine contractions stretch the cervix, causing it to dilate and efface, or become thinner. Cervical stretching induces reflexive uterine contractions that dilate and efface the cervix further. In addition, cervical dilation boosts oxytocin secretion from the pituitary, which in turn triggers more powerful uterine contractions. When labor begins, uterine contractions may occur only every 3–30 minutes and last only 20–40 seconds; however, by the end of this stage, contractions may occur as frequently as every 1.5–2 minutes and last for a full minute.

Each contraction sharply reduces oxygenated blood flow to the fetus. For this reason, it is critical that a period of relaxation occur after each contraction. Fetal distress, measured as a sustained decrease or increase in the fetal heart rate, can result from severe contractions that are too powerful or lengthy for oxygenated blood to be restored to the fetus. Such a situation can be cause for an emergency birth with vacuum, forceps, or surgically by Caesarian section.

The amniotic membranes rupture before the onset of labor in about 12 percent of women; they typically rupture at the end of the dilation stage in response to excessive pressure from the fetal head entering the birth canal.

Expulsion Stage

The expulsion stage begins when the fetal head enters the birth canal and ends with birth of the newborn. It typically takes up to 2 hours, but it can last longer or be completed in minutes, depending in part on the orientation of the fetus. The vertex presentation known as the occiput anterior vertex is the most common presentation and is associated with the greatest ease of vaginal birth. The fetus faces the maternal spinal cord and the smallest part of the head (the posterior aspect called the occiput) exits the birth canal first.

In fewer than 5 percent of births, the infant is oriented in the breech presentation, or buttocks down. In a complete breech, both legs are crossed and oriented downward. In a frank breech presentation, the legs are oriented upward. Before the 1960s, it was common for breech presentations to be delivered vaginally. Today, most breech births are accomplished by Caesarian section.

Vaginal birth is associated with significant stretching of the vaginal canal, the cervix, and the perineum. Until recent decades, it was routine procedure for an obstetrician to numb the perineum and perform an episiotomy, an incision in the posterior vaginal wall and perineum. The perineum is now more commonly allowed to tear on its own during birth. Both an episiotomy and a perineal tear need to be sutured shortly after birth to ensure optimal healing. Although suturing the jagged edges of a perineal tear may be more difficult than suturing an episiotomy, tears heal more quickly, are less painful, and are associated with less damage to the muscles around the vagina and rectum.

Upon birth of the newborn’s head, an obstetrician will aspirate mucus from the mouth and nose before the newborn’s first breath. Once the head is birthed, the rest of the body usually follows quickly. The umbilical cord is then double-clamped, and a cut is made between the clamps. This completes the second stage of childbirth.

Afterbirth

The delivery of the placenta and associated membranes, commonly referred to as the afterbirth, marks the final stage of childbirth. After expulsion of the newborn, the myometrium continues to contract. This movement shears the placenta from the back of the uterine wall. It is then easily delivered through the vagina. Continued uterine contractions then reduce blood loss from the site of the placenta. Delivery of the placenta marks the beginning of the postpartum period—the period of approximately 6 weeks immediately following childbirth during which the mother’s body gradually returns to a non-pregnant state. If the placenta does not birth spontaneously within approximately 30 minutes, it is considered retained, and the obstetrician may attempt manual removal. If this is not successful, surgery may be required.

It is important that the obstetrician examines the expelled placenta and fetal membranes to ensure that they are intact. If fragments of the placenta remain in the uterus, they can cause postpartum hemorrhage. Uterine contractions continue for several hours after birth to return the uterus to its pre-pregnancy size in a process called involution, which also allows the mother’s abdominal organs to return to their pre-pregnancy locations. Breastfeeding facilitates this process.

Although postpartum uterine contractions limit blood loss from the detachment of the placenta, the mother does experience a postpartum vaginal discharge called lochia. This is made up of uterine lining cells, erythrocytes, leukocytes, and other debris. Thick, dark, lochia rubra (red lochia) typically continues for 2–3 days, and is replaced by lochia serosa, a thinner, pinkish form that continues until about the tenth postpartum day. After this period, a scant, creamy, or watery discharge called lochia alba (white lochia) may continue for another 1–2 weeks.

28.5 Adjustments of the Infant at Birth and Postnatal Stages

barkerj1 — Wed, 06 Sep 2017 01:20:29 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the changes which occur in the fetal circulation following delivery

From a fetal perspective, the process of birth is a crisis. In the womb, the fetus was snuggled in a soft, warm, dark, and quiet world. The placenta provided nutrition and oxygen continuously. Suddenly, the contractions of labor and vaginal childbirth forcibly squeeze the fetus through the birth canal, limiting oxygenated blood flow during contractions and shifting the skull bones to accommodate the small space. After birth, the newborn’s system must make drastic adjustments to a world that is colder, brighter, and louder, and where he or she will experience hunger and thirst. The neonatal period (neo- = “new”; -natal = “birth”) spans the first to the thirtieth day of life outside of the uterus.

Respiratory Adjustments

Although the fetus “practices” breathing by inhaling amniotic fluid in utero, there is no air in the uterus and thus no true opportunity to breathe. (There is also no need to breathe because the placenta supplies the fetus with all the oxygenated blood it needs.) During gestation, the partially collapsed lungs are filled with amniotic fluid and exhibit very little metabolic activity. Several factors stimulate newborns to take their first breath at birth. First, labor contractions temporarily constrict umbilical blood vessels, reducing oxygenated blood flow to the fetus and elevating carbon dioxide levels in the blood. High carbon dioxide levels cause acidosis and stimulate the respiratory center in the brain, triggering the newborn to take a breath.

The first breath typically is taken within 10 seconds of birth, after mucus is aspirated from the infant’s mouth and nose. The first breaths inflate the lungs to nearly full capacity and dramatically decrease lung pressure and resistance to blood flow, causing a major circulatory reconfiguration. Pulmonary alveoli open, and alveolar capillaries fill with blood. Amniotic fluid in the lungs drains or is absorbed, and the lungs immediately take over the task of the placenta, exchanging carbon dioxide for oxygen by the process of respiration.

Circulatory Adjustments

The process of clamping and cutting the umbilical cord collapses the umbilical blood vessels. In the absence of medical assistance, this occlusion would occur naturally within 20 minutes of birth because the Wharton’s jelly within the umbilical cord would swell in response to the lower temperature outside of the mother’s body, and the blood vessels would constrict. Natural occlusion has occurred when the umbilical cord is no longer pulsating. For the most part, the collapsed vessels atrophy and become fibrotic remnants, existing in the mature circulatory system as ligaments of the abdominal wall and liver. The ductus venosus degenerates to become the ligamentum venosum beneath the liver. Only the proximal sections of the two umbilical arteries remain functional, taking on the role of supplying blood to the upper part of the bladder (Figure 1).

[caption id="" align="aligncenter" width="500"] Figure 1. Neonatal Circulatory System. A newborn’s circulatory system reconfigures immediately after birth. The three fetal shunts have been closed permanently, facilitating blood flow to the liver and lungs.[/caption]

The newborn’s first breath is vital to initiate the transition from the fetal to the neonatal circulatory pattern. Inflation of the lungs decreases blood pressure throughout the pulmonary system, as well as in the right atrium and ventricle. In response to this pressure change, the flow of blood temporarily reverses direction through the foramen ovale, moving from the left to the right atrium, and blocking the shunt with two flaps of tissue. Within 1 year, the tissue flaps usually fuse over the shunt, turning the foramen ovale into the fossa ovalis. The ductus arteriosus constricts as a result of increased oxygen concentration, and becomes the ligamentum arteriosum. Closing of the ductus arteriosus ensures that all blood pumped to the pulmonary circuit will be oxygenated by the newly functional neonatal lungs.

Thermoregulatory Adjustments

The fetus floats in warm amniotic fluid that is maintained at a temperature of approximately 98.6°F with very little fluctuation. Birth exposes newborns to a cooler environment in which they have to regulate their own body temperature. Newborns have a higher ratio of surface area to volume than adults. This means that their body has less volume throughout which to produce heat, and more surface area from which to lose heat. As a result, newborns produce heat more slowly and lose it more quickly. Newborns also have immature musculature that limits their ability to generate heat by shivering. Moreover, their nervous systems are underdeveloped, so they cannot quickly constrict superficial blood vessels in response to cold. They also have little subcutaneous fat for insulation. All these factors make it harder for newborns to maintain their body temperature.

Newborns, however, do have a special method for generating heat: nonshivering thermogenesis, which involves the breakdown of brown adipose tissue, or brown fat, which is distributed over the back, chest, and shoulders. Brown fat differs from the more familiar white fat in two ways:

It is highly vascularized. This allows for faster delivery of oxygen, which leads to faster cellular respiration.
It is packed with a special type of mitochondria that are able to engage in cellular respiration reactions that produce less ATP and more heat than standard cellular respiration reactions.

The breakdown of brown fat occurs automatically upon exposure to cold, so it is an important heat regulator in newborns. During fetal development, the placenta secretes inhibitors that prevent metabolism of brown adipose fat and promote its accumulation in preparation for birth.

Gastrointestinal and Urinary Adjustments

In adults, the gastrointestinal tract harbors bacterial flora—trillions of bacteria that aid in digestion, produce vitamins, and protect from the invasion or replication of pathogens. In stark contrast, the fetal intestine is sterile. The first consumption of breast milk or formula floods the neonatal gastrointestinal tract with beneficial bacteria that begin to establish the bacterial flora.

The fetal kidneys filter blood and produce urine, but the neonatal kidneys are still immature and inefficient at concentrating urine. Therefore, newborns produce very dilute urine, making it particularly important for infants to obtain sufficient fluids from breast milk or formula.

Homeostasis in the Newborn: Apgar Score

In the minutes following birth, a newborn must undergo dramatic systemic changes to be able to survive outside the womb. An obstetrician, midwife, or nurse can estimate how well a newborn is doing by obtaining an Apgar score. The Apgar score was introduced in 1952 by the anesthesiologist Dr. Virginia Apgar as a method to assess the effects on the newborn of anesthesia given to the laboring mother. Healthcare providers now use it to assess the general wellbeing of the newborn, whether or not analgesics or anesthetics were used.

Five criteria—skin color, heart rate, reflex, muscle tone, and respiration—are assessed, and each criterion is assigned a score of 0, 1, or 2. Scores are taken at 1 minute after birth and again at 5 minutes after birth. Each time that scores are taken, the five scores are added together. High scores (out of a possible 10) indicate the baby has made the transition from the womb well, whereas lower scores indicate that the baby may be in distress.

The technique for determining an Apgar score is quick and easy, painless for the newborn, and does not require any instruments except for a stethoscope. A convenient way to remember the five scoring criteria is to apply the mnemonic APGAR, for “appearance” (skin color), “pulse” (heart rate), “grimace” (reflex), “activity” (muscle tone), and “respiration.”

Of the five Apgar criteria, heart rate and respiration are the most critical. Poor scores for either of these measurements may indicate the need for immediate medical attention to resuscitate or stabilize the newborn. In general, any score lower than 7 at the 5-minute mark indicates that medical assistance may be needed. A total score below 5 indicates an emergency situation. Normally, a newborn will get an intermediate score of 1 for some of the Apgar criteria and will progress to a 2 by the 5-minute assessment. Scores of 8 or above are normal.

28.6 Lactation

barkerj1 — Wed, 06 Sep 2017 01:20:30 +0000

Learning Objectives

By the end of this section, you will be able to:

Describe the roles of the following hormones in lactation:
- Estrogen
- Progesterone
- Prolactin
- Oxytocin
Describe the hormonal changes involved in breast development
Describe the hormonal changes involved in lactation

Lactation is the process by which milk is synthesized and secreted from the mammary glands of the postpartum female breast in response to an infant sucking at the nipple. Breast milk provides ideal nutrition and passive immunity for the infant, encourages mild uterine contractions to return the uterus to its pre-pregnancy size (i.e., involution), and induces a substantial metabolic increase in the mother, consuming the fat reserves stored during pregnancy.

Structure of the Lactating Breast

Mammary glands are modified sweat glands. The non-pregnant and non-lactating female breast is composed primarily of adipose and collagenous tissue, with mammary glands making up a very minor proportion of breast volume. The mammary gland is composed of milk-transporting lactiferous ducts, which expand and branch extensively during pregnancy in response to estrogen, growth hormone, cortisol, and prolactin. Moreover, in response to progesterone, clusters of breast alveoli bud from the ducts and expand outward toward the chest wall. Breast alveoli are balloon-like structures lined with milk-secreting cuboidal cells, or lactocytes, that are surrounded by a net of contractile myoepithelial cells. Milk is secreted from the lactocytes, fills the alveoli, and is squeezed into the ducts. Clusters of alveoli that drain to a common duct are called lobules; the lactating female has 12–20 lobules organized radially around the nipple. Milk drains from lactiferous ducts into lactiferous sinuses that meet at 4 to 18 perforations in the nipple, called nipple pores. The small bumps of the areola (the darkened skin around the nipple) are called Montgomery glands. They secrete oil to cleanse the nipple opening and prevent chapping and cracking of the nipple during breastfeeding.

The Process of Lactation

The pituitary hormone prolactin is instrumental in the establishment and maintenance of breast milk supply. It also is important for the mobilization of maternal micronutrients for breast milk.

Near the fifth week of pregnancy, the level of circulating prolactin begins to increase, eventually rising to approximately 10–20 times the pre-pregnancy concentration. We noted earlier that, during pregnancy, prolactin and other hormones prepare the breasts anatomically for the secretion of milk. The level of prolactin plateaus in late pregnancy, at a level high enough to initiate milk production. However, estrogen, progesterone, and other placental hormones inhibit prolactin-mediated milk synthesis during pregnancy. It is not until the placenta is expelled that this inhibition is lifted and milk production commences.

After childbirth, the baseline prolactin level drops sharply, but it is restored for a 1-hour spike during each feeding to stimulate the production of milk for the next feeding. With each prolactin spike, estrogen and progesterone also increase slightly.

When the infant suckles, sensory nerve fibers in the areola trigger a neuroendocrine reflex that results in milk secretion from lactocytes into the alveoli. The posterior pituitary releases oxytocin, which stimulates myoepithelial cells to squeeze milk from the alveoli so it can drain into the lactiferous ducts, collect in the lactiferous sinuses, and discharge through the nipple pores. It takes less than 1 minute from the time when an infant begins suckling (the latent period) until milk is secreted (the let-down). Figure 1 summarizes the positive feedback loop of the let-down reflex.

[caption id="" align="aligncenter" width="550"] Figure 1. Let-Down Reflex. A positive feedback loop ensures continued milk production as long as the infant continues to breastfeed.[/caption]

The prolactin-mediated synthesis of milk changes with time. Frequent milk removal by breastfeeding (or pumping) will maintain high circulating prolactin levels for several months. However, even with continued breastfeeding, baseline prolactin will decrease over time to its pre-pregnancy level. In addition to prolactin and oxytocin, growth hormone, cortisol, parathyroid hormone, and insulin contribute to lactation, in part by facilitating the transport of maternal amino acids, fatty acids, glucose, and calcium to breast milk.

Changes in the Composition of Breast Milk

In the final weeks of pregnancy, the alveoli swell with colostrum, a thick, yellowish substance that is high in protein but contains less fat and glucose than mature breast milk (Table 3). Before childbirth, some women experience leakage of colostrum from the nipples. In contrast, mature breast milk does not leak during pregnancy and is not secreted until several days after childbirth.

*Cow’s milk should never be given to an infant. Its composition is not suitable and its proteins are difficult for the infant to digest.
Compositions of Human Colostrum, Mature Breast Milk, and Cow’s Milk (g/L) (Table 3)
	Human colostrum	Human breast milk	Cow’s milk*
Total protein	23	11	31
Immunoglobulins	19	0.1	1
Fat	30	45	38
Lactose	57	71	47
Calcium	0.5	0.3	1.4
Phosphorus	0.16	0.14	0.90
Sodium	0.50	0.15	0.41

Colostrum is secreted during the first 48–72 hours postpartum. Only a small volume of colostrum is produced—approximately 3 ounces in a 24-hour period—but it is sufficient for the newborn in the first few days of life. Colostrum is rich with immunoglobulins, which confer gastrointestinal, and also likely systemic, immunity as the newborn adjusts to a nonsterile environment.

After about the third postpartum day, the mother secretes transitional milk that represents an intermediate between mature milk and colostrum. This is followed by mature milk from approximately postpartum day 10 (see Table 3). As you can see in the accompanying table, cow’s milk is not a substitute for breast milk. It contains less lactose, less fat, and more protein and minerals. Moreover, the proteins in cow’s milk are difficult for an infant’s immature digestive system to metabolize and absorb.

The first few weeks of breastfeeding may involve leakage, soreness, and periods of milk engorgement as the relationship between milk supply and infant demand becomes established. Once this period is complete, the mother will produce approximately 1.5 liters of milk per day for a single infant, and more if she has twins or triplets. As the infant goes through growth spurts, the milk supply constantly adjusts to accommodate changes in demand. A woman can continue to lactate for years, but once breastfeeding is stopped for approximately 1 week, any remaining milk will be reabsorbed; in most cases, no more will be produced, even if suckling or pumping is resumed.

Mature milk changes from the beginning to the end of a feeding. The early milk, called foremilk, is watery, translucent, and rich in lactose and protein. Its purpose is to quench the infant’s thirst. Hindmilk is delivered toward the end of a feeding. It is opaque, creamy, and rich in fat, and serves to satisfy the infant’s appetite.

During the first days of a newborn’s life, it is important for meconium to be cleared from the intestines and for bilirubin to be kept low in the circulation. Recall that bilirubin, a product of erythrocyte breakdown, is processed by the liver and secreted in bile. It enters the gastrointestinal tract and exits the body in the stool. Breast milk has laxative properties that help expel meconium from the intestines and clear bilirubin through the excretion of bile. A high concentration of bilirubin in the blood causes jaundice. Some degree of jaundice is normal in newborns, but a high level of bilirubin—which is neurotoxic—can cause brain damage. Newborns, who do not yet have a fully functional blood–brain barrier, are highly vulnerable to the bilirubin circulating in the blood. Indeed, hyperbilirubinemia, a high level of circulating bilirubin, is the most common condition requiring medical attention in newborns. Newborns with hyperbilirubinemia are treated with phototherapy because UV light helps to break down the bilirubin quickly.

28.7 Patterns of Inheritance

barkerj1 — Wed, 06 Sep 2017 01:20:30 +0000

Learning Objectives

By the end of this section, you will be able to:

Define the following terms: character, trait, gene, allele, phenotype, genotype
Define the term mutation
Distinguish between hereditary and congenital defects
Explain the roles of chromosomes and genes in heredity
Explain the role of mitosis in genetics and development
Explain what is meant by "dominant" and "recessive" alleles
Distinguish between autosomal inheritance and sex-linked inheritance
Describe the interaction between heredity and environment in the determination of phenotypes
Describe the inheritance of disorders due to dominant alleles using Huntington’s disease as an example
Describe the two primary methods used to detect genetic abnormalities in the fetus and give examples of the genetic disorders which may be detected by each method
Describe the inheritance and characteristics of the following recessive disorders:
- Phenylketonuria
- Aalbinism
- Tay-Sachs disease
Describe the inheritance and characteristics of the following chromosomal abnormalities:
- Down syndrome
- Turner syndrome
- Klinefelter’s syndrome

We have discussed the events that lead to the development of a newborn. But what makes each newborn unique? The answer lies, of course, in the DNA in the sperm and oocyte that combined to produce that first diploid cell, the human zygote.

From Genotype to Phenotype

Each human body cell has a full complement of DNA stored in 23 pairs of chromosomes. Figure 1 shows the pairs in a systematic arrangement called a karyotype. Among these is one pair of chromosomes, called the sex chromosomes, that determines the sex of the individual (XX in females, XY in males). The remaining 22 chromosome pairs are called autosomal chromosomes. Each of these chromosomes carries hundreds or even thousands of genes, each of which codes for the assembly of a particular protein—that is, genes are “expressed” as proteins. An individual’s complete genetic makeup is referred to as his or her genotype. The characteristics that the genes express, whether they are physical, behavioral, or biochemical, are a person’s phenotype.

You inherit one chromosome in each pair—a full complement of 23—from each parent. This occurs when the sperm and oocyte combine at the moment of your conception. Homologous chromosomes—those that make up a complementary pair—have genes for the same characteristics in the same location on the chromosome. Because one copy of a gene, an allele, is inherited from each parent, the alleles in these complementary pairs may vary. Take for example an allele that encodes for dimples. A child may inherit the allele encoding for dimples on the chromosome from the father and the allele that encodes for smooth skin (no dimples) on the chromosome from the mother.

[caption id="" align="aligncenter" width="480"] Figure 1. Chromosomal Complement of a Male. Each pair of chromosomes contains hundreds to thousands of genes. The banding patterns are nearly identical for the two chromosomes within each pair, indicating the same organization of genes. As is visible in this karyotype, the only exception to this is the XY sex chromosome pair in males. (credit: National Human Genome Research Institute)[/caption]

Although a person can have two identical alleles for a single gene (a homozygous state), it is also possible for a person to have two different alleles (a heterozygous state). The two alleles can interact in several different ways. The expression of an allele can be dominant, for which the activity of this gene will mask the expression of a nondominant, or recessive, allele. Sometimes dominance is complete; at other times, it is incomplete. In some cases, both alleles are expressed at the same time in a form of expression known as codominance.

In the simplest scenario, a single pair of genes will determine a single heritable characteristic. However, it is quite common for multiple genes to interact to confer a feature. For instance, eight or more genes—each with their own alleles—determine eye color in humans. Moreover, although any one person can only have two alleles corresponding to a given gene, more than two alleles commonly exist in a population. This phenomenon is called multiple alleles. For example, there are three different alleles that encode ABO blood type; these are designated I^A, I^B, and i.

Over 100 years of theoretical and experimental genetics studies, and the more recent sequencing and annotation of the human genome, have helped scientists to develop a better understanding of how an individual’s genotype is expressed as their phenotype. This body of knowledge can help scientists and medical professionals to predict, or at least estimate, some of the features that an offspring will inherit by examining the genotypes or phenotypes of the parents. One important application of this knowledge is to identify an individual’s risk for certain heritable genetic disorders. However, most diseases have a multigenic pattern of inheritance and can also be affected by the environment, so examining the genotypes or phenotypes of a person’s parents will provide only limited information about the risk of inheriting a disease. Only for a handful of single-gene disorders can genetic testing allow clinicians to calculate the probability with which a child born to the two parents tested may inherit a specific disease.

Mendel’s Theory of Inheritance

Our contemporary understanding of genetics rests on the work of a nineteenth-century monk. Working in the mid-1800s, long before anyone knew about genes or chromosomes, Gregor Mendel discovered that garden peas transmit their physical characteristics to subsequent generations in a discrete and predictable fashion. When he mated, or crossed, two pure-breeding pea plants that differed by a certain characteristic, the first-generation offspring all looked like one of the parents. For instance, when he crossed tall and dwarf pure-breeding pea plants, all of the offspring were tall. Mendel called tallness dominant because it was expressed in offspring when it was present in a purebred parent. He called dwarfism recessive because it was masked in the offspring if one of the purebred parents possessed the dominant characteristic. Note that tallness and dwarfism are variations on the characteristic of height. Mendel called such a variation a trait. We now know that these traits are the expression of different alleles of the gene encoding height.

Mendel performed thousands of crosses in pea plants with differing traits for a variety of characteristics. And he repeatedly came up with the same results—among the traits he studied, one was always dominant, and the other was always recessive. (Remember, however, that this dominant–recessive relationship between alleles is not always the case; some alleles are codominant, and sometimes dominance is incomplete.)

Using his understanding of dominant and recessive traits, Mendel tested whether a recessive trait could be lost altogether in a pea lineage or whether it would resurface in a later generation. By crossing the second-generation offspring of purebred parents with each other, he showed that the latter was true: recessive traits reappeared in third-generation plants in a ratio of 3:1 (three offspring having the dominant trait and one having the recessive trait). Mendel then proposed that characteristics such as height were determined by heritable “factors” that were transmitted, one from each parent, and inherited in pairs by offspring.

In the language of genetics, Mendel’s theory applied to humans says that if an individual receives two dominant alleles, one from each parent, the individual’s phenotype will express the dominant trait. If an individual receives two recessive alleles, then the recessive trait will be expressed in the phenotype. Individuals who have two identical alleles for a given gene, whether dominant or recessive, are said to be homozygous for that gene (homo- = “same”). Conversely, an individual who has one dominant allele and one recessive allele is said to be heterozygous for that gene (hetero- = “different” or “other”). In this case, the dominant trait will be expressed, and the individual will be phenotypically identical to an individual who possesses two dominant alleles for the trait.

It is common practice in genetics to use capital and lowercase letters to represent dominant and recessive alleles. Using Mendel’s pea plants as an example, if a tall pea plant is homozygous, it will possess two tall alleles (TT). A dwarf pea plant must be homozygous because its dwarfism can only be expressed when two recessive alleles are present (tt). A heterozygous pea plant (Tt) would be tall and phenotypically indistinguishable from a tall homozygous pea plant because of the dominant tall allele. Mendel deduced that a 3:1 ratio of dominant to recessive would be produced by the random segregation of heritable factors (genes) when crossing two heterozygous pea plants. In other words, for any given gene, parents are equally likely to pass down either one of their alleles to their offspring in a haploid gamete, and the result will be expressed in a dominant–recessive pattern if both parents are heterozygous for the trait.

Because of the random segregation of gametes, the laws of chance and probability come into play when predicting the likelihood of a given phenotype. Consider a cross between an individual with two dominant alleles for a trait (AA) and an individual with two recessive alleles for the same trait (aa). All of the parental gametes from the dominant individual would be A, and all of the parental gametes from the recessive individual would be a (Figure 2). All of the offspring of that second generation, inheriting one allele from each parent, would have the genotype Aa, and the probability of expressing the phenotype of the dominant allele would be 4 out of 4, or 100 percent.

This seems simple enough, but the inheritance pattern gets interesting when the second-generation Aa individuals are crossed. In this generation, 50 percent of each parent’s gametes are A and the other 50 percent are a. By Mendel’s principle of random segregation, the possible combinations of gametes that the offspring can receive are AA, Aa, aA (which is the same as Aa), and aa. Because segregation and fertilization are random, each offspring has a 25 percent chance of receiving any of these combinations. Therefore, if an Aa × Aa cross were performed 1000 times, approximately 250 (25 percent) of the offspring would be AA; 500 (50 percent) would be Aa (that is, Aa plus aA); and 250 (25 percent) would be aa. The genotypic ratio for this inheritance pattern is 1:2:1. However, we have already established that AA and Aa (and aA) individuals all express the dominant trait (i.e., share the same phenotype), and can therefore be combined into one group. The result is Mendel’s third-generation phenotype ratio of 3:1.

[caption id="" align="aligncenter" width="350"] Figure 2. Random Segregation. In the formation of gametes, it is equally likely that either one of a pair alleles from one parent will be passed on to the offspring. This figure follows the possible combinations of alleles through two generations following a first-generation cross of homozygous dominant and homozygous recessive parents. The recessive phenotype, which is masked in the second generation, has a 1 in 4, or 25 percent, chance of reappearing in the third generation.[/caption]

Mendel’s observation of pea plants also included many crosses that involved multiple traits, which prompted him to formulate the principle of independent assortment. The law states that the members of one pair of genes (alleles) from a parent will sort independently from other pairs of genes during the formation of gametes. Applied to pea plants, that means that the alleles associated with the different traits of the plant, such as color, height, or seed type, will sort independently of one another. This holds true except when two alleles happen to be located close to one other on the same chromosome. Independent assortment provides for a great degree of diversity in offspring.

Mendelian genetics represent the fundamentals of inheritance, but there are two important qualifiers to consider when applying Mendel’s findings to inheritance studies in humans. First, as we’ve already noted, not all genes are inherited in a dominant–recessive pattern. Although all diploid individuals have two alleles for every gene, allele pairs may interact to create several types of inheritance patterns, including incomplete dominance and codominance.

Secondly, Mendel performed his studies using thousands of pea plants. He was able to identify a 3:1 phenotypic ratio in second-generation offspring because his large sample size overcame the influence of variability resulting from chance. In contrast, no human couple has ever had thousands of children. If we know that a man and woman are both heterozygous for a recessive genetic disorder, we would predict that one in every four of their children would be affected by the disease. In real life, however, the influence of chance could change that ratio significantly. For example, if a man and a woman are both heterozygous for cystic fibrosis, a recessive genetic disorder that is expressed only when the individual has two defective alleles, we would expect one in four of their children to have cystic fibrosis. However, it is entirely possible for them to have seven children, none of whom is affected, or for them to have two children, both of whom are affected. For each individual child, the presence or absence of a single gene disorder depends on which alleles that child inherits from his or her parents.

Autosomal Dominant Inheritance

In the case of cystic fibrosis, the disorder is recessive to the normal phenotype. However, a genetic abnormality may be dominant to the normal phenotype. When the dominant allele is located on one of the 22 pairs of autosomes (non-sex chromosomes), we refer to its inheritance pattern as autosomal dominant. An example of an autosomal dominant disorder is neurofibromatosis type I, a disease that induces tumor formation within the nervous system that leads to skin and skeletal deformities. Consider a couple in which one parent is heterozygous for this disorder (and who therefore has neurofibromatosis), Nn, and one parent is homozygous for the normal gene, nn. The heterozygous parent would have a 50 percent chance of passing the dominant allele for this disorder to his or her offspring, and the homozygous parent would always pass the normal allele. Therefore, four possible offspring genotypes are equally likely to occur: Nn, Nn, nn, and nn. That is, every child of this couple would have a 50 percent chance of inheriting neurofibromatosis. This inheritance pattern is shown in Figure 3, in a form called a Punnett square, named after its creator, the British geneticist Reginald Punnett.

[caption id="" align="aligncenter" width="350"] Figure 3. Autosomal Dominant Inheritance. Inheritance pattern of an autosomal dominant disorder, such as neurofibromatosis, is shown in a Punnett square.[/caption]

Other genetic diseases that are inherited in this pattern are achondroplastic dwarfism, Marfan syndrome, and Huntington’s disease. Because autosomal dominant disorders are expressed by the presence of just one gene, an individual with the disorder will know that he or she has at least one faulty gene. The expression of the disease may manifest later in life, after the childbearing years, which is the case in Huntington’s disease (discussed in more detail later in this section).

Autosomal Recessive Inheritance

When a genetic disorder is inherited in an autosomal recessive pattern, the disorder corresponds to the recessive phenotype. Heterozygous individuals will not display symptoms of this disorder, because their unaffected gene will compensate. Such an individual is called a carrier. Carriers for an autosomal recessive disorder may never know their genotype unless they have a child with the disorder.

An example of an autosomal recessive disorder is cystic fibrosis (CF), which we introduced earlier. CF is characterized by the chronic accumulation of a thick, tenacious mucus in the lungs and digestive tract. Decades ago, children with CF rarely lived to adulthood. With advances in medical technology, the average lifespan in developed countries has increased into middle adulthood. CF is a relatively common disorder that occurs in approximately 1 in 2000 Caucasians. A child born to two CF carriers would have a 25 percent chance of inheriting the disease. This is the same 3:1 dominant:recessive ratio that Mendel observed in his pea plants would apply here. The pattern is shown in Figure 4, using a diagram that tracks the likely incidence of an autosomal recessive disorder on the basis of parental genotypes.

On the other hand, a child born to a CF carrier and someone with two unaffected alleles would have a 0 percent probability of inheriting CF, but would have a 50 percent chance of being a carrier. Other examples of autosome recessive genetic illnesses include the blood disorder sickle-cell anemia, the fatal neurological disorder Tay–Sachs disease, and the metabolic disorder phenylketonuria.

[caption id="" align="aligncenter" width="550"] Figure 4. Autosomal Recessive Inheritance. The inheritance pattern of an autosomal recessive disorder with two carrier parents reflects a 3:1 probability of expression among offspring. (credit: U.S. National Library of Medicine)[/caption]

X-linked Dominant or Recessive Inheritance

An X-linked transmission pattern involves genes located on the X chromosome of the 23rd pair (Figure 5). Recall that a male has one X and one Y chromosome. When a father transmits a Y chromosome, the child is male, and when he transmits an X chromosome, the child is female. A mother can transmit only an X chromosome, as both her sex chromosomes are X chromosomes.

When an abnormal allele for a gene that occurs on the X chromosome is dominant over the normal allele, the pattern is described as X-linked dominant. This is the case with vitamin D–resistant rickets: an affected father would pass the disease gene to all of his daughters, but none of his sons, because he donates only the Y chromosome to his sons (see Figure 5a). If it is the mother who is affected, all of her children—male or female—would have a 50 percent chance of inheriting the disorder because she can only pass an X chromosome on to her children (see Figure 5b). For an affected female, the inheritance pattern would be identical to that of an autosomal dominant inheritance pattern in which one parent is heterozygous and the other is homozygous for the normal gene.

[caption id="" align="aligncenter" width="410"] Figure 5. X-Linked Patterns of Inheritance. A chart of X-linked dominant inheritance patterns differs depending on whether (a) the father or (b) the mother is affected with the disease. (credit: U.S. National Library of Medicine)[/caption]

X-linked recessive inheritance is much more common because females can be carriers of the disease yet still have a normal phenotype. Diseases transmitted by X-linked recessive inheritance include color blindness, the blood-clotting disorder hemophilia, and some forms of muscular dystrophy. For an example of X-linked recessive inheritance, consider parents in which the mother is an unaffected carrier and the father is normal. None of the daughters would have the disease because they receive a normal gene from their father. However, they have a 50 percent chance of receiving the disease gene from their mother and becoming a carrier. In contrast, 50 percent of the sons would be affected (Figure 6).

With X-linked recessive diseases, males either have the disease or are genotypically normal—they cannot be carriers. Females, however, can be genotypically normal, a carrier who is phenotypically normal, or affected with the disease. A daughter can inherit the gene for an X-linked recessive illness when her mother is a carrier or affected, or her father is affected. The daughter will be affected by the disease only if she inherits an X-linked recessive gene from both parents. As you can imagine, X-linked recessive disorders affect many more males than females. For example, color blindness affects at least 1 in 20 males, but only about 1 in 400 females.

[caption id="" align="aligncenter" width="410"] Figure 6. X-Linked Recessive Inheritance. Given two parents in which the father is normal and the mother is a carrier of an X-linked recessive disorder, a son would have a 50 percent probability of being affected with the disorder, whereas daughters would either be carriers or entirely unaffected. (credit: U.S. National Library of Medicine)[/caption]

Other Inheritance Patterns: Incomplete Dominance, Codominance, and Lethal Alleles

Not all genetic disorders are inherited in a dominant–recessive pattern. In incomplete dominance, the offspring express a heterozygous phenotype that is intermediate between one parent’s homozygous dominant trait and the other parent’s homozygous recessive trait. An example of this can be seen in snapdragons when red-flowered plants and white-flowered plants are crossed to produce pink-flowered plants. In humans, incomplete dominance occurs with one of the genes for hair texture. When one parent passes a curly hair allele (the incompletely dominant allele) and the other parent passes a straight-hair allele, the effect on the offspring will be intermediate, resulting in hair that is wavy.

Codominance is characterized by the equal, distinct, and simultaneous expression of both parents’ different alleles. This pattern differs from the intermediate, blended features seen in incomplete dominance. A classic example of codominance in humans is ABO blood type. People are blood type A if they have an allele for an enzyme that facilitates the production of surface antigen A on their erythrocytes. This allele is designated I^A. In the same manner, people are blood type B if they express an enzyme for the production of surface antigen B. People who have alleles for both enzymes (I^A and I^B) produce both surface antigens A and B. As a result, they are blood type AB. Because the effect of both alleles (or enzymes) is observed, we say that the I^A and I^B alleles are codominant. There is also a third allele that determines blood type. This allele (i) produces a nonfunctional enzyme. People who have two i alleles do not produce either A or B surface antigens: they have type O blood. If a person has I^A and i alleles, the person will have blood type A. Notice that it does not make any difference whether a person has two I^A alleles or one I^A and one i allele. In both cases, the person is blood type A. Because I^A masks i, we say that I^A is dominant to i. Table 4 summarizes the expression of blood type.

Expression of Blood Types (Table 4)
Blood type	Genotype	Pattern of inheritance
A	I^AI^Aor I^Ai	I^Ais dominant to i
B	I^BI^Bor^{I^Bi}	I^B is dominant to i
AB	I^AI^B	I^Ais co-dominant to I^B
O	ii	Two recessive alleles

Certain combinations of alleles can be lethal, meaning they prevent the individual from developing in utero, or cause a shortened life span. In recessive lethal inheritance patterns, a child who is born to two heterozygous (carrier) parents and who inherited the faulty allele from both would not survive. An example of this is Tay–Sachs, a fatal disorder of the nervous system. In this disorder, parents with one copy of the allele for the disorder are carriers. If they both transmit their abnormal allele, their offspring will develop the disease and will die in childhood, usually before age 5.

Dominant lethal inheritance patterns are much more rare because neither heterozygotes nor homozygotes survive. Of course, dominant lethal alleles that arise naturally through mutation and cause miscarriages or stillbirths are never transmitted to subsequent generations. However, some dominant lethal alleles, such as the allele for Huntington’s disease, cause a shortened life span but may not be identified until after the person reaches reproductive age and has children. Huntington’s disease causes irreversible nerve cell degeneration and death in 100 percent of affected individuals, but it may not be expressed until the individual reaches middle age. In this way, dominant lethal alleles can be maintained in the human population. Individuals with a family history of Huntington’s disease are typically offered genetic counseling, which can help them decide whether or not they wish to be tested for the faulty gene.

Mutations

A mutation is a change in the sequence of DNA nucleotides that may or may not affect a person’s phenotype. Mutations can arise spontaneously from errors during DNA replication, or they can result from environmental insults such as radiation, certain viruses, or exposure to tobacco smoke or other toxic chemicals. Because genes encode for the assembly of proteins, a mutation in the nucleotide sequence of a gene can change amino acid sequence and, consequently, a protein’s structure and function. Spontaneous mutations occurring during meiosis are thought to account for many spontaneous abortions (miscarriages).

Chromosomal Disorders

Sometimes a genetic disease is not caused by a mutation in a gene, but by the presence of an incorrect number of chromosomes. For example, Down syndrome is caused by having three copies of chromosome 21. This is known as trisomy 21. The most common cause of trisomy 21 is chromosomal nondisjunction during meiosis. The frequency of nondisjunction events appears to increase with age, so the frequency of bearing a child with Down syndrome increases in women over 36. The age of the father matters less because nondisjunction is much less likely to occur in a sperm than in an egg.

Whereas Down syndrome is caused by having three copies of a chromosome, Turner syndrome is caused by having just one copy of the X chromosome. This is known as monosomy. The affected child is always female. Women with Turner syndrome are sterile because their sexual organs do not mature. Having two copies of the X chromosome and one of the Y is also possible, and is known as Klinefelter's syndrome. The affected child is genetically male, since the Y chromosome is present, and again is sterile. Individuals are normal intellectually, but the incidence of intellectual disability increases as the number of X chromosomes present increases.

Detecting Genetic Disorders

For many genetic diseases, a DNA test can determine whether a person is a carrier. For instance, carrier status for Fragile X, an X-linked disorder associated with mental retardation, or for cystic fibrosis can be determined with a simple blood draw to obtain DNA for testing. A genetic counselor can educate a couple about the implications of such a test and help them decide whether to undergo testing. For chromosomal disorders, the available testing options include a blood test, amniocentesis (in which amniotic fluid is tested), and chorionic villus sampling (in which tissue from the placenta is tested). Each of these has advantages and drawbacks. A genetic counselor can also help a couple cope with the news that either one or both partners is a carrier of a genetic illness, or that their unborn child has been diagnosed with a chromosomal disorder or other birth defect.

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Book Information

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1203 Chapter 1. An Introduction to the Human Body

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1203 Chapter 2. The Chemical Level of Organization

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1203 Chapter 3. The Cellular Level of Organization

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1203 Chapter 4. The Tissue Level of Organization

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1203 Chapter 12. The Nervous System and Nervous Tissue

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1203 Chapter 13. The Central Nervous System

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1203 Chapter 14. The Somatic Nervous System

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1203 Chapter 15. The Autonomic Nervous System

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1203 Chapter 17. The Endocrine System

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1203 Chapter 20. The Cardiovascular System: Blood Vessels and Circulation

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1203 Chapter 22. The Respiratory System

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1203 Chapter 23. The Digestive System

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1203 Chapter 24. Metabolism and Nutrition

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1203 Chapter 25. The Urinary System

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1203 Chapter 26. Fluid, Electrolyte, and Acid-Base Balance

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1203 Chapter 27. The Reproductive System

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1203 Chapter 28. Development and Inheritance

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