Unit 9: The Nervous System

 

Part 1: Anatomical and Functional Organization 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.

Anatomical Divisions

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 (Figures 1 and 2). 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 central nervous system 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.

Nervous tissue, present in both the central and peripheral nervous system, contains two basic types of cells: neurons and glial (or neuroglial) 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). The colors ascribed to these regions are what would be seen in “fresh,” or unstained, nervous tissue (Figure 3). 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 central nervous system —for example, a frontal section of the brain or cross section of the spinal cord.

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 central nervous system is referred to as a nucleus. In the peripheral nervous system, a cluster of neuron cell bodies is referred to as a ganglion. 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 central nervous system (Figure 4). 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.

Table 1: Structures of the Central and Peripheral Nervous System

	CNS	PNS
Group of neuron cell bodies (i.e., gray matter)	Nucleus	Ganglion
Bundle of axons (i.e., white matter)	Tract	Nerve

Terminology applied to bundles of axons also differs depending on location. A bundle of axons, or fibers, found in the central nervous system is called a tract whereas the same thing in the peripheral nervous system 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 peripheral nervous system, the term is nerve, but if they are central nervous system, 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 5). A similar situation outside of science can be described for some roads. For example, you might know of a street named Canada Way in the city of Burnaby. If you travel south long enough on this road, eventually you will leave Burnaby and enter the city of New Westminster. In New Westminster, Canada Way changes its name to Eighth Street. That is the idea behind the naming of the retinal axons. In the peripheral nervous system, they are called the optic nerve, and in the central nervous system, they are the optic tract. Table 1 helps to clarify which of these terms apply to the central or peripheral nervous systems.

Functional Divisions

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 (Figure 6). 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: Sensation, Integration, and Response

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.

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 particular event in the external or internal environment, known as a stimulus. The senses we think of most are the “big five”: taste, smell, touch, sight, and hearing. The stimuli for taste and smell are both chemical substances (molecules, compounds, ions, etc.), touch is physical or mechanical stimuli that interact with the skin, sight is 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, but that list represents the major senses. Those five are all senses that receive stimuli from the outside world, and of which there is conscious perception. Additional sensory stimuli might be from the internal environment (inside the body), such as the stretch of an organ wall or the concentration of certain ions in the blood.

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.

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 apocrine 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.

Somatic, Autonomic and Enteric Nervous Systems

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 peripheral nervous system, and is not dependent on the central nervous system. 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 (Figure 7). There are some differences between the two, but for our purposes here there will be a good bit of overlap.

 

Part 2: Nervous Tissue

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 fibre that emerges from the cell body and projects to target cells (Figure 8). 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 (Figure 8), 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.

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 fibre. 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 9).

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 10). 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).

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.

Table 2: Glial Cell Types by Location and Basic Function

CNS glia	PNS glia	Basic function
Astrocyte	Satellite cell	Support
Oligodendrocyte	Schwann cell	Insulation, myelination
Microglia	–	Immune surveillance, phagocytosis
Ependymal cell	–	Creating cerebrospinal fluid

There are six types of glial cells (Table 2). Four of them are found in the central nervous system (Figure 11) and two are found in the peripheral nervous system (Figure 12). For reference, Table 2 outlines some common characteristics and functions of the various glial cell types, but the specific names and roles of the glial cell types are not examinable material in this course.

Myelin

The insulation for axons in the nervous system is provided by glial cells: oligodendrocytes in the central nervous system, and Schwann cells in the peripheral nervous system. 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.

Part 3: The Central Nervous System

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 gray mantle of the human brain, which appears to make up most of the mass of the brain, is the cerebrum with two distinct halves, a right and left cerebral hemisphere (Figure 13). Many of the higher neurological functions, such as memory, emotion, and consciousness, are the result of cerebral function. The cerebrum comprises of a continuous, wrinkled and thin layer of gray matter that wraps around both hemispheres, the cerebral cortex, and several deep nuclei. 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 (Figure 14).

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 (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 The results from Brodmann’s work on the anatomy align very well with the functional differences within the cortex. For example, 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.

Beneath the cerebral cortex are sets of nuclei known as basal nuclei that augment cortical processes (Figure 15). Some of the basal nuclei in the forebrain, for example, 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 cholinergic basal forebrain nuclei. Some other basal nuclei control the initiation of movement. For example, while a student is sitting in a classroom listening to a lecture, the basal nuclei will keep an 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 Diencephalon

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 peripheral nervous system 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.

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 16). There are other structures, such as the epithalamus, which contains the pineal gland, and the subthalamus, which includes the subthalamic nucleus, one 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.

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.

The Brain Stem

The midbrain and hindbrain (composed of the pons and the medulla) are collectively referred to as the brain stem (Figure 17). 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.

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.

 

Midbrain

One of the original regions of the embryonic brain, the midbrain is a small region between the thalamus and pons. The cerebral aqueduct passes through the center of the midbrain, such that these regions are the roof and floor of that canal.

The midbrain includes 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.

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.

Medulla

The gray matter of the midbrain and pons continues into the medulla, also known as medulla oblongata. This diffuse region of gray matter throughout the brain stem, known as the reticular formation, is related to sleep and wakefulness, general brain activity and attention. The medulla contains autonomic nuclei with motor neurons that control the rate and force of heart contraction, the diameter of blood vessels and the rate and depth of breathing, among other essential physiological processes.

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 18). The cerebellum integrates motor commands from the cerebral cortex with sensory feedback from the periphery, allowing for the coordination and precise execution of motor activities, such as walking, cycling, writing or playing a musical instrument.

 

The Spinal Cord

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.

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 (Figures 24 and 25).

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 19, 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 fibres 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 metre in length. The neuronal cell body that maintains that long fiber must be quite large, possibly several hundred micrometres in diameter, making it one of the largest cells in the body.

 

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 fibres in these columns carry sensory information up to the brain, whereas descending tracts carry motor commands from the brain.

 

The Meninges

The outer surface of the central nervous system 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 central nervous system. 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 central nervous system 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 (Figures 20).

 

The Ventricular System and Cerebrospinal Fluid Circulation

Cerebrospinal fluid (CSF) circulates throughout and around the central nervous system. cerebrospinal fluid is produced in special structures to perfuse through the nervous tissue of the central nervous system and is continuous with the interstitial fluid. Specifically, cerebrospinal fluid 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 cerebrospinal fluid circulates. In some of these spaces, cerebrospinal fluid is produced by filtering of the blood that is performed by a specialized membrane known as a choroid plexus. The cerebrospinal fluid circulates through all of the ventricles to eventually emerge into the subarachnoid space where it will be reabsorbed into the blood.

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 21).

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 cerebrospinal fluid can flow through the ventricles and around the outside of the central nervous system. Cerebrospinal fluid is produced within the ventricles by a type of specialized membrane called a choroid plexus. Ependymal cells (a type of glial cell; see Figure 11) surround blood capillaries and filter the blood to make cerebrospinal fluid. 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 cerebrospinal fluid, 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 millilitres 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 cerebrospinal fluid flows around all of the central nervous system, providing two important functions. As with elsewhere in its circulation, the cerebrospinal fluid picks up metabolic wastes from the nervous tissue and moves it out of the central nervous system. 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 cerebrospinal fluid 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 re-oxygenated by the lungs and wastes to be filtered out by the kidneys (Table 3).

Table 3: Components of Cerebrospinal Fluid Circulation

	Lateral ventricles	Third ventricle	Cerebral aqueduct	Fourth ventricle	Central canal	Subarachnoid space
Location	Cerebrum	Diencephalon	Midbrain	Between pons/upper medulla oblongata and cerebellum	Spinal cord	External to entire central nervous system
Blood vessel structure	Choroid plexus	Choroid plexus	None	Choroid plexus	None	Arachnoid granulations

Part 4: The Peripheral Nervous System

The peripheral nervous system is not as contained as the central nervous system because it is defined as everything that is not the central nervous system. Some peripheral structures are incorporated into the other organs of the body. In describing the anatomy of the peripheral nervous system, 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 peripheral nervous system.

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 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 central nervous system through the dorsal nerve root.

The other major category of ganglia, those of the autonomic nervous system, will be examined later in this chapter.

 

Nerves

Bundles of axons in the peripheral nervous system 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. Nerves are associated with the region of the central nervous system to which they are connected, either as cranial nerves (12 pairs) connected to the brain or spinal nerves (31 pairs) connected to the spinal cord.

The cranial nerves are primarily responsible for the sensory and motor functions of the head and neck, although one of these nerves, the vagus, targets organs in the thoracic and abdominal cavities as part of the parasympathetic nervous system. 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.

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 fibres, both somatic and autonomic, emerge as the ventral nerve root. The dorsal root ganglion for each nerve is an enlargement of the spinal nerve.

The Somatic Nervous System

The somatic nervous system is traditionally considered a division within the peripheral nervous system. However, this misses an important point: somatic refers to a functional division, whereas peripheral refers to an anatomic division. The somatic nervous system is responsible for our conscious perception of the environment and for our voluntary responses to that perception by means of skeletal muscles. Peripheral sensory neurons receive input from environmental stimuli, but the neurons that produce motor responses originate in the central nervous system. The distinction between the structures of the peripheral and central nervous systems and the functions of the somatic and autonomic systems can most easily be demonstrated through a simple reflex, an automatic response that the nervous system produces in response to specific stimuli. The neurons and neural pathways responsible for a reflex action constitute the reflex arc. One of the simplest reflex acts is the stretch reflex, by which the nervous system responds to the stretching of a muscle (the stimulus) with contraction of that same muscle (the response). This response protects the muscle from over-stretching, but more importantly, it has a crucial role in maintaining posture and balance. The patellar reflex (or knee-jerk reflex) is an example of stretch reflex and it occurs through the following steps (Figure 23):

• Tapping of the patellar tendon with a hammer causes the stretching of muscle fibres in the quadriceps muscle, which stimulates sensory neurons innervating those fibres.
• In the sensory neuron, a nerve impulse (action potential) is generated, which travels along the sensory nerve fibre from the muscle, through the dorsal root ganglion, to the spinal cord.
• The sensory neuron stimulates a motor neuron in the ventral horn of the spinal cord.
• That motor neuron sends a nerve impulse (action potential) along its axon.
• This impulse reaches the quadriceps muscle, causing its contraction and the extension of the leg (a kick).

The sensory neuron can also activate an interneuron (e.g., Figure 23), which inhibits the motor neuron responsible for the contraction of the antagonistic muscle to quadriceps (i.e. hamstring).

Another example of a simple spinal reflex is the withdrawal reflex, which occurs, for example, when you touch a hot stove and pull your hand away. This reflex occurs through a similar sequence of steps:

• Sensory receptors in the skin sense extreme temperature and the early signs of tissue damage.
• In a sensory neuron, a nerve impulse (action potential) is generated, which travels along the sensory nerve fibre from the skin, through the dorsal root ganglion, to the spinal cord.
• The sensory neuron stimulates a motor neuron in the ventral horn motor of the spinal cord.
• That motor neuron sends a nerve impulse (action potential) along its axon.
• This impulse reaches the biceps brachii, causing contraction of the muscle and flexion of the forearm at the elbow to withdraw the hand from the hot stove.

The basic withdrawal reflex includes sensory input (the painful stimulus), central processing (the synapse in the spinal cord), and motor output (activation of a ventral motor neuron that causes contraction of the biceps brachii). As seen for the patellar reflex, the withdrawal reflex can also include inhibition of the antagonistic muscle (triceps brachii in our example). Another possible motor output of the withdrawal reflex is cross extension: counterbalancing movement on the other side of the body by stimulation of the extensor muscles in the contralateral limb.

The somatic nervous system also controls voluntary movement and more complex motor functions. For example, reading of this text starts with visual sensory input to the retina, which then projects to the thalamus, and on to the cerebral cortex. A sequence of regions of the cerebral cortex process the visual information, starting in the primary visual cortex of the occipital lobe, and resulting in the conscious perception of these letters. Subsequent cognitive processing results in understanding of the content. As you continue reading, regions of the cerebral cortex in the frontal lobe plan how to move the eyes to follow the lines of text. The output from the cortex causes activity in motor neurons in the brain stem that cause movement of the extraocular muscles through the third, fourth, and sixth cranial nerves. This example also includes sensory input (the retinal projection to the thalamus), central processing (the thalamus and subsequent cortical activity), and motor output (activation of neurons in the brain stem that lead to coordinated contraction of extraocular muscles).

The Autonomic Nervous System

The autonomic nervous system is often associated with the “fight-or-flight response,” which refers to the preparation of the body to either run away from a threat or to stand and fight in the face of that threat. To suggest what this means, consider the (very unlikely) situation of seeing a lioness hunting out on the savannah. Though this is not a common threat that humans deal with in the modern world, it represents the type of environment in which the human species thrived and adapted. The spread of humans around the world to the present state of the modern age occurred much more quickly than any species would adapt to environmental pressures such as predators. However, the reactions modern humans have in the modern world are based on these prehistoric situations. If your boss is walking down the hallway on Friday afternoon looking for “volunteers” to come in on the weekend, your response is the same as the prehistoric human seeing the lioness running across the savannah: fight or flight.

Most likely, your response to your boss—not to mention the lioness—would be flight. Run away! The autonomic system is responsible for the physiological response to make that possible, and hopefully successful. Adrenaline starts to flood your circulatory system. Your heart rate increases. Sweat glands become active. The bronchi of the lungs dilate to allow more air exchange. Pupils dilate to increase visual information. Blood pressure increases in general, and blood vessels dilate in skeletal muscles. Time to run. Similar physiological responses would occur in preparation for fighting off the threat.

This response should sound a bit familiar. The autonomic nervous system is tied into emotional responses as well, and the fight-or-flight response probably sounds like a panic attack. In the modern world, these sorts of reactions are associated with anxiety as much as with response to a threat. It is engrained in the nervous system to respond like this. In fact, the adaptations of the autonomic nervous system probably predate the human species and are likely to be common to all mammals, and perhaps shared by many animals. That lioness might herself be threatened in some other situation

However, the autonomic nervous system is not just about responding to threats. Besides the fight-or-flight response, there are the responses referred to as “rest and digest.” If that lioness is successful in her hunting, then she is going to rest from the exertion. Her heart rate will slow. Breathing will return to normal. The digestive system has a big job to do. Much of the function of the autonomic system is based on the connections within an autonomic, or visceral, reflex.

As we have seen, 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. 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 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. 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 (Figure 24, wherein the “circuits” of the sympathetic system are intentionally simplified).

An axon from the central neuron that projects to a sympathetic ganglion is referred to as a preganglionic fibre or neuron, and represents the output from the central nervous system to the ganglion. Because the sympathetic ganglia are adjacent to the vertebral column, preganglionic sympathetic fibres are relatively short, and they are myelinated. A postganglionic fibre—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 fibres, postganglionic sympathetic fibres are long because of the relatively greater distance from the ganglion to the target effector. These fibres 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 fibre is postganglionic. Typically, the term neuron applies to the entire cell.)

One type of preganglionic sympathetic fibre 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 fibres, 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 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 fibre 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

When not responding to an immediate threat, the parasympathetic system is generally more active than the sympathetic system.  Many of the same effectors in the body are innervated by both divisions of the autonomic nervous system, but activation of each division tends to have opposing effects.  Sympathetic system activation tends to increase activity in the respiratory, cardiovascular, and musculoskeletal systems while reducing activity in the digestive system.  Parasympathetic system activation on the other hand tends to decrease activity in the respiratory, cardiovascular, and musculoskeletal systems while increasing activity in the digestive, urinary, and reproductive systems.  Generally speaking, the activity of the many organs that receive input from both systems is dependent on whether neurons of the parasympathetic or sympathetic system are releasing more of their neurotransmitter onto each organ at a given time.

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 25). The preganglionic fibres from the cranial region travel in cranial nerves, whereas preganglionic fibres 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 organ. The postganglionic fibre projects from the terminal ganglia a short distance to the effector. These ganglia are often referred to as intramural ganglia when they are found within the walls target effector, or to the specific target tissue within the organ. Comparing the relative lengths of axons in the parasympathetic system, the preganglionic fibres are long and the postganglionic fibres are short because the ganglia are close to – and sometimes within – the target effectors.

 

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 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.

All preganglionic fibres, both sympathetic and parasympathetic, release ACh. The postganglionic parasympathetic fibres also release ACh. Postganglionic sympathetic fibers release norepinephrine, except for fibers that project to sweat glands and to blood vessels associated with skeletal muscles, which release ACh.

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 fibres release norepinephrine, which can be considered a neurotransmitter. But the adrenal medulla releases epinephrine and norepinephrine into circulation, so they should be considered hormones.

Part 5: Neuronal Signalling

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 (summarized in Figure 26).

Imagine you are about to take a shower. 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 27), 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.

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.

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 central nervous system 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 28).

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 primary motor 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 fibres 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.

Ion Channels and the Resting Membrane Potential

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. (The way these signals work in more variable circumstances involves graded potentials.)

Most cells in the body make use of charged particles, ions, to build up a charge across the cell membrane. 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 29). Transmembrane proteins, specifically channel proteins, make this possible. Several passive ion channels, as well as active transport pumps, are necessary to generate a transmembrane potential and an action potential. Ion channels are pores that allow specific charged particles to cross the membrane in response to an existing concentration gradient.

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. 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 do not always freely allow ions to diffuse across the membrane. Some are opened by certain events, meaning the channels are gated.

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 30).

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 31).

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 32).

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 33).

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 34).

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 the most commonly recorded value. This voltage would actually be much lower except for the contributions of some important proteins in the membrane. Leakage channels K⁺ channels allow K⁺ to slowly move out of the cells. To a much lesser extent, leakage Na⁺ channels allow Na⁺ to slowly move into the cell. The constant activity of the Na⁺/K⁺ pump maintains the ion gradients. This may appear to be a waste of energy, but each has a role in maintaining the membrane potential.

Generation of an 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 (Figure 35). 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.

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 36). While an action potential is in progress, another one cannot be initiated. That effect is referred to as the refractory period.

Propagation of Action Potentials

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 (Figure 37).

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 (Figure 38). 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 (1-3 mm) 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.

Neurotransmission

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, the connection between electrically active cells.

There are two types of synapses: 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 described in the chapter on muscle tissue. In the nervous system, there are many more synapses that are essentially the same as the neuromuscular junction. 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

Synaptic transmission (or neurotransmission) takes place through the following steps (Figure 39):

• An action potential reaches the axon terminal.
• The change in voltage causes voltage-gated Ca²⁺ channels in the membrane of the synaptic end bulb to open.
• The concentration of Ca²⁺ increases inside the end bulb, and Ca²⁺ ions associate with proteins in the outer surface of neurotransmitter vesicles facilitating the merging of the vesicle with the presynaptic membrane. The neurotransmitter is then 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.
• The interaction of the neurotransmitter with the receptor can result in depolarization or hyperpolarization of the postsynaptic cell membrane, leading to excitation of the postsynaptic cell (and possibly the generation of a new action potential) or inhibition, respectively.
• The neurotransmitter is removed from the synaptic cleft by diffusion, due to the action of enzymes that break it down chemically or by transporters in the presynaptic cell membrane.

 

 

Neurotransmitter Systems

There are several systems of neurotransmitters that are found at various synapses in the nervous system (Figure 40).  In this course, you are not required to know all the neurotransmitters, but only to be able to provide one example of a neurotransmitter from each of the systems below.

• Amino acids: This includes glutamate (Glu), GABA (gamma-aminobutyric acid, a derivative of glutamate), and glycine (Gly).
• Biogenic amines: This is a group of neurotransmitters that are enzymatically made from amino acids. For example, the neurotransmitter serotonin is made from tryptophan. Other biogenic amines are made from tyrosine, and include dopamine, norepinephrine, and epinephrine. 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.
• Cholinergic system: It is the system based on acetylcholine. This includes the neuromuscular junction 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.
• Neuropeptides: These are neurotransmitter molecules 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. For example, when acetylcholine binds to a type of receptor called 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 another type of receptor called muscarinic receptor, of which there are several variants, it might cause depolarization or hyperpolarization of the target cell.

On the other hand, 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.