Bruce R. Ransom
The human brain is the most complex tissue in the body. It mediates behavior ranging from simple movements and sensory perception to learning and memory. It is the organ of the mind. Many of the brain’s functions are poorly understood. In fact, the most prominent function of the human brain, its capacity to think, is hardly understood at all. Our lack of knowledge about fundamental aspects of brain function stands in marked contrast to the level of comprehension that we have about the primary functions of other organ systems, such as the heart, lungs, and kidneys. Nevertheless, tremendous strides have been made in the past few decades. While philosophers ponder the paradox of a person thinking about thinking, physiologists are trying to learn about learning.
In this part of the book, we present the physiology of the nervous system in a manner that is intended to be complementary to texts on neurobiology and neuroanatomy. In this chapter, we review the basic cellular, developmental, and gross anatomy of the nervous system. In Chapter 11, we discuss the fluid environment of the neurons in the brain, how this environment interacts with the rest of the extracellular fluid of the body, and the role of glial cells. Chapters 12 and 13 focus on the broad physiological principles that underlie how the brain’s cellular elements operate. Another major goal of this section is to provide more detailed information on those parts of the nervous system that play key roles in the physiology of other systems in the body. Thus, in Chapter 14, we discuss the autonomic nervous system, which controls “viscera” such as the heart, lungs, and gastrointestinal tract. Finally, in Chapters 15and 16, we discuss the special senses and simple neuronal circuits.
The nervous system can be divided into central, peripheral, and autonomic nervous systems
The manner in which the nervous system is subdivided is somewhat arbitrary. All elements of the nervous system work closely together in a way that has no clear boundaries. Nevertheless, the traditional definitions of the subdivisions provide a useful framework for talking about the brain and its connections and are important if only for that reason.
The central nervous system (CNS) consists of the brain and spinal cord (Table 10-1). It is covered by three “membranes”—the meninges. The outer membrane is the dura mater; the middle is the arachnoid; and the delicate inner membrane is called the pia mater. Within the CNS, some neurons that share similar functions are grouped into aggregations called nuclei.
Table 10-1 Subdivisions of the Nervous System
The peripheral nervous system (PNS) consists of those parts of the nervous system that lie outside the dura mater (Table 10-1). These elements include sensory receptors for various kinds of stimuli, the peripheral portions of spinal and cranial nerves, and all the peripheral portions of the autonomic nervous system (see the next paragraph). The sensory nerves that carry messages from the periphery to the CNS are termed afferent nerves (Latin, ad + ferens, or carrying toward). Conversely, the peripheral motor nerves that carry messages from the CNS to peripheral tissues are called efferent nerves (Latin, ex + ferens,or carrying away). Peripheral ganglia are groups of nerve cells concentrated into small knots or clumps that are located outside the CNS.
The autonomic nervous system (ANS) is that portion of the nervous system that regulates and controls visceral functions, including heart rate, blood pressure, digestion, temperature regulation, and reproductive function. Although the ANS is a functionally distinct system, it is anatomically composed of parts of the CNS and PNS (Table 10-1). Visceral control is achieved by reflex arcs that consist of visceral afferent (i.e., sensory) neurons that send messages from the periphery to the CNS, control centers in the CNS that receive this input, and visceral motor output. Moreover, visceral afferent fibers typically travel together with visceral efferent fibers.
Each area of the nervous system has unique nerve cells and a different function
Nervous tissue is composed of neurons and neuroglial cells. Neurons vary greatly in their structure throughout the nervous system, but they all share certain features that tailor them for the unique purpose of electrical communication (see Chapter 12). Neuroglial cells, often simply called glia, are not primary signaling cells and have variable structures that are suited for their diverse functions (see Chapter 11).
The human brain contains ~1011 neurons and several times as many glial cells. Each of these neurons may interact with thousands of other neurons, which helps explain the awesome complexity of the nervous system.
No evidence suggests that the human brain contains receptors, ion channels, or cells that are unique to humans and not seen in other mammals. The unparalleled capabilities of the human brain are presumed to result from its unique patterns of connectivity and its large size.
The brain’s diverse functions are the result of tremendous regional specialization. Different brain areas are composed of neurons that have special shapes, physiological properties, and connections. One part of the brain, therefore, cannot substitute functionally for another part that has failed. Any compensation of neural function by a patient with a brain lesion (e.g., a stroke) reflects enhancement of existing circuits or recruitment of latent circuits. A corollary is that damage to a specific part of the brain causes predictable symptoms that can enable a clinician to establish the anatomical location of the problem, a key step in diagnosis of neurological diseases.
CELLS OF THE NERVOUS SYSTEM
The neuron doctrine first asserted that the nervous system is composed of many individual signaling units—the neurons
In 1838, Schleiden and Schwann proposed that the nucleated cell is the fundamental unit of structure and function in both plants and animals. They reached this conclusion by microscopic observation of plant and animal tissues that had been stained to reveal their cellular composition. However, the brain proved to be more difficult to stain than other tissues, and until 1885, when Camillo Golgi introduced his silver impregnation method, “the black reaction,” there was no clear indication that the brain is composed of individual cells. The histologist Santiago Ramón y Cajal worked relentlessly with the silver-staining method and eventually concluded that not only is nervous tissue composed of individual cells but the anatomy of these cells also confers a functional polarization to the passage of nervous signals; the tapering branches near the cell body are the receptive end of the cell, and the long-axis cylinder conveys signals away from the cell. In the absence of any reliable physiological evidence, Cajal was nevertheless able to correctly anticipate how complex cell aggregates in the brain communicate with each other.
The pathologist Heinrich von Waldeyer referred to the individual cells in the brain as neurons. He wrote a monograph in 1891 that assembled the evidence in favor of the cellular composition of nervous tissue, a theory that became known as the neuron doctrine. It is ironic that Golgi, whose staining technique made these advances possible, never accepted the neuron doctrine, and he argued vehemently against it when he received his Nobel Prize along with Cajal in 1906. The ultimate proof of the neuron doctrine was established by electron microscopic observations that definitively demonstrated that neurons are entirely separate from one another, even though their processes come into very close contact. (See Note: Santiago Ramón y Cajal)
Nerve cells have four specialized regions: cell body, dendrites, axon, and presynaptic terminals
Neurons are specialized for sending and receiving signals, a purpose reflected in their unique shapes and physiological adaptations. The structure of a typical neuron can generally be divided into four distinct domains: (1) the cell body, also called the soma or perikaryon; (2) the dendrites; (3) the axon; and (4) the presynaptic terminals (Fig. 10-1).
Figure 10-1 Structure of a typical neuron.
Cell Body As the name perikaryon implies, the cell body is the portion of the cell surrounding the nucleus. It contains much of the cell’s complement of endoplasmic reticular membranes as well as the Golgi complex. The cell body appears to be responsible for many of the neuronal housekeeping functions, including the synthesis and processing of proteins.
Dendrites Dendrites are tapering processes of variable complexity that arise from the cell body. The dendrites and cell body are the main areas for receiving information. Thus, their membranes are endowed with receptors that bind and respond to the neurotransmitters released by neighboring cells. The chemical message is translated by membrane receptors into an electrical or a biochemical event that influences the state of excitability of the receiving neuron. The cytoplasm of the dendrites contains dense networks of microtubules as well as extensions of the endoplasmic reticulum.
Axon Perhaps the most remarkable feature of the neuron, the axon is a projection that arises from the cell body, like the dendrites. Its point of origin is a tapered region known as the axon hillock. Just distal to the cone-shaped hillock is an untapered, unmyelinated region known as the initial segment. This area is also called the spike initiation zone because it is where an action potential (see Chapter 7) normally arises as the result of the electrical events that have occurred in the cell body and dendrites. In contrast to the dendrites, the axon is thin, does not taper, and can extend for more than a meter. Because of its length, the typical axon contains much more cytoplasm than does the cell body, up to 1000 times as much. The neuron uses special metabolic mechanisms to sustain this unique structural component. The cytoplasm of the axon, the axoplasm, is packed with parallel arrays of microtubules and microfilaments that provide structural stability and a means to rapidly convey materials back and forth between the cell body and the axon terminus.
Axons are the message-sending portion of the neuron. The axon carries the neuron’s signal, the action potential, to a specific target, such as another neuron or a muscle. Some axons have a special electrical insulation, called myelin, that consists of the coiled cell membranes of glial cells that wrap themselves around the nerve axon (see Chapter 11). If the axon is not covered with myelin, the action potential travels down the axon by continuous propagation. On the other hand, if the axon is myelinated, the action potential jumps from one node of Ranvier (the space between adjacent myelin segments) to another in a process called saltatory conduction (see Chapter 7). This adaptation greatly speeds impulse conduction.
Presynaptic Terminals At its target, the axon terminates in multiple endings—the presynaptic terminals—usually designed for rapid conversion of the neuron’s electrical signal into a chemical signal. When the action potential reaches the presynaptic terminal, it causes the release of chemical signaling molecules in a complex process called synaptic transmission (see Chapters 8 and 13).
The junction formed between the presynaptic terminal and its target is called a chemical synapse. Synapse is derived from the Greek for “joining together” or “junction”; this word and concept were introduced in 1897 by the neurophysiologist Charles Sherrington, whose contributions led to a share of the 1932 Nobel Prize in Medicine or Physiology. A synapse comprises the presynaptic terminal, the membrane of the target cell (postsynaptic membrane), and the space between the two (synaptic cleft). In synapses between two neurons, the presynaptic terminals primarily contact dendrites and the cell body. The area of the postsynaptic membrane is frequently amplified to increase the surface that is available for receptors. This amplification can occur either through infolding of the plasma membrane or through the formation of small projections called dendritic spines. (See Note: Sir Charles Scott Sherrington)
The molecules released by the presynaptic terminals diffuse across the synaptic cleft and bind to receptors on the postsynaptic membrane. The receptors then convert the chemical signal of the transmitter molecules—either directly or indirectly—back into an electrical signal.
In many ways, neurons can be thought of as highly specialized endocrine cells. They package and store hormones and hormone-like molecules, which they release rapidly into the extracellular space by exocytosis (see Chapter 2) in response to an external stimulus, in this case a nerve action potential. However, instead of entering the bloodstream to exert systemic effects, the substances secreted by neurons act over the very short distance of a synapse to communicate locally with a single neighboring cell (see Chapter 5).
In a different sense, neurons can be thought of as polarized cells with some of the properties of epithelial cells. Like epithelial cells, neurons have different populations of membrane proteins at each of the distinct domains of the neuronal plasma membrane, an arrangement that reflects the individual physiological responsibilities of these domains. Thus, the design of the nervous system permits information transfer across synapses in a selective and coordinated way that serves the needs of the organism and summates to produce complex behavior.
The cytoskeleton helps compartmentalize the neuron and also provides the tracks along which material travels between different parts of the neuron
Neurons are compartmentalized in both structure and function. Dendrites are tapered, have limited length, and contain neurotransmitter receptor proteins in their membranes. Axons can be very long and have a high density of Na+channels. Dendrites and the cell body contain mRNA, ribosomes, and a Golgi apparatus. These structures are absent in axons.
How does this compartmentalization come about? The answer is not certain, but microtubule-associated proteins (MAPs) appear to play an important role. (Note that these MAPs are totally unrelated to the mitogen-activated protein [MAP] kinase introduced in Chapter 4.) Two major classes of MAPs are found in the brain: high-molecular-weight proteins such as MAP-1 and MAP-2 and lower molecular weight tau proteins. Both classes of MAPs associate with microtubules and help link them to other cell components. MAP-2 is found only in cell bodies and dendrites. Dephosphorylated tau proteins are confined entirely to axons. In cultured neurons, suppressing the expression of tau protein prevents formation of the axon without altering formation of the dendrites.
Microtubules may also help create the remarkable morphological and functional divisions in neurons. In axons, microtubules assemble with their plus ends pointed away from the cell body; this orientation polarizes the flow of material into and out of the axon. The cytoskeletal “order” provided in part by the microtubules and the MAPs helps define what should or should not be in the axonal cytoplasm. In dendrites, the microtubules do not have a consistent orientation, which gives the dendrites a greater structural and functional similarity to the cell body.
The neuron cell body is the main manufacturing site for the membrane proteins and membranous organelles that are necessary for the structural integrity and function of its processes. Axons have no protein synthetic ability, whereas dendrites have some free ribosomes and may be able to engage in limited protein production. The transport of proteins from the cell body all the way to the end of long axons is a challenging task. The neuron also has a second task: moving various material in the opposite direction, from presynaptic terminals at the end of the axon to the cell body. The neuron solves these problems by using two distinct mechanisms for moving material to the presynaptic terminals in an “anterograde” direction and a third mechanism for transport in the opposite or “retrograde” direction (Table 10-2).
Table 10-2 Features of Axoplasmic Transport
Fast Axoplasmic Transport If the flow of materials from the soma to the distant axon terminus were left to the whims of simple diffusion, their delivery would be far too slow to be of practical use. It could take months for needed proteins to diffuse to the end of an axon, and the presynaptic terminals are high-volume consumers of these molecules. To overcome this difficulty, neurons exploit a rapid, pony express–style system of conveyance known as fast axoplasmic transport (Table 10-2). Membranous organelles, including vesicles and mitochondria, are the principal freight of fast axoplasmic transport. The proteins, lipids, and polysaccharides that move at fast rates in axons do so because they have caught a ride with a membranous organelle (i.e., sequestered inside the organelle, or bound to or inserted into the organellar membrane). The peptide and protein contents of dense-core secretory granules, which are found in the presynaptic axonal terminals, are synthesized as standard secretory proteins (see Chapter 2). Thus, they are cotranslationally inserted across the membranes of the rough endoplasmic reticulum and subsequently processed in the cisternae of the Golgi complex. They are shipped to the axon in the lumens of Golgi-derived carrier vesicles (Table 10-2).
Organelles and vesicles, and their macromolecule payloads, move along microtubules with the help of a microtubule-dependent motor protein called kinesin (Fig. 10-2A). The kinesin motor is itself an ATPase that produces vectorial movement of its payload along the microtubule (see Chapter 2). This system can move vesicles down the axon at rates of up to 400 mm/day; variations in cargo speed simply reflect more frequent pauses during the journey. Kinesins always move toward the plus end of microtubules (i.e., away from the cell body), and transport function is lost if the microtubules are disrupted. The nervous system has many forms of kinesin that recognize and transport different cargo. It is not known how the motor proteins recognize and attach to their intended payloads.
Figure 10-2 Fast axoplasmic transport. ER, endoplasmic reticulum.
Fast Retrograde Transport Axons move material back toward the cell body with a different motor protein called dynein (Fig. 10-2B). Like kinesin, dynein (see Chapter 2) also moves along microtubule tracks and is an ATPase (Table 10-2). However, dynein moves along microtubules in the opposite direction of kinesin (Fig. 10-2C). Retrograde transport provides a mechanism for target-derived growth factors, like nerve growth factor, to reach the nucleus of a neuron where it can influence survival. How this signal is transmitted up the axon has been a persistent question. It may be endocytosed at the axon’s terminal and transported to the cell body in a “signaling endosome.” The loss of ATP production, as occurs with blockade of oxidative metabolism, causes fast axonal transport in both the anterograde and retrograde directions to fail.
Slow Axoplasmic Transport Axons also have a need for hundreds of other proteins, including cytoskeletal proteins and soluble proteins that are used as enzymes for intermediary metabolism. These proteins are delivered by a slow anterograde axoplasmic transport mechanism that moves material at a mere 0.2 to 8 mm/day, the nervous system’s equivalent of snail mail. The slowest moving proteins are neurofilament and microtubule subunits (0.2 to 1 mm/day). The mechanism of slow axoplasmic transport is not well understood, but motor molecules appear to be involved. In fact, the difference between slow and fast axonal transport may primarily be the number of transport interruptionsduring the long axonal journey.
Neurons can be classified on the basis of their axonal projection, their dendritic geometry, and the number of processes emanating from the cell body
The trillions of nerve cells in the CNS have great structural diversity. Typically, neurons are classified on the basis of where their axons go (i.e., where they “project”), the geometry of their dendrites, and the number of processes that emanate from the cell body (Fig. 10-3). The real significance of these schemes is that they have functional implications.
Figure 10-3 Classification of neurons based on their structure.
Axonal Projection Neurons with long axons that connect with other parts of the nervous system are called projection neurons (or principal neurons or Golgi type I cells). Each of these cells has a clearly defined axon that arises from the axon hillock located on the cell body or proximal dendrite and extends away from the cell body, sometimes for remarkable distances. Some neurons in the cortex, for example, project to the distal part of the spinal cord, a stretch of nearly a meter. All the other processes that a projection neuron has are dendrites. The other type of neuron that is defined in this way has all of its processes confined to one region of the brain. These neurons are called interneurons (or intrinsic neurons or Golgi type II cells). Some of these cells have very short axons, whereas others seem to lack a conventional axon altogether and may be referred to as anaxonal. The anaxonal neuron in the retina is called an amacrine (from the Greek for “no large/long fiber”) cell.
Dendritic Geometry A roughly pyramid-shaped set of dendritic branches characterizes pyramidal cells, whereas a radial pattern of dendritic branches defines stellate cells. This classification often includes mention of the presence or absence of dendritic spines, those small, protuberant projections that are sites for synaptic contact. All pyramidal cells appear to have spines, but stellate cells may have them (spiny) or not (aspiny).
Number of Processes Neurons can also be classified by the number of processes that extend from their cell bodies. The dorsal root ganglion cell is the classic unipolar neuron. The naming of the processes of primary sensory neurons, like the dorsal root ganglion cell, is often ambiguous. The process that extends into the CNS from this unipolar neuron is easily recognized as an axon because it carries information away from the cell body. On the other hand, the process that extends to sensory receptors in the skin and elsewhere is less easily defined. It is a typical axon in the sense that it can conduct an action potential, has myelin, and is characterized by an axonal cytoskeleton. However, it conveys information toward the cell body, which is usually the function of a dendrite. Bipolar neurons, such as the retinal bipolar cell, have two processes extending from opposite sides of the cell body. Most neurons in the brain are multipolar. Cells with many dendritic processes are designed to receive large numbers of synapses.
Most neurons in the brain can be categorized by two or more of these schemes. For example, the large neurons in the cortical area devoted to movement (i.e., the motor cortex) are multipolar, pyramidal, projection neurons. Similarly, a retinal bipolar cell is both an interneuron and a bipolar cell.
Glial cells provide a physiological environment for neurons
Glial cells are defined in part by what they lack: axons, action potentials, and synaptic potentials. They are much more numerous than neurons and are diverse in structure and function. The main types of CNS glial cells are oligodendrocytes, astrocytes, and microglial cells. In the PNS, the main types of glial cells are satellite cells in autonomic and sensory ganglia, Schwann cells, and enteric glial cells. Glial function is discussed in Chapter 11. Oligodendrocytes form the myelin sheaths of CNS axons, and Schwann cells myelinate peripheral nerves. Glial cells are involved in nearly every function of the brain and are far more than simply “nerve glue,” a literal translation of the name neuroglia (from the Greek neuron, nerve, and glia, glue).
In depictions of the nervous system, the presence of glial cells is sometimes minimized or neglected altogether. Glia fills in almost all the space around neurons, with a narrow extracellular space left between neurons and glial cells that has an average width of only ~0.02 μm. The composition of the extracellular fluid, which has a major impact on brain function, as well as the function of glial cells is taken up in detail in Chapter 11.
Definitions of Neural Modalities
The type of information, or neural modality, that a neuron transmits is classically categorized by three terms that refer to different attributes of the neuron.
1. The first category defines the direction of information flow.
Afferent (sensory): neurons that transmit information into the CNS from sensory cells or sensory receptors outside the nervous system. Examples are the dorsal root ganglion cell and neurons in the sensory nucleus of the fifth cranial nerve.
Efferent (motor): neurons that transmit information out of the CNS to muscles or secretory cells. Examples are spinal motor neurons and motor neurons in the ANS.
2. The second category defines the anatomical distribution of the information flow.
Visceral: neurons that transmit information to or from internal organs or regions that arise embryologically from the branchial arch (e.g., chemoreceptors of the carotid body).
Somatic: neurons that transmit information to or from all nonvisceral parts of the body, including skin and muscle.
3. The third category, which is somewhat arbitrary, defines the information flow on the basis of the embryological origin of the structure being innervated.
Special: neurons that transmit information to or from a “special” subset of visceral or somatic structures. For example, in the case of special visceral neurons, information travels to or from structures derived from the branchial arch region of the embryo (e.g., pharyngeal muscles). In the case of special somatic neurons, which handle only sensory information, the neurons arise from the organs of special sense (e.g., retina, taste receptors, cochlea).
General: neurons that transmit information to or from visceral or somatic structures that are not in the special group.
Each axon in the body conveys information of only a single modality. In this classification scheme, a motor neuron in the spinal cord is described as a general somatic efferent neuron. A motor neuron in the brain stem that innervates branchial arch–derived chewing muscles is described as a special visceral efferent neuron. Because each of these three categories defines two options, you might expect a total of eight distinct neural modalities. In practice, however, only seven neural modalities exist. The term special somatic efferent neuron is not used.
DEVELOPMENT OF NEURONS AND GLIAL CELLS
Neurons differentiate from the neuroectoderm
Although the embryology of the nervous system may seem like an odd place to begin studying the physiology of the brain, there are a number of reasons to start here. Knowledge of the embryology of the nervous system greatly facilitates comprehension of its complex organization. Events in the development of the nervous system highlight how different neuronal cell types evolve from a single type of precursor cell and how these neurons establish astonishingly specific connections. Finally, the characteristics of brain cell proliferation as well as the growth of neuronal processes during development provide insight into the consequences of brain injury.
The vertebrate embryo consists of three primitive tissue layers at the stage of gastrulation: endoderm, mesoderm, and ectoderm (Fig. 10-4). The entire nervous system arises from ectoderm, which also gives rise to the skin. Underlying the ectoderm is a specialized cord of mesodermal cells called the notochord. Cells of the notochord somehow direct or “induce” the overlying ectoderm, or neuroectoderm, to form the neural tube in a complex process called neurulation.
Figure 10-4 Development of the nervous system. The left column provides a dorsal view of the developing nervous system at three different time points. The right column shows cross sections of the dorsal portion of the embryo at five different stages, three of which correspond to the dorsal views shown at the left.
The first step in neurulation is formation of the neural plate at about the beginning of the third fetal week. Initially, the neural plate is only a single layer of neuroectoderm cells. Rapid proliferation of these cells, especially at the lateral margins, creates a neural groove bordered by neural folds. Continued cell division enlarges the neural folds, and they eventually fuse dorsally to form the neural tube. The neural tube is open at both ends, the anterior and posterior neuropores. The neural tube ultimately gives rise to the brain and spinal cord. The lumen of the neural tube, the neural canal, becomes the four ventricles of the brain and the central canal of the spinal cord. Congenital malformations of the brain commonly arise from developmental defects in the neural tube.
The neural crest derives from symmetric lateral portions of the neural plate. Neural crest cells migrate to sites in the body where they form the vast majority of the PNS and most of the peripheral cells of the ANS, including the sympathetic ganglia and the chromaffin cells of the adrenal medulla. On the sensory side, these neural crest derivatives include unipolar neurons whose cell bodies are in the dorsal root ganglia, as well as the equivalent sensory cells of cranial nerves V, VII, IX, and X. Neural crest cells also give rise to several nonneuronal structures, including Schwann cells, satellite glial cells in spinal and cranial ganglia, and pigment cells of the skin.
The human brain begins to exhibit some regional specialization around the fourth gestational week (Fig. 10-5A, B). By then, it is possible to discern an anterior part called the prosencephalon, a midsection called the mesencephalon, and a posterior part called the rhombencephalon. Rapid brain growth ensues, and important new regions emerge in just another week (Fig. 10-5C). Distinct regions called brain vesicles, which are destined to become separate parts of the adult brain, are set apart as swellings in the rostral-caudal plane (Fig. 10-5B, C). The prosencephalon is now divisible into the telencephalon, which will give rise to the basal ganglia and cerebral cortex, and the diencephalon, which becomes the thalamus, subthalamus, hypothalamus, and neurohypophysis (the posterior or neural portion of the pituitary). Similarly, the rhombencephalon can now be divided into the metencephalon, which will give rise to the pons and cerebellum, and the myelencephalon, which becomes the medulla. Robust development of the cerebral cortex becomes apparent in mammals, especially humans, after the seventh week. This structure gradually expands so that it enwraps the rostral structures.
Figure 10-5 Embryonic development of the brain.
As the neural tube thickens with cell proliferation, a groove called the sulcus limitans forms on the inner, lateral wall of the neural tube (Fig. 10-6A). This anatomical landmark extends throughout the neural tube except in the farthest rostral area that will become the diencephalon and cortex. The sulcus limitans divides the neural tube into a ventral area called the basal plate and a dorsal area called the alar plate.
Figure 10-6 Development of the spinal cord and medulla. A, In this cross section through the neural tube, the sulcus limitans is the landmark that separates the ventral basal plate from the dorsal alar plate. The basal plate will form efferent (or motor-type) structures, whereas the alar plate will form afferent and associative (or sensory-type) functions. B, The true afferent neurons are those in the dorsal root ganglion, which derive from neural crest cells. These afferents will contact the neurons in the alar plate, which will become associative. C, The basal plate has developed into the ventral horn and intermediolateral column (motor), whereas the alar plate has developed into the dorsal horn (associative). D, The basal plate has developed into nuclei with motor functions, whereas the alar plate has developed into nuclei with sensory functions. The roof of the rostral medulla becomes the fourth ventricle. E, This cross section shows the same gross separation between motor and associative-sensory functions as is seen with the rostral medulla and the spinal cord.
Structures that derive from the basal plate mediate efferent functions, and structures that arise from the alar plate mediate afferent and associative functions. Efferent neurons are mainly motor neurons that convey information from the CNS to outside effectors (i.e., muscles or secretory cells). In a strict sense, the only true afferent neurons are those that derive from neural crest cells and that convey sensory information from various kinds of receptors to the CNS. In the CNS, these afferent neurons synapse on other neurons derived from the alar plate; these alar plate neurons may be referred to as afferent because they receive sensory information and pass it along to other parts of the CNS. However, it is also appropriate to call these alar plate–derived neurons associative.
The development of the spinal cord and medulla illustrates how this early anatomical division into alar and basal plates helps make sense of the final organization of these complex regions. Neurons of the alar and basal plates proliferate, migrate, and aggregate into discrete groups that have functional specificity. In the spinal cord (Fig. 10-6B, C), the basal plate develops into the ventral horn, which contains the cell bodies of somatic motor neurons, and the intermediolateral column, which contains the cell bodies of autonomic motor neurons. Both regions contain interneurons. The alar plate in the spinal cord develops into the dorsal horn, which contains the cell bodies onto which sensory neurons synapse.
In the medulla (Fig. 10-6D, E), as well as in the rest of the brain, aggregates of neurons are called nuclei. Nuclei that develop from the alar plate are generally afferent, such as the nucleus tractus solitarii, which plays an important sensory role in the ANS. Nuclei that develop from the basal plate are generally efferent, such as the dorsal motor nucleus of the vagus nerve, which plays an important motor role in the ANS. The choroid plexus that invaginates into the lumen of the central canal is responsible for secreting cerebrospinal fluid (see Chapter 11).
Abnormalities of Neural Tube Closure
Closure of the neural tube in humans normally occurs between 26 and 28 days of gestation. A disturbance in this process results in a midline congenital abnormality called a dysraphism (from the Greek dys, abnormal, + rhaphē, seam or suture). The defect can be so devastating that it is incompatible with life or, alternatively, have so little consequence that it goes unnoticed throughout life. These midline embryonic abnormalities also involve the primitive mesoderm and ectoderm associated with the neural tube. Therefore, the vertebral bodies or skull (derived from mesoderm) and the overlying skin (derived from ectoderm) may be affected along with the nervous system.
The most serious neural tube defect, occurring in 1 of 1000 deliveries, is anencephaly, in which the cerebral hemispheres are absent and the rest of the brain is severely malformed. Overlying malformations of the skull, brain coverings, and scalp are present (Table 10-3). Affected fetuses are often spontaneously aborted.
Table 10-3 Defects of Neural Tube Closure
The most common dysraphisms affect formation of the spinal vertebral bodies and are called spina bifida. The problem may be slight and cause only a minor problem in closure of the vertebral arch, called spina bifida occulta (Fig. 10-7A). This malformation affects ~10% of the population, usually at the fifth lumbar or first sacral vertebra, and generally causes no significant sequelae. If the dura and arachnoid membranes herniate (i.e., protrude) through the vertebral defect, the malformation is called spina bifida cystica (Fig. 10-7B); if the spinal cord also herniates through the defect, it is called myelomeningocele (Fig. 10-7C). These problems are often more significant and may cause severe neurological disability.
Figure 10-7 Variations of spina bifida. A, An incomplete vertebral arch with no herniation. B, The dura and arachnoid membranes herniate through the vertebral defect. C, The spinal cord and meninges herniate through the vertebral defect.
Genetic and nongenetic factors can cause dysraphism. Some severe forms of this condition appear to be inherited, although the genetic pattern suggests that multiple genes are involved. Nongenetic factors may also play a role, as in the case of folic acid deficiency. Mothers taking folic acid (see Chapter 56) before and during the periconceptional period have a decreased risk of having a fetus with a neural tube closure defect. Current medical recommendations are that women contemplating becoming pregnant receive folic acid supplementation, and it has been suggested that bread products should be enriched with folic acid to ensure that women will have the protective advantage of this vitamin if they become pregnant. Other factors that increase the risk of these defects are maternal heat exposure (e.g., from a hot tub) and certain drugs such as the anticonvulsant valproate. Neural tube disorders can be detected during pregnancy by measuring the concentration of α-fetoprotein in maternal blood or amniotic fluid. α-Fetoprotein is synthesized by the fetal liver and, for unclear reasons, increases in concentration abnormally with failure of neural tube closure.
Neurons and glial cells originate from cells in the proliferating germinal matrix near the ventricles
The trillions of neurons and glial cells that populate the brain arise from rapidly dividing stem cells called neuroepithelial cells located near the ventricles (which derive from the neural canal) of the embryonic CNS. This germinal area (Fig. 10-8A) is divided into two regions, the ventricular zone (VZ) and the subventricular zone (SVZ). Most of the neurons in the human brain are generated during the first 120 days of embryogenesis. Growth factors such as epidermal growth factor and platelet-derived growth factor and hormones such as growth hormone influence the rate of cell division of the neuroepithelial cells. The signals that direct one immature neuron to become a cortical pyramidal cell and another to become a retinal ganglion cell are not understood. Neuroepithelial cells generate different classes of neural precursor cells that develop into different mature cell types. In the developing brain, radial cells (Fig. 10-8), so called because their processes extend from the ventricular surface to the brain’s outer surface, appear very early in neurogenesis and generate most of the projection neurons in forebrain cortex. Inhibitory interneurons, in contrast, arise from neural precursor cells located in the SVZ. Neurons are probably not fully differentiated when first created and their mature characteristics may depend on their interactions with the chemical environment or other cells in a specific anatomical region of the nervous system. (See Note: Stem Cells)
Figure 10-8 Arrangement of radial cells and migrating neurons. A, The upper portion is a coronal section of developing occipital cerebral lobe of fetal monkey brain. The lower portion is a magnified view. The ventricular zone contains the germinal cells that give rise to the neurons as well as to the cell bodies of the radial cells. These radial cells extend from the ventricular surface to the pial surface, which overlies the developing cortex. B, The more magnified view on the left shows the cell bodies of two radial cells as well as their processes that extend upward toward the cortex. Also shown are two migratory neuroblasts moving from the ventricular zone toward the cortex along the fibers of the radial cells. The black arrows indicate possible pathways of proliferation and differentiation. (Data from Rakic P: Mode of cell migration to the superficial layers of fetal monkey neocortex. J Comp Neurol 1972; 145:61-84; and Tramontin AD, Garcia-Verdugo JM, Lim DA, Alvarez-Buylla A: Postnatal development of radial glia and the ventricular zone (VZ): a continuum of the neural stem cell compartment. Cerebral Cortex 2003; 13:580-587.)
The VZ appears to produce separate progenitor cells that produce only neurons, oligodendrocytes, astrocytes, and ependymal cells (Fig. 10-8B). The VZ does not contribute to the population of Schwann cells, which derive from neural crest tissue, or to microglial cells, which arise from the mesodermal cells that briefly invade the brain during early postnatal development. Recent work shows that the embryonic and perinatal VZ and SVZ may give rise to the adult SVZ, which is in part responsible for limited adult neurogenesis.
Neuronal progenitor cells appear earliest and produce nearly the entire complement of adult neurons during early embryonic life. Glial cells arise later in development. Neurons are confined to specific locations of the brain, whereas glial cells are more evenly distributed.
Many more neurons are created during fetal development than are present in the adult brain. Most neurons, having migrated to a final location in the brain and differentiated, are lost through a process called programmed cell death, or apoptosis (Greek for “falling off”). Apoptosis is a unique form of cell death that requires protein synthesis and can be triggered by removal of specific trophic influences, such as the action of a growth factor. In contrast to necrotic cell death, which rapidly leads to loss of cell membrane integrity after some insult causes a toxic increase in [Ca2+]i, apoptosis evolves more slowly. For example, in the retina, ~60% of the ganglion cells and thus ~60% of the retinal axons are lost in the first 2 weeks of extrauterine life as a result of programmed retinal ganglion cell death. This process of sculpting the final form of a neuronal system by discarding neurons through programmed death is a common theme in developmental biology.
The number of glial cells in different areas of the brain appears to be determined by signals from nearby neurons or axons. For example, in the optic nerve, the final number of glia in the nerve is closely determined by the number of axons. When programmed cell death is prevented by expression of the bcl-2 gene in transgenic animals, the number of axons in the optic nerve is dramatically increased, as well as the number of astrocytes and oligodendrocytes. Thus, glial cell–axon ratios remain relatively constant. The axon-dependent signal or signals responsible for these adjustments in glial cell number are not known, but the process appears to operate by influencing both glial cell survival and proliferation.
Neurons migrate to their correct anatomical position in the brain with the help of adhesion molecules
During embryogenesis, the long processes of radial cells create an organized, cellular scaffolding on which neurons can migrate to their final position in the brain shortly after they appear. Migrating neurons contact radial cells (Fig. 10-8B) and move along their processes toward their final positions in the developing cortex. Thus, the prearranged positions of these radial processes determine the direction of neuronal migration. The importance of the radial framework for assisting neuronal migration is illustrated by the failure of neurons to populate the cortex normally when the radial processes are interrupted by hemorrhage in the fetal brain.
The navigation mechanisms used by migrating cells in the nervous system and elsewhere in the body are only partially understood. Proteins that promote selective cellular aggregation are called cell-cell adhesion molecules(CAMs; see Chapter 2) and include the Ca2+-dependent cadherins and Ca2+-independent neural cell adhesion molecules (N-CAMs). These molecules are expressed by developing cells in an organized, sequential manner. Cells that express the appropriate adhesion molecules have a strong tendency to adhere to one another. These Velcro-like molecules can assemble cells in a highly ordered fashion; experimentally, disrupted germ cells can properly reorganize themselves into a three-layered structure that replicates the normal embryonic pattern.
Another mechanism that assists migrating cells is the presence of extracellular matrix molecules such as laminin and fibronectin. These glycoproteins are selectively secreted by both neurons and astrocytes and form a kind of extracellular roadway with which migrating cells can interact. Growing axons express at their surface cell matrix adhesion molecules called integrins that bind laminin and fibronectin (see Chapter 2). As a result, growing axons move together in fascicles.
Perhaps the least understood mechanism related to cell migration is chemotaxis, the ability of a cell to follow a chemical signal emitted from a target cell. The tips of developing axons, called growth cones, appear to follow such chemical cues as they grow toward their specific targets. For example, a molecule called netrin, secreted by midline cells, attracts developing axons destined to cross the midline. On the other hand, molecules like slit repel axons by interacting with specific receptors on the growth cone. Such signals steer axon growth cones, perhaps by localized changes in intracellular [Ca2+], leading to the strategic insertion of new patches of membrane on the surface of the growth cone.
Neurons do not regenerate
Neurons Most human neurons arise in about the first 4 months of intrauterine life. After birth, neurons do not divide, and if a neuron is lost for any reason, it is generally not replaced, which is the main reason for the relatively limited recovery from serious brain and spinal cord injuries. It has been argued that this lack of regenerative ability is a design principle to ensure that learned behavior and memories are preserved in stable populations of neurons throughout life. A notable exception to this rule is olfactory bulb neurons, which are continually renewed throughout adult life by a population of stem cells or neuronal progenitor cells. As noted earlier, cells in the adult SVZ have the capacity to generate neurons and may do so to a limited extent throughout life. Learning how to induce these cells to make functional new CNS neurons after severe neural injury is the holy grail of regeneration research. (See Note: Stem Cells)
Axonal Degeneration and Regeneration
Axons have their own mitochondria and produce the ATP that they need to maintain the steep ion gradients necessary for excitability and survival. In this sense, they are metabolically independent of the cell body. However, they cannot make proteins and are unable to sustain themselves if separated from the cell body (Fig. 10-2). If an axon is cut, in either the PNS or the CNS, a characteristic series of changes takes place (Fig. 10-9):
Step 1: Degeneration of the synaptic terminals distal to the lesion. Synaptic transmission occurring at the axon terminal fails within hours because this complex process is dependent on material provided by axonal transport. Visible changes in the degenerating terminal are seen a few days after the lesion. The terminal retracts from the postsynaptic target.
Step 2: Wallerian degeneration. The lesion divides the axon into proximal and distal segments. The distal segment degenerates slowly during a period of several weeks in a process named after its discoverer, Augustus Waller. Eventually, the entire distal segment is destroyed and removed.
Step 3: Myelin degeneration. If the affected axon is myelinated, the myelin degenerates. The myelinating cell (i.e., the Schwann cell in the PNS and the oligodendrocyte in the CNS) usually survives this process. Schwann cells are immediately induced to divide, and they begin to synthesize trophic factors that may be important for regeneration.
Step 4: Scavenging of debris. Microglia in the CNS and macrophages and Schwann cells in the PNS scavenge the debris created by the breakdown of the axon and its myelin. This step is more rapid in the PNS than in the CNS.
Step 5: Chromatolysis. After axonal injury, most neuron cell bodies swell and undergo a characteristic rearrangement of organelles called chromatolysis. The nucleus also swells and moves to an eccentric position. The endoplasmic reticulum, normally close to the nucleus, reassembles around the periphery of the cell body. Chromatolysis is reversible if the neuron survives and is able to re-establish its distal process and contact the appropriate target.
Step 6: Retrograde transneuronal degeneration. Neurons that are synaptically connected to injured neurons may themselves be injured, a condition called transneuronal or trans-synaptic degeneration. If the neuron that synapses on the injured cell undergoes degeneration, it is called retrograde degeneration.
Step 7: Anterograde transneuronal degeneration. If a neuron that received synaptic contacts from an injured cell degenerates, it is called anterograde degeneration. The magnitude of these transneuronal effects (retrograde and anterograde degeneration) is quite variable.
Figure 10-9 Nerve degeneration. A, Normal neuron. B, Degenerating neuron. ER, endoplasmic reticulum.
Glia Unlike neurons, glial cells can be replaced if they are lost or injured in an adult. Such repopulation depends on progenitor cells committed to the glial cell lineage. Either the progenitor cells reside in a latent state (or are slowly turning over) in adult brains or true multipotential stem cells are activated by specific conditions, such as brain injury, to produce de novo glial progenitors. The most typical reaction of mammalian brains to a wide range of injuries is the formation of an astrocytic glial scar. This scar is produced primarily by an enlargement of individual astrocytes, a process called hypertrophy, and increased expression of a particular cytoskeleton protein, glial acidic fibrillary protein. Only a small degree of astrocytic proliferation (i.e., an increase in cell number) accompanies this reaction. Microglial cells, which derive from cells related to the monocyte-macrophage lineage in blood and not from neuroepithelium, also react strongly to brain injury and are the main cells that proliferate at the injury site.
Axons Another reason that relatively little recovery follows severe brain and spinal cord injury is that axons within the CNS do not regenerate effectively. This lack of axon regeneration in the CNS is in sharp contrast to the behavior of axons in the PNS, which can regrow and reconnect to appropriate end organs, either muscle or sensory receptors. For example, if the median nerve of the forearm is crushed by blunt trauma, the distal axon segments die off in a process called wallerian degeneration (see the box titled Axonal Degeneration and Regeneration) because the sustaining relationship with their proximal cell bodies is lost. These PNS axons can slowly regenerate and connect to muscles and sensory receptors in the hand. It is believed that the inability of CNS axons to regenerate is the fault of the local environment more than it is an intrinsic property of these axons. For example, on their surface, oligodendrocytes and myelin carry molecules, such as myelin-associated glycoprotein, that inhibit axon growth. Experiments have shown that if severed CNS axons are given the opportunity to regrow in the same environment that surrounds axons in the PNS, they are capable of regrowth and can make functional connections with CNS targets. The remarkable ability of damaged peripheral nerves to regenerate, even in mammals, has encouraged hope that CNS axons might, under the right conditions, be able to perform this same feat. It would mean that victims of spinal cord injury might walk again.
SUBDIVISIONS OF THE NERVOUS SYSTEM
A rudimentary knowledge of the anatomy of the nervous system is a prerequisite to discussion of its physiology. This section provides an overview of nervous system anatomy that builds on what has already been discussed about its embryological development. We in turn consider the CNS, PNS, and ANS (Table 10-1).
The directional terms used to describe brain structures can be somewhat confusing because the human nervous system, unlike that of lower vertebrates, bends during development. Thus, the dorsal surface of the cerebral cortex is also superior, whereas the dorsal surface of the spinal cord is also posterior (Fig. 10-10A).
Figure 10-10 Gross anatomy of the CNS.
The CNS consists of the telencephalon, cerebellum, diencephalon, midbrain, pons, medulla, and spinal cord
The CNS can be conveniently divided into five major areas: (1) telencephalon, (2) cerebellum, (3) diencephalon, (4) brainstem (consisting of the midbrain, pons, and medulla), and (5) spinal cord (Fig. 10-10B). Each of these areas has symmetric right and left sides.
Telencephalon One of the crowning glories of evolution is the human cerebral cortex, the most conspicuous part of the paired cerebral hemispheres. The human cerebral cortex has a surface area of ~2200 cm2and is estimated to contain 1.5 to 2 × 1010 neurons. The number of synaptic contacts between these cells is ~3 × 1014. The cortical surface area of mammals increases massively from mouse to monkey to humans in a ratio of 1 : 100 : 1000. The capacity for information processing by this neuronal machine is staggering and includes a remarkable range of functions: thinking, learning, memory, and consciousness.
The cortex is topographically organized in two ways. First, certain areas of the cortex mediate specific functions. For example, the area that mediates motor control is a well-defined strip of cortex located in the frontal lobe (Fig. 10-10C). Second, within a portion of cortex that manages a specific function (e.g., motor control, somatic sensation, hearing, or vision), the parts of the body spatially map onto this cortex in an orderly way. We discuss this principle of somatotopy in Chapter 16.
Another part of the telencephalon is the great mass of axons that stream into and out of the cerebral cortex and connect it with other regions. The volume of axons needed to interconnect cortical neurons increases as a power function of cortical surface area, which increases so dramatically from mice to humans. Thus, the relative volume of white matter to gray matter is 5-fold greater in humans versus mice. The final part of the telencephalon includes the basal ganglia, which comprise the striatum (caudate nucleus and putamen) and globus pallidus. These structures have indirect connections with motor portions of the cerebral cortex and are involved in motor control.
Cerebellum This brain region lies immediately dorsal to the brainstem. Although the cerebellum represents only ~10% of the CNS by volume, it contains ~50% of all CNS neurons. The exceedingly large number of input connections to the cerebellum conveys information from nearly every type of receptor in the nervous system, including visual and auditory input. Combined, these afferent fibers outnumber the efferent projections by an estimated ratio of 40 : 1.
Functionally and by virtue of its connections, the cerebellum can be divided into three parts. Phylogenetically, the vestibulocerebellum (also called the archicerebellum) is the oldest of these three parts, followed by the spinocerebellum (also called the paleocerebellum) and then by the cerebrocerebellum (also called the neocerebellum).
The vestibulocerebellum is closely related to the vestibular system, whose sensors are located in the inner ear and whose way stations are located in the pons and medulla. It helps maintain the body’s balance. The spinocerebellum receives strong input from muscle stretch receptors through connections in the spinal cord and brainstem. It helps regulate muscle tone. The cerebrocerebellum, the largest part of the human cerebellum, receives a massive number of projections from sensorimotor portions of the cerebral cortex through neurons in the pons. It coordinates motor behavior. Much of the cerebellum’s output reaches the contralateral (i.e., on the opposite side of the body) motor cortex by way of the thalamus. Other efferent projections reach neurons in all three parts of the brainstem.
Diencephalon This brain region consists of the thalamus, the subthalamus, and the hypothalamus, each with a very different function. The thalamus is the main integrating station for sensory information that is bound for the cerebral cortex, where it will reach the level of conscious perception. Along with the subthalamus, the thalamus also receives projections from the basal ganglia that are important for motor function. Input to the thalamus from the cerebellum (specifically, the cerebrocerebellum) is important for normal motor control. Patients with Parkinson disease, a severe movement disorder, gradually lose the ability to make voluntary movements; in some of these patients, it is possible to improve movement by stimulating certain areas of the thalamus or subthalamus. Control of arousal and certain aspects of memory function also reside in discrete areas of the thalamus.
The hypothalamus is the CNS structure that most affects the ANS. It performs this function through strong, direct connections with autonomic nuclei in the brainstem and spinal cord. It also acts as part of the endocrine system in two major ways. First, specialized neurons located within specific nuclei in the hypothalamus synthesize certain hormones (e.g., arginine vasopressin and oxytocin) and transport them down their axons to the posterior pituitary gland, where the hormones are secreted into the blood. Second, other specialized neurons in other nuclei synthesize “releasing hormones” (e.g., gonadotropin-releasing hormone) and release them into a plexus of veins, called a portal system, that carries the releasing hormones to cells in the anterior pituitary. There, the releasing hormones stimulate certain cells (e.g., gonadotrophs) to secrete hormones (e.g., follicle-stimulating hormone or luteinizing hormone) into the bloodstream. We discuss these principles in Chapter 47. The hypothalamus also has specialized centers that play important roles in controlling body temperature and hunger (see Chapters 58 and 59), thirst (see Chapter 40), and the cardiovascular system. It is the main control center of the ANS.
Brainstem (Midbrain, Pons, and Medulla) This region lies immediately above, or rostral to, the spinal cord. Like the spinal cord, the midbrain, pons, and medulla have a segmental organization, receive sensory (afferent) information, and send out motor (efferent) signals through paired nerves that are called cranial nerves. The midbrain, pons, and medulla also contain important control centers for the ANS (see Chapter 14). In addition to motor neurons, autonomic neurons, and sensory neurons present at each level, the caudal brainstem serves as a conduit for a large volume of axons traveling from higher CNS centers to the spinal cord (descending pathways) and vice versa (ascending pathways). In addition, this portion of the brainstem contains a loosely organized interconnected collection of neurons and fibers called the reticular formation. This neuronal network has diffuse connections with the cortex and other brain regions and affects the level of consciousness or arousal.
The midbrain has somatic motor neurons that control eye movement. These neurons reside in the nuclei for CN III and CN IV. Other midbrain neurons are part of a system, along with the cerebellum and cortex, for motor control. The midbrain also contains groups of neurons that are involved in relaying signals related to hearing and vision.
Just caudal to the midbrain is the pons, which contains the somatic motor neurons that control mastication (nucleus for CN V), eye movement (nucleus for CN VI), and facial muscles (nucleus for CN VII). The pons also receives somatic sensory information from the face, scalp, mouth, and nose (portion of the nucleus for CN V). It is also involved in processing information that is related to hearing and equilibrium (nucleus for CN VIII). Neurons in the ventral pons receive input from the cortex, and these neurons in turn form a massive direct connection with the cerebellum (see earlier) that is crucial for coordinating motor movements.
The most caudal portion of the brainstem is the medulla. The organization of the medulla is most similar to that of the spinal cord. The medulla contains somatic motor neurons that innervate the muscles of the neck (nucleus of CN XI) and tongue (nucleus of CN XII). Along with the pons, the medulla is involved in controlling blood pressure, heart rate, respiration, and digestion (nuclei of CN IX and X). The medulla is the first CNS way station for information traveling from the special senses of hearing and equilibrium.
Spinal Cord Continuous with the caudal portion of the medulla is the spinal cord. The spinal cord runs from the base of the skull to the body of the first lumbar vertebra. Thus, it does not run the full length of the vertebral column in adults.
The spinal cord consists of 31 segments that each have a motor and sensory nerve root. (The sensory nerve root of the first cervical segment is very small and can be missing.) These nerve roots combine to form 31 bilaterally symmetric pairs of spinal nerves. The spinal roots, nerves, and ganglia are part of the PNS (see later).
Sensory information from the skin, muscle, and visceral organs enters the spinal cord through fascicles of axons called dorsal roots (Fig. 10-11A). The point of entry is called the dorsal root entry zone. Dorsal root axons have their cell bodies of origin in the spinal ganglia (i.e., dorsal root ganglia) associated with that spinal segment.
Figure 10-11 Spinal cord. A, Each spinal segment has dorsal and ventral nerve roots that carry sensory and motor nerve fibers, respectively. B, The simple “flexor” reflex arc is an illustration of the four functions of the PNS: (1) a receptor transduces a painful stimulus into an action potential, (2) a primary sensory neuron conveys the information to the CNS, (3) the CNS conveys information to the target organ by a motor neuron, and (4) the electrical signals are converted to signals at the motor end plate. C, Ascending pathways, which carry information to more rostral areas of the CNS, are shown on the left. Descending pathways, which carry information in the opposite direction, are shown on the right.
Ventral roots contain strictly efferent fibers (Fig. 10-11B). These fibers arise from motor neurons (i.e., general somatic efferent neurons) whose cell bodies are located in the ventral (or anterior) gray horns of the spinal cord (gray because they contain mainly cell bodies without myelin) and from preganglionic autonomic neurons (i.e., general visceral efferent neurons) whose cell bodies are located in the intermediolateral gray horns (i.e., between the dorsal and ventral gray horns) of the cord. Most of the efferent fibers are somatic efferents that innervate skeletal muscle to mediate voluntary movement. The other fibers are visceral efferents that synapse with postganglionic autonomic neurons, which in turn innervate visceral smooth muscle or glandular tissue.
Each segment of the spinal cord contains groups of associative neurons in its dorsal gray horns. Some but not all incoming sensory fibers synapse on these associative neurons, which in turn contribute axons to fiber paths that both mediate synaptic interactions within the spinal cord and convey information to more rostral areas of the CNS by way of several conspicuous ascending tracts of axons (Fig. 10-11C). Similarly, descending tracts of axons from the cerebral cortex and brainstem control the motor neurons whose cell bodies are in the ventral horn, thus leading to coordinated voluntary or posture-stabilizing movements. The most important of these descending tracts is called the lateral corticospinal tract; ~90% of its cell bodies of origin are in the contralateral cerebral cortex. These ascending and descending tracts are located in the white portion of the spinal cord (white because it contains mostly myelinated axons). The spatial organization of spinal cord neurons and fiber tracts is complex but orderly and varies somewhat among the 31 segments.
If sensory fibers enter the spinal cord and synapse directly on motor neurons in that same segment, this connection underlies a simple segmental reflex or interaction. If the incoming fibers synapse with neurons in other spinal segments, they can participate in an intersegmental reflex or interaction. Finally, if the incoming signals travel rostrally to the brainstem before they synapse, they constitute a suprasegmental interaction.
The peripheral nervous system comprises the cranial and spinal nerves, their associated sensory ganglia, and various sensory receptors
The PNS serves four main purposes: (1) it transduces physical or chemical stimuli both from the external environment and from within the body into raw sensory information through receptors; (2) it conveys sensory information to the CNS along axon pathways; (3) it conveys motor signals from the CNS along axon pathways to target organs, primarily skeletal and smooth muscle; and (4) it converts the motor signals to chemical signals at synapses on target tissues in the periphery. Figure 10-11B summarizes these four functions for a simple reflex arc in which a painful stimulus to the foot results in retraction of the foot from the source of the pain.
Like the CNS, the PNS can be divided into somatic and autonomic parts. The somatic division includes the sensory neurons and axons that innervate the skin, joints, and muscle as well as the motor axons that innervate skeletal muscle. The somatic division of the PNS primarily deals with the body’s external environment, either to gather information about this environment or to interact with it through voluntary motor behavior. The ANS, discussed in the next section and in Chapter 14, is a functionally distinct part of both the CNS and PNS (Table 10-1). The autonomic portion of the PNS consists of the motor and sensory axons that innervate smooth muscle, the exocrine glands, and other viscera. This division mainly deals with the body’s internal environment.
Three important aspects of the PNS are discussed in other chapters. Sensory transduction is reviewed in Chapter 15, synaptic transmission in Chapters 8 and 13, and peripheral neuronal circuits in Chapter 16. Here, we focus primarily on the system of axons that is such a prominent feature of the PNS.
Axons in the PNS are organized into bundles called peripheral nerves (Fig. 10-12). These nerves contain, in a large nerve such as the sciatic nerve, tens of thousands of axons. Individual axons are surrounded by loose connective tissue called the endoneurium. Within the nerve, axons are bundled together in small groups called fascicles, each one covered by a connective tissue sheath known as the perineurium. The perineurium contributes structural stability to the nerve. Fascicles are grouped together and surrounded by a matrix of connective tissue called the epineurium. Fascicles within a nerve anastomose with neighboring fascicles. Axons shift from one fascicle to another along the length of the nerve, but they tend to remain in roughly the same general area within the nerve over long distances. The interlocking meshwork of fascicles adds further mechanical strength to the nerve. Axons range in diameter from less than 1 to 20 μm. Because axons are extremely fragile, adaptations that enhance mechanical stability are very important. The PNS is designed to be much tougher, physically, than nervous tissue in the CNS. The PNS must be mechanically flexible, tolerant of minor physical trauma, and sustainable by a blood supply that is less dependable than the one providing for the CNS. A spinal cord transplanted to the lower part of the leg would not survive the running of a 100-meter dash.
Figure 10-12 Peripheral nerve.
Axons in peripheral nerves are closely associated with Schwann cells. In the case of a myelinated axon, a Schwann cell forms a myelinated wrap around a single adjacent axon, a single internodal myelin segment between 250 and 1000 μm in length. Many such internodal myelin segments, and thus many Schwann cells, are necessary to myelinate the entire length of the axon. In an unmyelinated nerve, the cytoplasm of a Schwann cell envelops but does not wrap around axons. Unmyelinated axons outnumber myelinated axons by about 2 : 1 in typical human nerves. Diseases that affect the PNS can disrupt nerve function by causing either loss of myelin or axonal injury.
The functional organization of a peripheral nerve is best illustrated by a typical thoracic spinal nerve and its branches. Every spinal nerve is formed by the dorsal and ventral roots joining together and emerging from the spinal cord at that segmental level (Fig. 10-11). The dorsal roots coalesce and display a spindle-shaped swelling called the spinal or dorsal root ganglion, which contains the cell bodies of the sensory axons in the dorsal roots. Individual neurons are called dorsal root ganglion cells or spinal ganglion cells and are typical unipolar neurons that give rise to a single process that bifurcates in a T-like manner into a peripheral and central branch (Fig. 10-3). The central branch carries sensory information into the CNS and the peripheral branch terminates as a sensory ending. The peripheral process, which brings information toward the cell body, meets one definition of a dendrite; however, it has all the physiological and morphological features of a peripheral axon.
Spinal nerves divide into several branches that distribute motor and sensory axons to the parts of the body associated with that segment. Axons conveying autonomic motor or autonomic sensory signals also travel in these branches. These branches are said to be “mixed” because they contain both efferent and afferent axons. Further nerve division occurs as axons travel to supply their targets, such as the skin, muscle, or blood vessels. In the case of thoracic spinal nerves, the subdivision is orderly and has a similar pattern for most of the nerves. In the cervical and lumbosacral areas, however, the spinal nerves from different segments of the spinal cord intermingle to form a nerve plexus. The subsequent course of the nerves in the upper and lower extremities is complex. The pattern of cutaneous innervation of the body is shown in Figure 10-13. The area of cutaneous innervation provided by a single dorsal root and its ganglion is called a dermatome. Severing a single dorsal root does not produce anesthesia in that dermatome because of overlap between the cutaneous innervation provided by adjacent dorsal roots. The sole exception to this rule is the C2 root, sectioning of which causes a patch of analgesia on the back of the head; neither C3 nor the trigeminal nerve innervates skin in this area. Also note that no dermatomes are shown for the first cervical and the coccygeal segments because they are small or may be missing (in the case of the first cervical segment).
Figure 10-13 Dermatomes. A dermatome is the area of cutaneous sensory innervation that a single spinal segment provides.
The autonomic nervous system innervates effectors that are not under voluntary control
The nervous system regulates some physiological mechanisms in a way that is independent or autonomous of voluntary control. Control of body temperature is an example of a fundamental process that most individuals cannot consciously regulate. Other examples include blood pressure and heart rate. The absence of voluntary control means that the ANS has little cortical representation.
The ANS has three divisions: sympathetic, parasympathetic, and enteric. The sympathetic and parasympathetic divisions have both CNS and PNS parts. The enteric division is entirely in the PNS. The parasympathetic and sympathetic efferent systems are composed of two neurons. The cell body of the first neuron is located in the CNS and that of the second in the PNS. The sympathetic and parasympathetic divisions innervate most visceral organs and have a yin-yang functional relationship. The enteric division regulates the rhythmic contraction of intestinal smooth muscle and also regulates the secretory functions of intestinal epithelial cells. It receives afferent input from the gut wall and is subject to modulation by the two other divisions of the ANS.
All the divisions have both efferent and afferent connections, although the efferent actions of the ANS are usually emphasized. We consider the ANS in detail in Chapter 14.
Peripheral Nerve Disease
The symptoms of peripheral nerve disease, or neuropathy, are numbness (i.e., a sensory deficit) and weakness (i.e., a motor deficit). Such symptoms may arise from disturbances in many parts of the nervous system. How, then, can one tell whether a problem is the result of disease in the PNS?
Motor axons directly innervate and have “trophic” effects on skeletal muscle. If the axon is cut or dies, this trophic influence is lost and the muscle undergoes denervation atrophy. In addition, individual muscle fibers may twitch spontaneously (fibrillation). The cause of fibrillation is still debated, but it may be related to the observation that acetylcholine receptors spread beyond the neuromuscular junction and become “supersensitive” to their agonist. If true, these observations imply continuing exposure to acetylcholine, even if it is in smaller quantities. Schwann cells at denervated junctions may be the source of acetylcholine. When a motor axon is first damaged but has not yet lost continuity with the muscle fibers that it innervates, these muscle cells may twitch in unison. These small twitches can be seen under the skin and are called fasciculations. They are probably due to spontaneous action potentials in dying or injured motor neurons or their axons.
When the PNS is affected by a diffuse or generalized disease (e.g., the result of a metabolic problem or toxin), all peripheral nerves are involved, but symptoms arise first in the longest nerves of the body (i.e., those traveling from the spinal cord to the feet). This predilection for affecting the longest nerves often causes a “stocking pattern” defect in sensation and sometimes in strength. If both the feet and hands are affected, the process is called a “stocking and glove” defect. With progression of the disease, the level of involvement moves centripetally (i.e., up the leg, toward the trunk), and the sensory or motor dysfunction comes to involve more proximal portions of the legs and arms. One of the most common causes of this diffuse pattern of PNS involvement is the sensorimotor polyneuropathy associated with diabetes. Other causes include chronic renal failure (uremia), thiamine deficiency (often seen with alcohol abuse), and heavy metal poisoning.
If a patient exhibits weakness or sensory loss that is associated with muscle fibrillation and atrophy and a stocking or stocking and glove pattern of sensory disturbance, a PNS problem is likely. Patients with peripheral neuropathy may also complain of tingling sensations (paresthesias) or pain in areas of the body supplied by the diseased nerves.
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