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Ovid: Clinical Neuroanatomy

Authors: Snell, Richard S. Title: Clinical Neuroanatomy, 7th Edition Copyright ©2010 Lippincott Williams & Wilkins > Table of Contents > Chapter 2 – The Neurobiology of the Neuron and the Neuroglia Chapter 2 The Neurobiology of the Neuron and the Neuroglia A 38-year-old man with a history of involuntary movements, personality changes, and mental deterioration was referred to a neurologist. The symptoms started insidiously 8 years ago and have gotten progressively worse. The first symptoms were involuntary, abrupt, and purposeless movements of the upper limbs associated with clumsiness and dropping of objects. At presentation, the patient had difficulty walking, speaking, and swallowing. Associated with these movement defects were an impairment of memory and loss of intellectual capacity. Impulsive behavior and bouts of depression also occurred. Close questioning of the patient and his wife revealed that the patient’s father and his older brother had had similar symptoms before they died. A diagnosis of Huntington disease was made. Huntington disease is an autosomal dominant disorder with the defect localized to the short arm of chromosome 4. Histologically, the caudate nucleus and the putamen show extensive degeneration, mainly involving the acetylcholine and gamma-aminobutyric acid (GABA)-producing neurons; the dopamine neurons are unaffected. There is also secondary degeneration of the cerebral cortex. This case is an example of a hereditary disorder that mainly involves a particular group of neurons. P.34 Chapter Objectives

  • To define the neuron and name its processes
  • To learn the varieties of neurons and identify them in the different parts of the nervous system
  • To review the cell biology of a neuron and understand the function of a nerve cell and its processes
  • To review the structure of the plasma membrane as it is related to its physiology
  • To learn the transport of materials from the cell body to the axon terminals
  • To understand the structure and function of synapses and neurotransmitters
  • To review the supporting function of the neuroglial cells for nerve cells and the possible role that they play in neuronal metabolism, function, and neuronal death

The purpose of this chapter is to prepare the student to understand how the basic excitable cell—the neuron—communicates with other neurons. It also considers certain injuries to the neuron and the effects of drugs on the mechanism by which neurons communicate with one another. Definition of a Neuron Neuron is the name given to the nerve cell and all its processes (Fig. 2-1). Neurons are excitable cells that are specialized for the reception of stimuli and the conduction of the nerve impulse. They vary considerably in size and shape, but each possesses a cell body from whose surface project one or more processes called neurites (Fig. 2-2). Those neurites responsible for receiving information and conducting it toward the cell body are called dendrites. The single long tubular neurite that conducts impulses away from the cell body is called the axon. The dendrites and axons are often referred to as nerve fibers. Neurons are found in the brain and spinal cord and in ganglia. Unlike most other cells in the body, normal neurons in the mature individual do not undergo division and replication. Varieties of Neurons Although the cell body of a neuron may be as small as 5 µm or as large as 135 µm in diameter, the processes or neurites may extend over a distance of more than 1 m. The number, length, and mode of branching of the neurites provide a morphologic method for classifying neurons. Unipolar neurons are those in which the cell body has a single neurite that divides a short distance from the cell body into two branches, one proceeding to some peripheral structure and the other entering the central nervous system (Fig. 2-3). The branches of this single neurite have the structural and functional characteristics of an axon. In this type of neuron, the fine terminal branches found at the peripheral end of the axon at the receptor site are often referred to as the dendrites. Examples of this form of neuron are found in the posterior root ganglion. Bipolar neurons possess an elongated cell body, from each end of which a single neurite emerges (Fig. 2-3). Examples of this type of neuron are found in the retinal bipolar cells and the cells of the sensory cochlear and vestibular ganglia. Multipolar neurons have a number of neurites arising from the cell body (Fig. 2-3). With the exception of the long process, the axon, the remainder of the neurites are dendrites. Most neurons of the brain and spinal cord are of this type. Neurons may also be classified according to size:

  • Golgi type I neurons have a long axon that may be 1 m or more in length in extreme cases (Figs. 2-4, 2-5, and 2-6). The axons of these neurons form the long fiber tracts of the brain and spinal cord and the nerve fibers of peripheral nerves. The pyramidal cells of the cerebral cortex, the Purkinje cells of the cerebellar cortex, and the motor cells of the spinal cord are good examples.
  • Golgi type II neurons have a short axon that terminates in the neighborhood of the cell body or is entirely absent (Figs. 2-5 and 2-6). They greatly outnumber the Golgi type I neurons. The short dendrites that arise from these neurons give them a star-shaped appearance. These neurons are numerous in the cerebral and cerebellar cortex and are often inhibitory in function. Table 2-1 summarizes the classification of neurons.

Structure of the Neuron Nerve Cell Body The nerve cell body, like that of other cells, consists essentially of a mass of cytoplasm in which a nucleus is embedded (Figs. 2-7 and 2-8), bounded externally by a plasma membrane. It is interesting to note that the volume of cytoplasm within the nerve cell body is often far less than the total volume of cytoplasm in the neurites. The cell bodies of the small granular cells of the cerebellar cortex measure about 5 µm in diameter, whereas those of the large anterior horn cells may measure as much as 135 µm in diameter. Nucleus The nucleus, which stores the genes, is commonly centrally located within the cell body and is typically large and rounded.1 In mature neurons, the chromosomes no longer P.35 duplicate themselves and function only in gene expression. The chromosomes are, therefore, not arranged as compact structures but exist in an uncoiled state. Thus, the nucleus is pale, and the fine chromatin granules are widely dispersed (Figs. 2-6 and 2-7). There is usually a single prominent nucleolus, which is concerned with ribosomal ribonucleic acid (rRNA) synthesis and ribosome subunit assembly. The large size of the nucleolus probably is due to the high rate of protein synthesis, which is necessary to maintain the protein level in the large cytoplasmic volume that is present in the long neurites as well as in the cell body. In the female, one of the two X chromosomes is compact and is known as the Barr body. It is composed of sex chromatin and is situated at the inner surface of the nuclear envelope. The nuclear envelope (Figs. 2-8 and 2-9) can be regarded as a special portion of the rough endoplasmic reticulum of the cytoplasm and is continuous with the endoplasmic reticulum of the cytoplasm. The envelope is double layered and possesses fine nuclear pores, through which materials can diffuse into and out of the nucleus (Fig. 2-8). The nucleoplasm and the cytoplasm can be considered as functionally continuous. Newly formed ribosomal subunits can be passed into the cytoplasm through the nuclear pores.

Figure 2-1 A neuron.
Figure 2-2 Photomicrograph of a smear preparation of the spinal cord showing a neuron with its cell body and its processes or neurites.

Cytoplasm The cytoplasm is rich in granular and agranular endoplasmic reticulum (Figs. 2-9 and 2-10) and contains the following organelles and inclusions: (a) Nissl substance; (b) the Golgi complex; (c) mitochondria; (d) microfilaments; (e) microtubules; (f) lysosomes; (g) centrioles; and (h) lipofuscin, melanin, glycogen, and lipid. Nissl substance consists of granules that are distributed throughout the cytoplasm of the cell body, except for the region close to the axon, called the axon hillock (Fig. 2-11). The granular material also extends into the proximal parts of the dendrites; it is not present in the axon. Electron micrographs show that the Nissl substance is composed of rough-surfaced endoplasmic reticulum (Fig. 2-12) arranged in the form of broad cisternae stacked one on top of the other. Although many of the ribosomes are attached to the surface of the endoplasmic reticulum, many more lie free in the intervals between the cisternae. P.36 P.37 P.38Since the ribosomes contain RNA, the Nissl substance is basophilic and can be well demonstrated by staining with toluidine blue or other basic aniline dyes (Fig. 2-11) and using the light microscope.

Figure 2-3 The classification of neurons according to the number, length, and mode of branching of the neurites.
Figure 2-4 Photomicrograph of a silver-stained section of the cerebellar cortex showing two Purkinje cells. These are examples of Golgi type I neurons.
Figure 2-5 Photomicrograph of a silver-stained section of the cerebral cortex. Note the presence of large pyramidal cells, which are examples of Golgi type I neurons, and numerous Golgi type II neurons.
Figure 2-6 Different types of neurons.
Table 2-1 Classification of Neurons
Morphologic Classification Arrangement of Neurites Location
Number, Length, and Mode of Branching of Neurites
Unipolar Single neurite divides a short distance from cell body Posterior root ganglion
Bipolar Single neurite emerges from either end of cell body Retina, sensory cochlea, and vestibular ganglia
Multipolar Many dendrites and one long axon Fiber tracts of brain and spinal cord, peripheral nerves, and motor cells of spinal cord
Size of Neuron
Golgi type I Single long axon Fiber tracts of brain and spinal cord, peripheral nerves, and motor cells of spinal cord
Golgi type II Short axon that with dendrites resembles a star Cerebral and cerebellar cortex

The Nissl substance is responsible for synthesizing protein, which flows along the dendrites and the axon and replaces the proteins that are broken down during cellular activity. Fatigue or neuronal damage causes the Nissl substance to move and become concentrated at the periphery of the cytoplasm. This phenomenon, which gives the impression that the Nissl substance has disappeared, is known as chromatolysis.

Figure 2-7 Photomicrograph of a section of the anterior gray column of the spinal cord showing two large motor nerve cells with nuclei. Note the prominent nucleolus in one of the nuclei.

The Golgi complex, when seen with the light microscope after staining with a silver-osmium method, appears as a network of irregular wavy threads around the nucleus. In electron micrographs, it appears as clusters of flattened cisternae and small vesicles made up of smooth-surfaced endoplasmic reticulum (Figs. 2-8 and 2-9). The protein produced by the Nissl substance is transferred to the inside of the Golgi complex in transport vesicles, where it is temporarily stored and where carbohydrate may be added to the protein to form glycoproteins. The proteins are believed to travel from one cisterna to another P.39via transport vesicles. Each cisterna of the Golgi complex is specialized for different types of enzymatic reaction. At the trans side of the complex, the macromolecules are packaged in vesicles for transport to the nerve terminals. The Golgi complex is also thought to be active in lysosome production and in the synthesis of cell membranes. The latter function is particularly important in the formation of synaptic vesicles at the axon terminals.

Figure 2-8 Diagrammatic representation of the fine structure of a neuron.

Mitochondria are found scattered throughout the cell body, dendrites, and axons (Figs. 2-8 and 2-9). They are spherical or rod shaped. In electron micrographs, the walls show a characteristic double membrane (Fig. 2-8). The inner membrane is thrown into folds or cristae that project into the center of the mitochondrion. Mitochondria possess many enzymes, which are localized chiefly on the inner mitochondrial membrane. These enzymes take part in the tricarboxylic acid cycle and the cytochrome chains of respiration. Therefore, mitochondria are important in nerve cells, as in other cells, in the production of energy. Neurofibrils, as seen with the light microscope after staining with silver, are numerous and run parallel to each other through the cell body into the neurites (Fig. 2-13). With the electron microscope, the neurofibrils may be resolved into bundles of neurofilaments—each filament measuring about 10 nm in diameter (Fig. 2-14). The neurofilaments form the main component of the cytoskeleton. Chemically, neurofilaments are very stable and belong to the cytokeratin family. Microfilaments measure about 3 to 5 nm in diameter and are formed of actin. Microfilaments are concentrated at the periphery of the cytoplasm just beneath the plasma membrane where they form a dense network. Together with microtubules, microfilaments play a key role in the formation of new cell processes and the retraction of old ones. They also assist the microtubules in axon transport. Microtubules are revealed with the electron microscope and are similar to those seen in other types of cells. They measure about 25 nm in diameter and are found P.40 P.41 interspersed among the neurofilaments (Fig. 2-14). They extend throughout the cell body and its processes. In the axon, all the microtubules are arranged in parallel, with one end pointing to the cell body and the other end pointing distally away from the cell body.

Figure 2-9 Electron micrograph of a neuron showing the structure of the nucleus and a number of cytoplasmic organelles. (Courtesy Dr. J. M. Kerns.)
Figure 2-10 Electron micrograph of a neuron showing nuclear and plasma membranes and cytoplasmic organelles. (Courtesy Dr. J. M. Kerns.)
Figure 2-11 Photomicrograph of a section of the anterior gray column of the spinal cord stained with toluidine blue. Note the presence of dark-staining Nissl substance in the cytoplasm of four neurons.

The microtubules and the microfilaments provide a stationary track that permits specific organelles to move by molecular motors. The stop-and-start movement is caused by the periodic dissociation of the organelles from the track or the collision with other structures.

Figure 2-12 Electron micrograph of the cytoplasm of two neurons showing the structure of Nissl bodies (substance). (Courtesy Dr. J. M. Kerns.)

Cell transport involves the movement of membrane organelles, secretory material, synaptic precursor membranes, large dense core vesicles, mitochondria, and smooth endoplasmic reticulum. Cell transport can take place in both directions in the cell body and its processes. It is of two kinds: rapid (100 to 400 mm per day) and slow (0.1 to 3.0 mm per day). Rapid transport (100 to 400 mm per day) is brought about by two motor proteins associated with the microtubule adenosine triphosphate (ATP)-ase sites; these are P.42 kinesin for anterograde (away from the cell) movement and dynein for retrograde movement. It is believed that in anterograde movement, kinesin-coated organelles are moved toward one end of the tubule, and that in retrograde movement, dynein-coated organelles are moved toward the other end of the tubule. The direction and speed of the movement of an organelle can be brought about by the activation of one of the motor proteins or of both of the motor proteins simultaneously. Slow transport (0.1 to 3.0 mm per day) involves the bulk movement of the cytoplasm and includes the movement of mitochondria and other organelles. Slow axonal transport occurs only in the anterograde direction. The molecular motor has not been identified but is probably one of the kinesin family. Lysosomes are membrane-bound vesicles measuring about 8 nm in diameter. They serve the cell by acting as intracellular scavengers and contain hydrolytic enzymes. They are formed by the budding off of the Golgi apparatus. Lysosomes exist in three forms: (1) primary lysosomes, which have just been formed; (2) secondary lysosomes, which contain partially digested material (myelin figures); and (3) residual bodies, in which the enzymes are inactive and the bodies have evolved from digestible materials such as pigment and lipid.

Figure 2-13 Photomicrograph of a silver-stained section of a neuron showing the presence of large numbers of neurofibrils in the cytoplasm of the cell body and the neurites.

Centrioles are small, paired structures found in immature dividing nerve cells. Each centriole is a hollow cylinder whose wall is made up of bundles of microtubules. They are associated with the formation of the spindle during cell division and in the formation of microtubules. Centrioles are also found in mature nerve cells, where they are believed to be involved in the maintenance of microtubules. Lipofuscin (pigment material) occurs as yellowish-brown granules within the cytoplasm (Fig. 2-15). It is believed to be formed as the result of lysosomal activity, and it represents a harmless metabolic by-product. Lipofuscin accumulates with age. Melanin granules are found in the cytoplasm of cells in certain parts of the brain (e.g., the substantia nigra of the midbrain). Their presence may be related to the catecholamine-synthesizing ability of these neurons, whose neurotransmitter is dopamine. The main structures present in a nerve cell body are summarized in Table 2-2. Plasma Membrane The plasma membrane forms the continuous external boundary of the cell body and its processes, and in the neuron, it is the site for the initiation and conduction of the nerve impulse (Figs. 2-10 and 2-14). The membrane is about 8 nm thick, which is too thin to be seen with the light microscope. When viewed under the electron microscope, the plasma membrane appears as two dark lines with a light line between them. The plasma membrane is composed of an inner and an outer layer of very loosely arranged protein molecules, each layer being about 2.5 nm thick, separated by a middle layer of lipid about 3 nm thick. The lipid layer is made up of two rows of phospholipid molecules arranged so that their hydrophobic ends are in contact with each other and their polar ends are in contact with the protein layers. Certain protein molecules lie within the phospholipid layer and span the entire width of the lipid layer. These molecules provide the membrane with hydrophilic channels through which inorganic ions may enter and leave the cell. Carbohydrate molecules are attached to the outside of the plasma membrane and are linked to the proteins or the lipids, forming what is known as the cell coat, or glycocalyx. The plasma membrane and the cell coat together form a semipermeable membrane that allows diffusion of certain ions through it but restricts others. In the resting state (unstimulated state), the K+ ions diffuse through the plasma membrane from the cell cytoplasm to the tissue fluid (Fig. 2-16). The permeability of the membrane to K+ ions is much greater than that to the Na+ ions; thus, the passive efflux of K+ is much greater than the influx of Na+. This results in a steady potential difference of about -80 mV, which can be measured across the plasma membrane since the inside of the membrane is negative with respect to the outside. This potential is known as the resting potential. P.43

Figure 2-14 Electron micrograph of dendrites showing the presence of neurofilaments and microtubules within their cytoplasm. (Courtesy Dr. J. M. Kerns.) A: Longitudinal section of two adjacent dendrites. B: Transverse section of a dendrite.
Figure 2-15 Photomicrograph of a longitudinal section of a posterior root ganglion showing the presence of lipofuscin granules within the cytoplasm of sensory neurons.

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Table 2-2 The Main Structures in a Nerve Cell Body
Structure Shape Appearance Location Function
Nucleus Large, rounded Pale, chromatin widely scattered; single prominent nucleolus; Barr body present in female Centrally placed, displaced to periphery in cell injury Controls cell activity
Cytoplasmic organelles
   Nissl substance Granules of rough endoplasmic reticulum Broad cisternae; ribosomes are basophilic Throughout cytoplasm and proximal part of dendrites, absent from axon hillock and axon, fatigue and injury result in concentration at periphery Synthesizes protein
   Golgi complex Wavy threads; clusters of flattened cisternae and small vesicles Smooth endoplasmic reticulum Close to the nucleus Adds carbohydrate to protein molecule; packages products for transport to nerve terminals; forms cell membranes
   Mitochondria Spherical, rod shaped Double membrane with cristae Scattered Form chemical energy
   Neurofibrils Linear fibrils Run parallel to each other; composed bundles of microfilaments, each 10 nm in diameter Run from dendrites through cell body to axon Determines the shape of the neuron
   Microfilaments Linear fibrils Filaments 3–5 nm in diameter Form a dense network beneath the plasma membrane Role in formation and retraction of cell processes and in cell transport
   Microtubules Linear tubes Run between neurofibrils, 25 nm in diameter Run from dendrites through cell body to axon Cell transport
   Lysosomes Vesicles 8 nm in diameter; three forms: primary, secondary, and residual bodies Throughout cell Cell scavengers
   Centrioles Paired hollow cylinders Wall made up of bundles of microtubules Confined to cytoplasm of cell body Take part in cell division; maintain microtubules
   Lipofuscin Granules Yellowish brown Scattered through cytoplasm Metabolic by-product
   Melanin Granules Yellowish brown Substantia nigra of midbrain Related to formation of dopa

Excitation of the Plasma Membrane of the Nerve Cell Body When the nerve cell is excited (stimulated) by electrical, mechanical, or chemical means, a rapid change in membrane permeability to Na+ ions takes place, and Na+ ions diffuse through the plasma membrane into the cell cytoplasm from the tissue fluid (Fig. 2-16). This results in the membrane becoming progressively depolarized. The sudden influx of Na+ ions followed by the altered polarity produces the so-called action potential, which is approximately +40 mV. This potential is very brief, lasting about P.45 5 msec. The increased membrane permeability for Na+ ions quickly ceases, and membrane permeability for K+ ions increases. Therefore, the K+ ions start to flow from the cell cytoplasm and return the localized area of the cell to the resting state. Once generated, the action potential spreads over the plasma membrane, away from the site of initiation, and is conducted along neurites as the nerve impulse. This impulse is self-propagated, and its size and frequency do not alter (Fig. 2-16). Once the nerve impulse has spread over a given region of plasma membrane, another action potential cannot be elicited immediately. The duration of this nonexcitable state is referred to as the refractory period, and it controls the maximum frequency that the action potentials can be conducted along the plasma membrane (see p. 46). The greater the strength of the initial stimulus, the larger the initial depolarization and the greater will be the spread into the surrounding areas of the plasma membrane. Should multiple excitatory stimuli be applied to the surface of a neuron, then the effect can be summated. For example, subthreshold stimuli may pass over the surface of the cell body and be summated at the origin of the axon and so initiate an action potential.

Figure 2-16 Ionic and electrical changes that occur in a neuron when it is stimulated.

Inhibitory stimuli are believed to produce their effect by causing an influx of Cl- ions through the plasma membrane into the neuron, thus producing hyperpolarization and reducing the excitatory state of the cell (Fig. 2-17). Sodium and Potassium Channels The sodium and potassium channels, through which the sodium and potassium ions diffuse through the plasma membrane, are formed of the protein molecules that extend through the full thickness of the plasma membrane P.46 (Fig. 2-18). Why a particular channel permits the passage of K+ ions while excluding Na+ ions is difficult to explain. The selectivity cannot be due to the diameter of the ions, since the K+ ion is larger than the Na+ ion. However, the movement of ions in solution depends not only on the size of the ion but also on the size of the shell of water surrounding it. K+ ions have weaker electric fields than Na+ ions; thus, K+ ions attract less water than Na+ ions. Therefore, K+ ions behave as if they are smaller than Na+ ions. This physicochemical explanation does not entirely account for why a channel is selective. It is possible that the channels have narrow regions along their length that act as sieves or molecular filters. The ions may also participate in electrostatic interactions with the amino acid residues lining the walls of the channel.

Figure 2-17 Ionic and electrical changes that occur in a neuron during hyperpolarization.
Figure 2-18 Ionic permeability of the plasma membrane. Diagram shows the interactions of the ions with water, the membrane lipid bilayer, and the ion channels.

The ion channel proteins are relatively stable, but they exist in at least two conformational states, which represent an open functional state and a closed functional state. The mechanism responsible for the opening and closing of a channel is not understood but may be likened to a gate that is opened and closed. Gating may involve the twisting and distortion of the channel, thus creating a wider or narrower lumen. Gating appears to occur in response to such stimuli as voltage change, the presence of a ligand, or stretch or pressure. In the nonstimulated state, the gates of the potassium channels are open wider than those of the sodium channels, which are nearly closed. This permits the potassium ions to diffuse out of the cell cytoplasm more readily than the sodium ions can diffuse in. In the stimulated state, the gates of the sodium channels are at first wide open; then, the gates of the potassium channels are opened, and the gates of the sodium channels are nearly closed again. It is the opening and closing of the sodium and potassium channels that is thought to produce the depolarization and repolarization of the plasma membrane. The absolute refractory period, which occurs at the onset of the action potential when a second stimulus is unable to produce a further electrical change, is thought to P.47be due to the inability to get the sodium channels open. During the relative refractory period, when a very strong stimulus can produce an action potential, presumably the sodium channels are opened. The Nerve Cell Processes The processes of a nerve cell, often called neurites, may be divided into dendrites and an axon. The dendrites are the short processes of the cell body (Fig. 2-19). Their diameter tapers as they extend from the cell body, and they often branch profusely. In many neurons, the finer branches bear large numbers of small projections called dendritic spines. The cytoplasm of the dendrites closely resembles that of the cell body and contains Nissl granules, mitochondria, microtubules, microfilaments, ribosomes, and agranular endoplasmic reticulum. Dendrites should be regarded merely as extensions of the cell body to increase the surface area for the reception of axons from other neurons. Essentially, they conduct the nerve impulse toward the cell body.

Figure 2-19 A: Light photomicrograph of a motor neuron in the anterior gray column of the spinal cord showing the nerve cell body, two dendrites, and the surrounding neuropil. B: Electron micrograph of a dendrite showing axodendritic synapses. (Courtesy Dr. J. M. Kerns.)

During early embryonic development, there is an overproduction of dendrites. Later, they are reduced in number and size in response to altered functional demand from afferent axons. There is evidence that dendrites remain plastic throughout life and elongate and branch or contract in response to afferent activity. Axon is the name given to the longest process of the cell body. It arises from a small conical elevation on the cell body, devoid of Nissl granules, called the axon hillock (Figs. 2-8 and 2-20). Occasionally, an axon arises from the proximal part of a dendrite. An axon is tubular and is uniform in diameter; it tends to have a smooth surface. Axons usually do not branch close to the cell body; collateral branches may occur along their length. Shortly before their termination, axons commonly branch profusely. The distal ends of the terminal branches of the axons are often enlarged; they are called terminals (Fig. 2-21). Some P.48 axons (especially those of autonomic nerves) near their termination show a series of swellings resembling a string of beads; these swellings are called varicosities. Axons may be very short (0.1 mm), as seen in many neurons of the central nervous system, or extremely long (3.0 m), as seen when they extend from a peripheral receptor in the skin of the toe to the spinal cord and thence to the brain. The diameter of axons varies considerably with different neurons. Those of larger diameter conduct impulses rapidly, and those of smaller diameter conduct impulses very slowly. The plasma membrane bounding the axon is called the axolemma. The cytoplasm of the axon is termed the axoplasm. Axoplasm differs from the cytoplasm of the cell body in possessing no Nissl granules or Golgi complex. The sites for the production of protein, namely RNA and ribosomes, are absent. Thus, axonal survival depends on the transport of substances from the cell bodies. The initial segment of the axon is the first 50 to 100 µm after it leaves the axon hillock of the nerve cell body (Fig. 2-20). This is the most excitable part of the axon and is the site at which an action potential originates. It is important to remember that under normal conditions, an action potential does not originate on the plasma membrane of the cell body but, instead, always at the initial segment.

Figure 2-20 Electron micrograph of a longitudinal section of a neuron from the cerebral cortex showing the detailed structure of the region of the axon hillock and the initial segment of the axon. Note the absence of Nissl substance (rough endoplasmic reticulum) in the axon hillock and the presence of numerous microtubules in the axoplasm. Note also the axon terminals (arrows) forming axoaxonal synapses with the initial segment of the axon. (Courtesy Dr. A. Peters.)

An axon always conducts impulses away from the cell body. The axons of sensory posterior root ganglion cells are an exception; here, the long neurite, which is indistinguishable from an axon, carries the impulse toward the cell body. (See unipolar neurons, p. 36.) Axon Transport Materials are transported from the cell body to the axon terminals (anterograde transport) and to a lesser extent in the opposite direction (retrograde transport). Fast anterograde transport of 100 to 400 mm per day refers to the transport of proteins and transmitter substances or their precursors. Slow anterograde transport of 0.1 to 3.0 mm per day refers to the transport of axoplasm and includes the microfilaments and microtubules. P.49

Figure 2-21 Electron micrograph showing multiple axodendritic synapses. Note the presence of large numbers of presynaptic vesicles within the axons. The definition has come to include the site at which a neuron comes into close proximity with a skeletal muscle cell and functional communication occurs. (Courtesy Dr. J. M. Kerns.)

Retrograde transport explains how the cell bodies of nerve cells respond to changes in the distal end of the axons. For example, activated growth factor receptors can be carried along the axon to their site of action in the nucleus. Pinocytotic vesicles arising at the axon terminals can be quickly returned to the cell body. Worn-out organelles can be returned to the cell body for breakdown by the lysosomes. Axon transport is brought about by microtubules assisted by the microfilaments. Synapses The nervous system consists of a large number of neurons that are linked together to form functional conducting pathways. Where two neurons come into close proximity and functional interneuronal communication occurs, the site of such communication is referred to as a synapse2 (Fig. 2-22). Most neurons may make synaptic connections to a 1,000 or more other neurons and may receive up to 10,000 connections from other neurons. Communication at a synapse, under physiologic conditions, takes place in one direction only. Synapses occur in a number of forms (Fig. 2-22). The most common type is that which occurs between an axon of one neuron and the dendrite or cell body of the second neuron. As the axon approaches the synapse, it may have a terminal expansion (bouton terminal), or it may have a series of expansions (bouton de passage), each of which makes synaptic contact. In other types of synapses, the axon synapses on the initial segment of another axon—that is, proximal to where the myelin sheath begins—or there may be synapses between terminal expansions from different neurons. Depending on the site of the synapse, they are often referred to as axodendritic, axosomatic, or axoaxonic (Fig. 2-22). The manner in which an axon terminates varies considerably in different parts of the nervous system. For example, a single axon may terminate on a single neuron, or a single axon may synapse with multiple neurons, as in the case of the parallel fibers of the cerebellar cortex synapsing with multiple Purkinje cells. In the same way, a single neuron may have synaptic junctions with axons of many different neurons. The arrangement of these synapses will determine the means by which a neuron can be stimulated or inhibited. Synaptic spines, extensions of the surface of a neuron, form receptive sites for synaptic contact with afferent boutons (Fig. 2-22). Synapses are of two types: chemical and electrical. Most synapses are chemical, in which a chemical substance, P.50 the neurotransmitter, passes across the narrow space between the cells and becomes attached to a protein molecule in the postsynaptic membrane called the receptor.

Figure 2-22 A–D. Different types of chemical synapses.

In most chemical synapses, several neurotransmitters may be present. One neurotransmitter is usually the principal activator and acts directly on the postsynaptic membrane, while the other transmitters function as modulators and modify the activity of the principal transmitter. Chemical Synapses Ultrastructure of Chemical Synapses On examination with an electron microscope, synapses are seen to be areas of structural specialization (Figs. 2-21 and 2-23). The apposed surfaces of the terminal axonal expansion and the neuron are called the presynaptic and postsynaptic membranes, respectively, and they are separated by a synaptic cleft measuring about 20 to 30 nm wide. The presynaptic and postsynaptic membranes are thickened, and the adjacent underlying cytoplasm shows increased density. On the presynaptic side, the dense cytoplasm is broken up into groups; on the postsynaptic side, the density often extends into a subsynaptic web. Presynaptic vesicles, mitochondria, and occasional lysosomes are present in the cytoplasm close to the presynaptic membrane (Fig. 2-23). On the postsynaptic side, the cytoplasm often contains parallel cisternae. The synaptic cleft contains polysaccharides. P.51

Figure 2-23 High-power electron micrograph of axodendritic synapses showing the thickening of the cell membranes at the synaptic sites, presynaptic vesicles, and the presence of mitochondria within the axons near their termination. (Courtesy Dr. J. M. Kerns.)

The presynaptic terminal contains many small presynaptic vesicles that contain the molecules of the neurotransmitter(s). The vesicles fuse with the presynaptic membrane and discharge the neurotransmitter(s) into the synaptic cleft by a process of exocytosis (Fig. 2-24). When synapses are first formed in the embryo, they are recognized as small zones of density separated by a synaptic cleft. Later, they mature into well-differentiated structures. The presence of simple, undifferentiated synapses in the postnatal nervous system has led to the suggestion that synapses can be developed as required and possibly undergo atrophy when redundant. This plasticity of synapses may be of great importance in the process of learning and in the development and maintenance of memory. Neurotransmitters at Chemical Synapses The presynaptic vesicles and the mitochondria play a key role in the release of neurotransmitter substances at synapses. The vesicles contain the neurotransmitter substance that is released into the synaptic cleft; the mitochondria provide adenosine triphosphate (ATP) for the synthesis of new transmitter substance. Most neurons produce and release only one principal transmitter at all their nerve endings. For example, acetylcholine is widely used as a transmitter by different neurons in the central and peripheral parts of the nervous system, whereas dopamine is released by neurons in the substantia nigra. Glycine, another transmitter, is found principally in synapses in the spinal cord. The following chemical substances act as neurotransmitters, and there are many more: acetylcholine (ACh), norepinephrine, epinephrine, dopamine, glycine, serotonin, gamma-aminobutyric acid (GABA), enkephalins, substance P, and glutamic acid. It should be noted that all skeletal neuromuscular junctions use only acetylcholine as the transmitter, whereas synapses between neurons use a large number of different transmitters. Action of Neurotransmitters All neurotransmitters are released from their nerve endings by the arrival of the nerve impulse (action potential). This results in an influx of calcium ions, which causes the synaptic vesicles to fuse with the presynaptic membrane. The neurotransmitters are then ejected into the extracellular fluid in the synaptic cleft. Once in the cleft, they diffuse across the gap to the postsynaptic membrane. There they achieve their objective by raising or lowering the resting potential of the postsynaptic membrane for a brief period of time. P.52

Figure 2-24 Release of neurotransmitters. A: Acetylcholine. B: Catecholamines.
Table 2-3 Examples of Principal (Classic) Neurotransmitters and Neuromodulators at Synapses
Neuromediatorsa Function Receptor Mechanism Ionic Mechanism Location
Principal Neurotransmitters
Acetylcholine (nicotinic), L-glutamate Rapid excitation Ion channel receptors Opens cation channel (fast EPSP) Main sensory and motor systems
GABA Rapid inhibition   Opens anion channel for Cl- (fast IPSP)  
Neuromodulators
Acetylcholine (muscarinic), serotonin, histamine, adenosine Modulation and modification of activity G-protein–coupled receptors Opens or closes K+ or Ca2+ channels (slow IPSP and slow EPSP) Systems that control homeostasis
GABA, gamma-aminobutyric acid; EPSP, excitatory postsynaptic potential; IPSP, inhibitory postsynaptic potential.
aNote that these are only a few examples of an ever-increasing number of known neuromediators.

The receptor proteins on the postsynaptic membrane bind the transmitter substance and undergo an immediate conformational change that opens the ion channel, generating an immediate but brief excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP). The rapid excitation is seen with acetylcholine (nicotinic) and L-glutamate, or the inhibition is seen with GABA (Table 2-3). Other receptor proteins bind the transmitter substance and activate a second messenger system, usually through a molecular transducer, a G-protein. These receptors have a longer latent period, and the duration of the response may last several minutes or longer. Acetylcholine (muscarinic), serotonin, histamine, neuropeptides, and adenosine are good examples of this type of transmitter, which is often referred to as a neuromodulator (see next section). The excitatory and the inhibitory effects on the postsynaptic membrane of the neuron will depend on the summation of the postsynaptic responses at the different synapses. If the overall effect is one of depolarization, the neuron will be excited, an action potential will be initiated at the initial segment of the axon, and a nerve impulse will travel along the axon. If, on the other hand, the overall effect is one of hyperpolarization, the neuron will be inhibited and no nerve impulse will arise. Distribution and Fate of Neurotransmitters The distribution of the neurotransmitters varies in different parts of the nervous system. Acetylcholine, for example, is found at the neuromuscular junction, in autonomic ganglia, and at parasympathetic nerve endings. In the central nervous system, the motor neuron collaterals to the Renshaw cells are cholinergic. In the hippocampus, the ascending reticular pathways, and the afferent fibers for the visual and auditory systems, the neurotransmitters are also cholinergic. Norepinephrine is found at sympathetic nerve endings. In the central nervous system, it is found in high P.53 concentration in the hypothalamus. Dopamine is found in high concentration in different parts of the central nervous system, such as in the basal nuclei (ganglia). The effect produced by a neurotransmitter is limited by its destruction or reabsorption. For example, in the case of acetylcholine, the effect is limited by the destruction of the transmitter in the synaptic cleft by the enzyme acetylcholinesterase (AChE) (Fig. 2-24). However, with the catecholamines, the effect is limited by the return of the transmitter to the presynaptic nerve ending (Fig. 2-24). Neuromodulators at Chemical Synapses It is interesting to note that in many synapses, certain substances other than the principal neurotransmitters are ejected from the presynaptic membrane into the synaptic cleft. These substances are capable of modulating and modifying the activity of the postsynaptic neuron and are called neuromodulators. Action of Neuromodulators Neuromodulators can coexist with the principal neurotransmitter at a single synapse. Usually, but not always, the neuromodulators are in separate presynaptic vesicles. Whereas on release into the synaptic cleft the principal neurotransmitters have a rapid, brief effect on the postsynaptic membrane, the neuromodulators on release into the cleft do not have a direct effect on the postsynaptic membrane. Rather, they enhance, prolong, inhibit, or limit the effect of the principal neurotransmitter on the postsynaptic membrane. The neuromodulators act through a second messenger system, usually through a molecular transducer, such as a G-protein, and alter the response of the receptor to the neurotransmitter. In a given area of the nervous system, many different afferent neurons can release several different neuromodulators that affect the postsynaptic neuron. Such an arrangement can lead to a wide variety of responses, depending on the input from the afferent neurons. Electrical Synapses Electrical synapses are gap junctions containing channels that extend from the cytoplasm of the presynaptic neuron to that of the postsynaptic neuron: They are rare in the human central nervous system. The neurons communicate electrically; there is no chemical transmitter. The bridging channels permit ionic current flow to take place from one cell to the other with a minimum of delay. In electrical synapses, the rapid spread of activity from one neuron to another ensures that a group of neurons performing an identical function act together. Electrical synapses also have the advantage that they are bidirectional; chemical synapses are not. Definition of Neuroglia The neurons of the central nervous system are supported by several varieties of nonexcitable cells, which together are called neuroglia (Fig. 2-25). Neuroglial cells are generally smaller than neurons and outnumber them by five to ten times; they comprise about half the total volume of the brain and spinal cord. There are four types of neuroglial cells: (1) astrocytes, (2) oligodendrocytes, (3) microglia, and (4) ependyma (Fig. 2-25). A summary of the structural features, location, and functions of the different neuroglial cells is provided in Table 2-4. Astrocytes Astrocytes have small cell bodies with branching processes that extend in all directions. There are two types of astrocytes: fibrous and protoplasmic. Fibrous astrocytes are found mainly in the white matter, where their processes pass between the nerve fibers (Fig. 2-26). Each process is long, slender, smooth, and not much branched. The cell bodies and processes contain many filaments in their cytoplasm. Protoplasmic astrocytes are found mainly in the gray matter, where their processes pass between the nerve cell bodies (Figs. 2-27 and 2-28). The processes are shorter, thicker, and more branched than those of the fibrous astrocyte. The cytoplasm of these cells contains fewer filaments than that of the fibrous astrocyte. Many of the processes of astrocytes end in expansions on blood vessels (perivascular feet), where they form an almost complete covering on the external surface of capillaries. Large numbers of astrocytic processes are interwoven at the outer and inner surfaces of the central nervous system, where they form the outer and inner glial limiting membranes. Thus, the outer glial limiting membrane is found beneath the pia mater, and the inner glial limiting membrane is situated beneath the ependyma lining the ventricles of the brain and the central canal of the spinal cord. Astrocytic processes are also found in large numbers around the initial segment of most axons and in the bare segments of axons at the nodes of Ranvier. Axon terminals at many sites are separated from other nerve cells and their processes by an envelope of astrocytic processes. Functions of Astrocytes Astrocytes, with their branching processes, form a supporting framework for the nerve cells and nerve fibers. Their processes are functionally coupled at gap junctions. In the embryo, they serve as a scaffolding for the migration of immature neurons. By covering the synaptic contacts between neurons, they may serve as electrical insulators preventing axon terminals from influencing neighboring and unrelated neurons. They may even form barriers for the spread of neurotransmitter substances released at synapses. Astrocytes have been shown to be affected by GABA and glutamic acid secreted by the nerve terminals, thereby limiting the influence of these neurotransmitters. Astrocytes appear to be able to take up excess K+ ions from the extracellular space so that they may have an important function during repetitive firing of a neuron. They store glycogen within their cytoplasm. The glycogen can be broken down into glucose and even further into lactate, both of which are P.54 released to surrounding neurons in response to norepinephrine.

Figure 2-25 Diagrammatic representation of the arrangement of different types of neuroglial cells.

Astrocytes may serve as phagocytes by taking up degenerating synaptic axon terminals. Following the death of neurons due to disease, astrocytes proliferate and fill in the spaces previously occupied by the neurons, a process called replacement gliosis. It is possible that astrocytes can serve as a conduit for the passage of metabolites or raw materials from blood capillaries to the neurons through their perivascular feet. The fact that astrocytes are linked together by gap junctions would enable ions to pass from one cell to another without entering the extracellular space. Astrocytes may produce substances that have a trophic influence on neighboring neurons. Recent research has suggested that astrocytes secrete cytokines that regulate the activity of immune cells entering the nervous system in disease. Finally, astrocytes play an important role in the structure of the blood-brain barrier. Here, the astrocyte processes terminate as expanded feet at the basement membrane of blood vessels (see p. 463). Oligodendrocytes Oligodendrocytes have small cell bodies and a few delicate processes; there are no filaments in their cytoplasm. Oligodendrocytes are frequently found in rows along myelinated nerve fibers and surround nerve cell bodies (Fig. 2-29). Electron micrographs show the processes of a single oligodendrocyte joining the myelin sheaths of several nerve fibers (Fig. 2-30). However, only one process joins the myelin between two adjacent nodes of Ranvier. Functions of Oligodendrocytes Oligodendrocytes are responsible for the formation of the myelin sheath of nerve fibers in the central nervous system, much as the myelin of peripheral nerves is formed from Schwann cells. This formation and maintenance of myelin around many of the axons of the central nervous system provides the axons with an insulating coat and greatly increases the speed of nerve conduction along these axons (see p. 86). P.55 P.56 P.57 Because oligodendrocytes have several processes, unlike Schwann cells, they can each form several internodal segments of myelin on the same or different axons. A single oligodendrocyte can form as many as 60 internodal segments. It should also be noted that unlike Schwann cells in the peripheral nervous system, oligodendrocytes and their associated axons are not surrounded by a basement membrane. Myelination begins at about the 16th week of intrauterine life and continues postnatally until practically all the major nerve fibers are myelinated by the time the child is walking.

Table 2-4 The Structural Features, Location, and Functions of the Different Neuroglial Cells
Neuroglial Cell Structure Location Function
Astrocytes
 Fibrous Small cell bodies, long slender processes, cytoplasmic filaments, perivascular feet White matter Provide supporting framework, are electrical insulators, limit spread of neurotransmitters, take up K+ ions
   Protoplasmic Small cell bodies, short thick processes, many branches, few cytoplasmic filaments, perivascular feet Gray matter Store glycogen, have a phagocytic function, take place of dead neurons, are a conduit for metabolites or raw materials, produce trophic substances
Oligodendrocytes Small cell bodies, few delicate processes, no cytoplasmic filaments In rows along myelinated nerves, surrounding neuron cell bodies Form myelin in CNS, influence biochemistry of neurons
Microglia Smallest of neuroglial cells, wavy branches with spines Scattered throughout CNS Are inactive in normal CNS, proliferate in disease and phagocytosis, joined by blood monocytes
Ependyma
 Ependymocytes Cuboidal or columnar in shape with cilia and microvilli, gap junctions Line ventricles, central canal Circulate CSF, absorb CSF
 Tanycytes Long basal processes with end feet on capillaries Line floor of third ventricle Transport substances from CSF to hypophyseal-portal system
 Choroidal epithelial cells Sides and bases thrown into folds, tight junctions Cover surfaces of choroid plexuses Produce and secrete CSF
CNS, central nervous system; CSF, cerebrospinal fluid.
Figure 2-26 A: Photomicrograph of a section of the gray matter of the spinal cord showing fibrous astrocytes. B: Electron micrograph showing an astrocyte. (Courtesy Dr. J. M. Kerns.)
Figure 2-27 Photomicrograph of a protoplasmic astrocyte in the cerebral cortex.
Figure 2-28 Electron micrograph of a protoplasmic astrocyte in the cerebral cortex. (Courtesy Dr. A. Peters.)
Figure 2-29 A: Photomicrograph of a group of oligodendrocytes. B: Electron micrograph of two oligodendrocytes. (Courtesy Dr. J. M. Kerns.)

Oligodendrocytes also surround nerve cell bodies (satellite oligodendrocytes) and probably have a similar function to the satellite or capsular cells of peripheral sensory ganglia. They are thought to influence the biochemical environment of neurons. Microglia The microglial cells are embryologically unrelated to the other neuroglial cells and are derived from macrophages outside the nervous system. They are the smallest of the neuroglial cells and are found scattered throughout the central nervous system (Fig. 2-31). From their small cell bodies arise wavy branching processes that give off numerous spinelike projections. They closely resemble connective tissue macrophages. They migrate into the nervous system during fetal life. Microglial cells increase in number in the presence of damaged nervous tissue resulting from trauma and ischemic injury and in the presence of diseases including Alzheimer disease, Parkinson disease, multiple sclerosis, and AIDS. Many of these new cells are monocytes that have migrated from the blood. Function of Microglial Cells Microglial cells in the normal brain and spinal cord appear to be inactive and are sometimes called resting microglial cells. In inflammatory disease of the central nervous system, they become the immune effector cells. They retract their processes and migrate to the site of the lesion. Here, they proliferate and become antigen presenting cells, which together with the invading T lymphocytes confront invading organisms. They are also actively phagocytic; their cytoplasm becomes filled with lipids and cell remnants. The P.58 microglial cells are joined by monocytes from neighboring blood vessels.

Figure 2-30 A single oligodendrocyte whose processes are continuous with the myelin sheaths of four nerve fibers within the central nervous system.

Ependyma Ependymal cells line the cavities of the brain and the central canal of the spinal cord. They form a single layer of cells that are cuboidal or columnar in shape and possess microvilli and cilia (Fig. 2-32). The cilia are often motile, and their movements contribute to the flow of the cerebrospinal fluid. The bases of the ependymal cells lie on the internal glial limiting membrane. Ependymal cells may be divided into three groups:

  • Ependymocytes, which line the ventricles of the brain and the central canal of the spinal cord and are in contact with the cerebrospinal fluid. Their adjacent surfaces have gap junctions, but the cerebrospinal fluid is in free communication with the intercellular spaces of the central nervous system.
  • Tanycytes, which line the floor of the third ventricle overlying the median eminence of the hypothalamus. These cells have long basal processes that pass between the cells of the median eminence and place end feet on blood capillaries.
  • Choroidal epithelial cells, which cover the surfaces of the choroid plexuses. The sides and bases of these cells are thrown into folds, and near their luminal surfaces, the cells are held together by tight junctions that encircle the cells. The presence of tight junctions prevents the leakage of cerebrospinal fluid into the underlying tissues.

Functions of Ependymal Cells Ependymocytes assist in the circulation of the cerebrospinal fluid within the cavities of the brain and the central canal of the spinal cord by the movements of the cilia. The microvilli on the free surfaces of the ependymocytes would indicate that they also have an absorptive function. Tanycytes are thought to transport chemical substances P.59from the cerebrospinal fluid to the hypophyseal portal system. In this manner, they may play a part in the control of the hormone production by the anterior lobe of the pituitary. Choroidal epithelial cells are involved in the production and secretion of cerebrospinal fluid from the choroid plexuses.

Figure 2-31 Electron micrograph of a microglial cell in the cerebral cortex. (Courtesy Dr. A. Peters.)

Extracellular Space When nervous tissue is examined under an electron microscope, a very narrow gap separates the neurons and the neuroglial cells. These gaps are linked together and filled with tissue fluid; they are called the extracellular space. The extracellular space is in almost direct continuity with the cerebrospinal fluid in the subarachnoid space externally and with the cerebrospinal fluid in the ventricles of the brain and the central canal of the spinal cord internally. The extracellular space also surrounds the blood capillaries in the brain and spinal cord. (There are no lymphatic capillaries in the central nervous system.) The extracellular space thus provides a pathway for the exchange of ions and molecules between the blood and the neurons and glial cells. The plasma membrane of the endothelial cells of most capillaries is impermeable to many chemicals, and this forms the blood-brain barrier. P.60

Figure 2-32 A: Photomicrograph of ependymal cells lining the central canal of the spinal cord. B: Electron micrograph of ependymal cells lining the cavity of the third ventricle. (Courtesy Dr. J. M. Kerns.)

P.61 P.62 Clinical Notes General Considerations The neuron is the basic functional unit of the nervous system. In the mature human, if it is destroyed by trauma or disease, it is not replaced. It is incapable of undergoing cell division. The neuron consists of the cell body and its processes, the axons, and the dendrites. All three parts are concerned with the process of conduction. The cell body is necessary for the normal metabolism of all its processes. Should these processes become separated from the cell body as the result of disease or simple trauma, they will quickly degenerate. This would explain the necessity for the transport of macromolecules down the axon from the cell body and also emphasizes the dependence of the axon on the cell body. The rate of axoplasmic transport is insufficient to satisfy the release of transmitter substances at the nerve terminals. This problem is overcome in two ways. First, enzymes are present within the nerve terminals in order to synthesize the transmitters from amino acids derived from the extracellular fluid, and second, at some terminals, the transmitter is reabsorbed back into the terminal following its release. Clinically, by the use of drugs, it is possible to influence this reuptake mechanism. Neuroglial cells, in contrast to neurons, are nonexcitable and do not have axons; furthermore, axon terminals do not synapse on them. They are smaller than neurons and yet outnumber them five to ten times. They comprise about one-half the total volume of the central nervous system. Reaction of a Neuron to Injury The first reaction of a nerve cell to injury is loss of function. Whether the cell recovers or dies will depend on the severity and duration of the damaging agent. If death occurs quickly, say in a few minutes from lack of oxygen, no morphologic changes will be immediately apparent. Morphologic evidence of cell injury requires a minimum of 6 to 12 hours of survival. The nerve cell becomes swollen and rounded off, the nucleus swells and is displaced toward the periphery of the cell, and the Nissl granules become dispersed toward the periphery of the cytoplasm. At this stage, the neuron could recover. If the kind of neuronal injury were not so severe as to cause death, the reparative changes would start to appear. The cell would resume its former size and shape, the nucleus would return to the center of the cell body, and the Nissl granules would take up their normal position. When cell death is imminent or has just occurred, the cell cytoplasm stains dark with basic dyes (hyperchromatism), and the nuclear structure becomes unclear. The final stage occurs after cell death. The cytoplasm becomes vacuolated, and the nucleus and cytoplasmic organelles disintegrate. The neuron now is dissolved and removed by the activity of the phagocytes. In the central nervous system, this function is performed by the microglial cells, and in the peripheral nervous system, this function is performed by local members of the reticuloendothelial system. In chronic forms of injury, the size of the cell body is reduced, the nucleus and cytoplasm show hyperchromatism, and the nuclear membranes and those of the cytoplasmic organelles show irregularity. Axonal Reaction and Axonal Degeneration Axonal reaction and axonal degeneration are the changes that take place in a nerve cell when its axon is cut or injured. The changes start to appear within 24 to 48 hours after injury; the degree of change will depend on the severity of the injury to the axon and will be greater if the injury occurred close to the cell body. The nerve cell becomes rounded off and swollen, the nucleus swells and becomes eccentrically placed, and the Nissl granules become dispersed toward the periphery of the cytoplasm. These changes reach their maximum in about 12 days. In the peripheral nervous system, section of an axon is followed by attempts at regeneration, and reparative changes take place in the cell body. In the central nervous system, degeneration is not followed by regeneration. If the corticospinal tracts, for example, are destroyed by disease, the nerve cells that give rise to these axons degenerate and disappear completely. There is an important exception to the axonal reaction of nerve cells described above. This occurs in the nerve cells of the posterior root ganglia of the spinal nerves. If the peripheral axons are sectioned, the nerve cells show degenerative changes; if, however, the central axons are sectioned or destroyed by disease, such as tabes dorsalis, the nerve cells show no degenerative changes. Axonal Transport and the Spread of Disease Rabies, which is an acute viral disease of the central nervous system, is transmitted by the bite of an infected animal. The virus is present in the saliva of the infected animal and following a bite travels to the central nervous system by way of axonal transport in both sensory and motor nerves. The incubation period is related to the length of the peripheral nerve involved. The longer the nerve, the longer will be the duration of the incubation period. Herpes simplex and herpes zoster are viral diseases that also involve axonal transport to spread to different parts of the body. Axonal transport is also believed to play a role in the spread of the poliomyelitis virus from the gastrointestinal tract to the motor cells of the anterior gray horns of the spinal cord and the brainstem. Tumors of Neurons When considering tumors of the nervous system, it must not be forgotten that the nervous system is made up of many different types of tissues. In the central nervous system, there are neurons, neuroglia, blood vessels, and meninges, and in the peripheral nervous system, there are neurons, Schwann cells, connective tissue, and blood vessels. Tumors of neurons in the central nervous system are rare, but tumors of peripheral neurons are not uncommon. The neuroblastoma occurs in association with the suprarenal gland; it is highly malignant and occurs in infants and children. The ganglioneuroma occurs in the suprarenal medulla or sympathetic ganglia; it is benign and occurs in children and adults. The pheochromocytoma occurs in the suprarenal medulla; it is usually benign and gives rise to hypertension since it secretes norepinephrine and epinephrine. Synaptic Blocking Agents Transmission of a nervous impulse across a synapse is accomplished by the release of neurotransmitters into the synaptic cleft. Transmission occurs in one direction, and subthreshold stimulation of many synapses leads to summation. The released transmitter then exerts its effect on the postsynaptic membrane by increasing the permeability of the postsynaptic membrane to sodium and causing excitation or by increasing the permeability of the postsynaptic membrane to chloride and causing inhibition. The synapse is a region in which transmission is easily blocked. As a general rule, long chains of neurons with multiple synapses are more easily blocked than shorter, simpler chains of neurons. General anesthetic agents are effective because they have the ability to block synaptic transmission. At autonomic ganglia, preganglionic fibers enter the ganglia and synapse with the postganglionic sympathetic or parasympathetic neurons. The nerve impulse, on reaching the termination of the preganglionic nerve, brings about the release of acetylcholine, which excites a nervous impulse in the postganglionic neuron. Ganglionic blocking agents may be divided into three groups, depending on their mechanism of action. The first group of agents, which includes the hexamethonium and tetraethylammonium salts, resembles acetylcholine at the postsynaptic membrane; thus, these agents inhibit transmission across a synapse. The second group of agents, which includes nicotine, has the same action as acetylcholine on the postsynaptic membrane, but these agents are not destroyed by the cholinesterase. This results in a prolonged depolarization of the postsynaptic membrane; therefore, it is insensitive to further stimulation by acetylcholine. Unfortunately, this depolarization block is associated with initial stimulation, so these drugs are not suitable for clinical use. The third group of agents, which includes procaine, inhibits the release of acetylcholine from the preganglionic fibers. In the central nervous system, it is much more difficult to demonstrate the release of a particular transmitter substance at specific synapses due to inaccessibility. For example, it is impossible to perfuse specific localized brain areas through their vascular system, and it is very difficult to stimulate an isolated neuronal pathway within the brain or spinal cord. The motor neuron collaterals to the Renshaw cells have been shown to liberate acetylcholine at their endings. Many synapses in the central nervous system are also cholinergic. The development of monoclonal antibody techniques has opened a whole new approach to the identification and localization of chemical mediators in the central nervous system. Substance P, somatostatin, and cholecystokinin are a few examples of the neuropeptides that have been located in the central nervous system. The nonuniform concentrations of norepinephrine in the central nervous system have led many investigators to believe that it might function as a central neurotransmitter. The concentrations are greater in gray matter than in white matter, and the highest concentrations are found in the hypothalamus. Dopamine is found in high concentrations in the central nervous system and is secreted by neurons that originate in the substantia nigra. Many of the cholinergic blocking agents used in the peripheral nervous system have little or no effect on the cholinergic synapses of the central nervous system because they are unable to cross the blood-brain barrier in significant concentrations. Atropine, scopolamine, and diisopropylphosphorofluoridate (DPF) can effectively cross the barrier, and their effects on human behavior have been extensively studied. Similarly, it is believed that many psychotropic drugs bring about changes in the activities of the central nervous system by influencing the release of catecholamines at synaptic sites. The phenothiazines, for example, are thought to block dopamine receptors on postsynaptic neurons. Treatment of Certain Neurologic Diseases by the Manipulation of Neurotransmitters The increasing numbers of neurotransmitters being discovered in the central nervous system and the location of their site of action are raising the possibility that certain diseases can be modified by the administration of specific drugs. In Huntington chorea, for example, there is a loss of neurons that use GABA and acetylcholine as transmitters. GABA is unable to cross the blood-brain barrier, but physostigmine, a cholinesterase inhibitor, can cross the barrier, and its use has brought about some improvement. The use of L-dopa in the treatment of parkinsonism has been most successful; in this disease, it replaces the deficiency of dopamine, which is normally released to the basal ganglia by the neurons of the substantia nigra. Drugs are now rapidly being developed to modify the process of synaptic transmission in a number of ways: (1) by interfering with the process of neurotransmitter synthesis. (2) by inhibiting the uptake of drugs by the postsynaptic membrane, (3) by binding the neurotransmitter at the receptor site on the postsynaptic membrane, and (4) by terminating the neurotransmitter action. Reactions of Neuroglia to Injury The reaction of neuroglial cells to injury, whether caused by physical trauma or by vascular occlusion, is characterized by the hyperplasia and hypertrophy of the astrocytes, which become fibrous irrespective of their antecedent morphology. The proliferation of the astrocytes is referred to as astrocytosis or gliosis. The loss of neuronal tissue is not compensated for in volume by the glial hypertrophy. The cytoplasm of the enlarged astrocytes contains large numbers of fibrils and glycogen granules. The dense feltwork of astrocytic processes that occurs in the areas of neuronal degeneration produces the so-called gliotic scar. The degree of gliosis is much greater in the presence of residual damaged neuronal tissue as compared with a clean surgical excision in which no traumatized brain remains. This is why in patients with focal epilepsy due to a large gliotic scar, the scar is excised surgically, leaving a minimal glial reaction. Oligodendrocytes respond to injury by expanding and showing vacuolation of their cytoplasm; the nuclei also tend to become pyknotic. Severe damage to oligodendrocytes would result in demyelination. Microglial cells in inflammatory and degenerative lesions of the central nervous system retract their processes and migrate to the site of the lesion. Here, they proliferate and are actively phagocytic, and their cytoplasm becomes filled with lipids and cell remnants. They are joined in their scavenger activity by monocytes that migrate from the neighboring blood vessels. Microglial cells are active in a number of diseases including multiple sclerosis, dementia in AIDS, Parkinson disease, and Alzheimer disease. Neoplasms of Neuroglia Tumors of neuroglia account for 40% to 50% of intracranial tumors. Such tumors are referred to as gliomas. Tumors of astrocytes are those most commonly encountered and include astrocytomas and glioblastomas. Apart from the ependymomas, tumors of the neuroglia are highly invasive. This explains the difficulty in achieving complete surgical removal and the great possibility of recurrence after surgery. Another feature is that as these tumors infiltrate, they often do so without interfering with the function of neighboring neurons. As a result, the tumor is often very much larger than the symptoms and physical signs would indicate. Multiple Sclerosis Multiple sclerosis is one of the most common central nervous system diseases, affecting about 250,000 Americans. It is characterized by the appearance of patches of demyelination in the white matter of the central nervous system, generally starting in the optic nerve, spinal cord, or cerebellum. The myelin sheaths degenerate, and the myelin is removed by microglial cells. Astrocytes proliferate, leading to the formation of a gliotic scar. As demyelination occurs, the conduction of the nerve impulses in the axons is impeded. Because raising the temperature shortens the duration of the action potential, one of the early signs of multiple sclerosis is that the symptoms and signs can be improved by cooling and made worse by heating by a hot bath. Most cases occur between the ages of 20 and 40 years. The cause of the disease is unknown, although an interplay between a viral infection and a host immune response may be responsible. For further discussion of this disease, see Chapter 4. Cerebral Edema Cerebral edema is a very common clinical condition that can follow head injuries, cerebral infections, or tumors. The resultant swelling of the brain may lead to flattening of the cerebral gyri, herniation of the brain through the tentorial notch or the foramen magnum, and even death. Cerebral edema may be defined as an abnormal increase in the water content of the tissues of the central nervous system. There are three forms: (1) vasogenic, (2) cytotoxic, and (3) interstitial. Vasogenic edema is the most common type and is due to the accumulation of tissue fluid in the extracellular space following damage to the vascular capillary walls or the presence of new capillaries without fully formed blood-brain barriers. It can result from infections, trauma, and tumors. Cytotoxic edema is due to the accumulation of fluid within the cells of nervous tissue (neurons and glial), resulting in cellular swelling. The cause may be toxic or metabolic and produces a failure in the plasma membrane ATP sodium pump mechanism. Interstitial edema occurs in obstructive hydrocephalus when the rise in cerebrospinal fluid pressure forces the fluid out of the ventricular system into the extracellular space. Two anatomical factors must always be remembered in cerebral edema: (1) the brain volume is restricted by the surrounding skull, and (2) the tissue fluid is drained primarily into the venous sinuses via cerebral veins because there is no lymphatic drainage. P.63 P.64 Clinical Problem Solving 1. During an operation for the repair of a sectioned radial nerve in the arm, the neurosurgeon understood that he was operating on a large bundle of nerve fibers supported by connective tissue. He realized that the nerve fibers were either axons or dendrites or the nerve was made up of a mixture of axons and dendrites. What is your understanding of the composition of the radial nerve? View Answer1. The radial nerve is made up of nerve fibers derived from motor, sensory, and autonomic neurons. By definition, the nerve fibers, or nerve cell processes, are referred to as neurites. The short neurites are called dendrites, and the long neurites are called axons. It is customary to refer to those neurites that conduct the nervous impulse toward the cell body as the dendrites and to those that conduct the impulses away from the cell body as the axons. However, in the case of the unipolar sensory neurons found in the posterior root ganglia, the neurite carrying nervous information toward the cell body has all the structural characteristics of an axon and is referred to as an axon. Thus, the radial nerve, which is composed of sensory and motor fibers, is made up of axons. 2. A well-known textbook of neurosurgery makes the following statements regarding the prognosis following peripheral nerve repair: (a) the younger the patient, the better will be the return of function; (b) the more distal the injury to a nerve, the more effective will be the regenerationok; (c) the closer a lesion is to the nerve cell body, the more profound will be the effect on this trophic center; and (d) sensory nerve cells are affected more by this retrograde phenomenon than are motor nerve cells. Comment on these statements. View Answer2. (a) It is a general rule that all reparative phenomena throughout the body occur more readily in the young than in the old. (b) As the distal end of a peripheral nerve is approached, fewer branches remain, and thus there are fewer structures yet to innervate; consequently, there are fewer possibilities of nerve fibers innervating the wrong structure during the process of regeneration. Moreover, the more distal the injury, the less the metabolism of the proximal nerve cell body is affected by the injury. (c) This is a physiologic fact. A very severe nerve injury close to its nerve cell body may result in the death of the entire neuron. (d) The physiology of sensory neurons is more susceptible to change by retrograde phenomena than that of motor neurons. 3. An 18-year-old male patient was examined by a neurosurgeon 12 months after injury to the right forearm in which the median nerve was severed. At the initial operation, shortly after the injury had occurred, debridement was performed, and the separated nerve ends were tagged with radiopaque sutures. Unfortunately, the wound was infected, and surgical repair of the nerve was deferred. Is it practical to consider repairing a peripheral nerve after a delay of 12 months? View Answer3. If the wound is not infected, the best time to perform a nerve suture is about 3 weeks after the injury. Satisfactory results have been obtained after a delay of as much as 14 months, provided that paralyzed muscles have not been overstretched and joint adhesions have been avoided by passive movements of the joints. In other words, the neuron still retains the ability to regenerate its processes even after 14 months, but the degree of recovery of function will depend a great deal on the care that the denervated structures receive in the intervening time. 4. While examining a pathology specimen of nervous tissue under a microscope, the pathologist was able to determine the sex of the individual from whom the tissue had been removed. How would you be able to do this? View Answer4. In 1949, Barr and Bertram noticed the presence of a small, stainable body of chromatin (Barr body) situated at the inner surface of the nuclear envelope in the female that could not be seen in the cells of the male. It is one of the two X chromosomes present in the female. The presence or absence of the Barr body enables one to readily determine the sex of the individual from whom the tissue was removed. 5. Axoplasmic flow is involved in the transport of certain viruses in the nervous system. What structures present in the cytoplasm of the neuron take part in this process? View Answer5. With an electron microscope, it is possible to resolve within the cytoplasm of a neuron small tubules that measure about 25 nm in diameter; there are also microfilaments measuring about 3 to 5 nm in diameter. The possible role that these structures play in cell transport is discussed on page 39. 6. About 1% of all deaths are due to intracranial tumors. Many different tissues are present within the skull in addition to the nervous system. Moreover, the nervous system itself is composed of many different types of tissues. In fact, tumors that arise as neoplasms of nerve cells and fibers are rare. Name the different types of tissues that are found in the central nervous system and in the peripheral nervous system. View Answer6. The central nervous system is made up of the following tissues: (a) neurons, (b) neuroglia, (c) blood vessels, and (d) meninges. The peripheral nervous system is composed of the following tissues: (a) neurons, (b) Schwann cells, (c) connective tissue, and (d) blood vessels. 7. When a nerve cell is stimulated, the permeability of the plasma membrane changes, permitting certain ionic movements to take place across the membrane. (a) What is the structure of the plasma membrane? (b) Is the permeability of the plasma membrane increased or decreased when the nerve cell is stimulated? (c) What is the action of local analgesics on the cell membrane? View Answer7. (a) The structure of the plasma membrane is described on page 42. (b) When a neuron is excited, the permeability of the plasma membrane to Na+ ions is increased, and these diffuse from the tissue fluid into the neuron cytoplasm. (c) Local analgesics act as membrane stabilizers and inhibit the increase in permeability to Na+ ions in response to stimulation. It is not understood how this stabilization is brought about. One theory is that the analgesic agent becomes attached to receptor sites on the protein layer of the plasma membrane, reducing the permeability to Na+ ions and preventing depolarization from taking place. Small-diameter nerve fibers are more readily blocked than large fibers, and nonmyelinated fibers are more readily blocked than myelinated ones. For these reasons, nerve fibers that conduct pain and temperature are most easily blocked, and the large motor fibers are the least easily blocked. The small autonomic nerve fibers are blocked early and account for the rapid appearance of vasodilatation. 8. The synapse is a region where nervous transmission is easily blocked. Clinically, the ganglion-blocking drugs used act by competing with acetylcholine released from the nerve endings in the ganglia. Name two groups of drugs that have been used for this purpose, and indicate the site at which they act. View Answer8. Tetraethylammonium salts and hexamethonium salts are the two groups of drugs. These salts closely resemble acetylcholine in structure and compete with acetylcholine at the postsynaptic membrane. By this means, they successfully block a ganglion, although the amount of acetylcholine released is unaffected. 9. A 2-year-old boy was taken to a pediatrician because his mother had noticed that his right eye was protruding (proptosis). When questioned, the mother stated that she had first noticed this protrusion 1 month previously and that it had progressively worsened since that time. The child was otherwise perfectly fit. On physical examination, the child was observed to be healthy in every respect except for the marked proptosis of the right eye. A careful palpation of the abdomen, however, revealed a large, soft mass in the upper part of the abdomen that extended across the midline. X-ray examination, including a computed tomography (CT) body scan, revealed a large, soft tissue mass that displaced the right kidney downward. A diagnosis of malignant tumor of the suprarenal or neighboring sympathetic nervous tissue, with metastases in the right orbital cavity, was made, the latter being responsible for the right-side proptosis. Name a tumor of the suprarenal gland or sympathetic nervous tissue that occurs commonly in children and may metastasize in the bones of the orbit. View Answer9. The neuroblastoma is a tumor of primitive neuroblasts and arises either in the suprarenal medulla or in the upper abdominal sympathetic ganglia. It is malignant and confined to children. The tumor metastasizes early, and the metastasis may be the reason why the child receives medical attention, as in this case. The bones of the orbit are a common site for metastasis of a neuroblastoma. 10. At an autopsy, a third-year medical student was handed a slice of the cerebrum and was asked what proportion of central nervous tissue is made up by neuroglia. How would you have answered that question? Which cells are present in the largest numbers—neurons or neuroglial cells? View Answer10. Neuroglia comprises about one-half the total volume of the central nervous system. Neuroglial cells outnumber neurons by five to ten times. 11. A 23-year-old man, while in the army in Vietnam, received a penetrating gunshot wound to the left side of his head. At the operation, the neurosurgeon was able to remove the bullet from the left frontal lobe of his brain. Apart from a slight weakness of his right leg, the patient made an uneventful recovery. Eighteen months later, the patient started to have severe generalized attacks of convulsions, during which he lost consciousness. Since this time, the attacks have occurred irregularly at about monthly intervals. Each attack is preceded by a feeling of mental irritability, and twitching of the right leg occurs. A diagnosis of epilepsy was made by the examining neurologist. Is it possible that this patient’s attacks of epilepsy are related to his gunshot wound in Vietnam? Is traumatic epilepsy a common condition? What treatment would you recommend? View Answer11. The reaction of tissue of the central nervous system to injury is characterized by the hyperplasia and hypertrophy of the astrocytes. The proliferation of the astrocytes is often referred to as astrocytosis or gliosis. The degree of gliosis is much greater in the presence of residual damaged brain tissue than with a clean surgical incision. The resulting scar tissue, the so-called gliotic scar, in the case of a penetrating gunshot wound, may be extensive and may give rise to focal or generalized epileptic attacks. The majority of such patients who become epileptic do so within 2 years. After careful examination of these patients, including the performance of radiography, CT brain scans, MRIs, and electroencephalography, the trauma site should be explored with a view to removing the gliotic scar. Such a scar will be replaced by a much smaller surgical scar. This operative intervention cures many of these patients. 12. A 42-year-old woman visited her physician because she was suffering from very severe headaches. Until 6 months ago, she experienced only an occasional mild headache. Since that time, her headaches gradually have become more severe, and their duration has increased. They now last 3 to 4 hours and are so intense that she has to lie down. She has felt sick on two occasions, but she has vomited on only one occasion. The headaches are generalized in nature and are made worse by coughing or straining. A physical examination revealed swelling of both optic discs with congestion of the retinal veins and the presence of multiple retinal hemorrhages. Weakness of the lateral rectus muscle of the right eye also was detected. Anteroposterior radiographs of the skull showed displacement of the calcified pineal gland to the left side. Anteroposterior and lateral radiographs of the skull showed some degree of calcification in a localized area in the right cerebral hemisphere. These findings, together with those obtained from CT scans of the brain and magnetic resonance imaging (MRI), made the diagnosis of a right-sided cerebral tumor certain. Surgical exploration confirmed the presence of a large infiltrating tumor of the right parietal lobe. What is the most common type of tumor found in such a site in a middle-aged patient? How would you treat such a patient? View Answer12. A history of severe headaches and nausea and the finding of a choked optic disc (swelling of the optic disc, congestion of the retinal veins, and retinal hemorrhages) are not always diagnostic of a brain tumor. However, the finding of weakness of the lateral rectus muscle of the right eye owing to compression of the right sixth cranial nerve against the floor of the skull, together with the positive results on radiologic and other laboratory tests, made the diagnosis certain. The glioma (tumor of neuroglia) is the most common type of tumor found in such a patient. Unfortunately, gliomas tend to infiltrate the brain tissue and cannot be completely removed surgically. Biopsy is performed to establish the diagnosis, as much of the tumor is removed as is clinically feasible, and the area is treated by deep x-ray therapy postoperatively. Survival time may also be increased by the use of chemotherapy. P.65 P.66 P.67 Review Questions Directions: Each of the numbered items in this section is followed by answers. Select the ONE lettered answer that is CORRECT. 1. The following statements concern the cytology of a neuron: (a) A unipolar neuron is one that gives rise to a single neurite that divides a short distance from the cell body into two branches, one proceeding to some peripheral structure and the other entering the central nervous system. (b) A bipolar neuron is one that has two neurites that emerge together from the cell body. (c) Nissl substance is found in the axon of a neuron. (d) The Golgi complex does not synthesize cell membranes. (e) Melanin granules are not found in the neurons of the substantia nigra. View Answer1. A is correct. A unipolar neuron is one that gives rise to a single neurite that divides a short distance from the cell body into two branches, one proceeding to some peripheral structure and the other entering the central nervous system (see p. 34). B. A bipolar neuron is one that gives rise to a neurite that emerges from each end of the cell body. The sensory ganglia of the vestibulocochlear nerve (eighth cranial nerve) possess bipolar neurons. C. Nissl substance is not found in the axon of a neuron but in the cell body of a neuron. D. The Golgi complex is important in the synthesis of cell membranes. E. Melanin granules are found in the neurons of the substantia nigra, and it is these neurons that are responsible for the neurotransmitter dopamine. 2. The following statements concern the cytology of a neuron: (a) The protein molecules projecting from the surface of the microtubules take no part in rapid transport in axoplasm. (b) The protein molecules that extend through the full thickness of the plasma membrane of a neuron serve as sodium and potassium channels. (c) There is strong experimental evidence to suggest that the gates of the sodium and potassium channels are formed by actin molecules. (d) The size of the nucleolus in a neuron is unrelated to the volume of cytoplasm possessed by neurons. (e) A synapse is the site where two neurons come together and their membranes are in contact; interneuronal communication occurs. View Answer2. B is correct. The protein molecules that extend through the full thickness of the plasma membrane of a neuron serve as sodium and potassium channels (see p. 45). A. The protein molecules projecting from the surface of the microtubules take part in rapid transport in axoplasm. C. The gates of the sodium and potassium channels are formed of protein molecules but not actin molecules. D. The large size of the nucleolus in a neuron is related to the very large volume of cytoplasm possessed by certain neurons. E. A synapse is the site where two neurons come into close proximity and where functional interneuronal communication occurs. 3. The following statements concern the axon: (a) The initial segment of the axon is the first 500 µm after it leaves the axon hillock. (b) The nerve impulse generated by a neuron does not originate at the initial segment of an axon but on the dendrite. (c) The action potential is produced by the sudden influx of Na+ ions into the cytoplasm. (d) Following the influx of Na+ ions in the production of the action potential, the permeability for Na+ ions increases further, and the permeability for K+ ions ceases. (e) The spread of the action potential along the microtubules of the axon constitutes the nerve impulse. View Answer3. C is correct. The action potential within an axon is produced by the sudden influx of Na+ ions into the cytoplasm (see p. 44). A. The initial segment of the axon is the first 50 to 100 µm after it leaves the axon hillock. B. The nerve impulse generated by a neuron does originate at the initial segment of an axon but not on the dendrite. D. Following the influx of Na+ ions in the production of the action potential, the permeability for Na+ ions ceases, and the permeability for K+ ions increases; thus K+ ions start to flow from the cell cytoplasm. E. The spread of the action potential along the plasma membrane of the axon constitutes the nerve impulse. 4. The following statements concern a nerve impulse: (a) The refractory period is the duration of the nonexcitable state of the plasma membrane following the passage of a wave of repolarization. (b) Subthreshold stimuli, when applied to the surface of a neuron, cannot be summated. (c) Inhibitory stimuli are believed to produce their effect by causing an influx of K+ ions through the plasma membrane of the neuron. (d) Hyperpolarization can be produced by causing an influx of K+ ions through the plasma membrane. (e) The axolemma is the site of nerve conduction. View Answer4. E is correct. The axolemma is the site of nerve conduction. A. The refractory period is the duration of the nonexcitable state of the plasma membrane following the passage of a wave of depolarization (see p. 45). B. Subthreshold stimuli, when applied to the surface of a neuron, can be summated. C. Inhibitory stimuli are believed to produce their effect by causing an influx of Cl- ions through the plasma membrane of the neuron. D. Hyperpolarization can be produced by causing an influx of Cl- ions through the plasma membrane. 5. The following statements concern the structure of a synapse: (a) Synapses may be axodendritic, axosomatic, or axoaxonic. (b) The synaptic cleft is the space between the presynaptic and postsynaptic membranes and measures about 200 nm. (c) The subsynaptic web lies beneath the presynaptic membrane. (d) Presynaptic vesicles do not contain the neurotransmitter substance. (e) All neurons produce and release several types of transmitter substances at all their nerve endings. View Answer5. A is correct. The synapses may be axodendritic, axosomatic, or axoaxonic (see Fig. 2-22). B. The synaptic cleft is the space between the presynaptic and postsynaptic membranes and measures about 20 nm. C. The subsynaptic web lies beneath the postsynaptic membrane. D. Presynaptic vesicles may contain the neurotransmitter substance (see p. 50). E. The majority of neurons produce and release only one principal transmitter at all their nerve endings. 6. The following statements concern a neuron: (a) Nerve fibers are the dendrites and axons of a neuron. (b) The volume of cytoplasm within the nerve cell body always far exceeds that found in the neurites. (c) Golgi type I neurons have very short axons. (d) Golgi type II neurons have very long axons. (e) Golgi type II neurons form the Purkinje cells of the cerebellar cortex. View Answer6. A is correct. Nerve fibers are the dendrons and axons of a neuron (see p. 34). B. The volume of cytoplasm within the nerve cell body is often far less than the total volume of cytoplasm in the neurites. C. Golgi type I neurons have very long axons. D. Golgi type II neurons have very short axons. E. Golgi type I neurons form the Purkinje cells of the cerebellar cortex. 7. The following statements concern the neuron organelles and inclusions: (a) Centrioles are not found in mature nerve cells. (b) Lipofuscin granules tend to disappear with age. (c) The Nissl substance fills the axon hillock but is absent from other areas of the cytoplasm. (d) Microfilaments contain actin and do not assist in cell transport. (e) Mitochondria are found in the dendrites and axons. View Answer7. E is correct. Mitochondria are found in the dendrites and axons. A. Centrioles are found in mature nerve cells as well as in immature dividing nerve cells. B. Lipofuscin granules tend to accumulate with age. C. The Nissl substance is absent from the axon hillock. D. Microfilaments contain actin and probably assist in cell transport (see p. 39). 8. The following statements concern dendrites: (a) A dendrite conveys a nerve impulse away from the nerve cell body. (b) Dendritic spines are small projections of the plasma membrane that increase the receptor surface area of the dendrite. (c) The cytoplasm of dendrites does not contain ribosomes and agranular endoplasmic reticulum. (d) Most dendrites expand in width as they extend from the nerve cell body. (e) Dendrites rarely branch. View Answer8. B is correct. Dendritic spines are small projections of the plasma membrane that increase the receptor surface area of the dendrite. A. A dendrite conveys a nerve impulse toward the nerve cell body (see p. 34). C. The cytoplasm of dendrites contains ribosomes and agranular endoplasmic reticulum as well as Nissl granules, microtubules, and microfilaments. D. Most dendrites taper in width as they extend from the nerve cell body. E. Dendrites often branch profusely. 9. The following statements concern neuromodulators: (a) Neuromodulators may coexist with the principal (classic) transmitter at a single synapse. (b) They often diminish and shorten the effect of the principal transmitter. (c) They never act through a second messenger. (d) They have a brief effect on the postsynaptic membrane. (e) Acetylcholine (muscarinic) is not a good example of a neuromodulator. View Answer9. A is correct. Neuromodulators may coexist with the principal (classic) transmitter at a single synapse (see p. 53). B. Neuromodulators often enhance and prolong the effect of the principal transmitter. C. Neuromodulators act through a second messenger (see p. 53). D. Neuromodulators may have a prolonged effect on the postsynaptic membrane. E. Acetylcholine (muscarinic) is a good example of a neuromodulator. 10. The following statements concern the neurobiology of neuron structures: (a) A lysosome is a membrane-bound vesicle covered with ribosomes. (b) A terminal bouton is the postsynaptic part of an axon. (c) A receptor is a protein molecule on the postsynaptic membrane. (d) Nissl substance is formed of the smooth surfaced endoplasmic reticulum. (e) Microtubules provide a mobile track that allows specific organelles to move by molecular motors. View Answer10. C is correct. A receptor is a protein molecule on the postsynaptic membrane. A. A lysosome is a membrane-bound vesicle that is not covered with ribosomes. B. A terminal bouton is the presynaptic part of an axon. D. Nissl substance is formed of the rough-surfaced endoplasmic reticulum. E. Microtubules provide a stationary track that allows specific organelles to move by molecular motors. 11. The following statements concern neuroglia: (a) Fibrous astrocytes are located mainly in the gray matter of the central nervous system. (b) Replacement gliosis follows the death of neurons in the central nervous system and is due to the proliferation of astrocytes. (c) Astrocytes are not involved in the absorption of gamma-aminobutyric acid (GABA)GABA secreted by the nerve terminals. (d) Oligodendrocytes are responsible for the formation of the myelin of nerve fibers in the peripheral nervous system. (e) A single oligodendrocyte can form, by means of its processes, only one internodal segment of myelin on the same axon. View Answer11. B is correct. Replacement gliosis follows the death of neurons in the central nervous system and is due to the proliferation of astrocytes (see p. 54). A. Fibrous astrocytes are located mainly in the white matter of the central nervous system. C. Astrocytes are involved in the absorption of gamma-aminobutyric acid (GABA)leave as is secreted by the nerve terminals. D. Oligodendrocytes are responsible for the formation and maintenance of the myelin of nerve fibers in the central nervous system (see p. 00). E. Unlike Schwann cells in the peripheral nervous system, a single oligodendrocyte can form, by means of its many processes, several internodal segments of myelin on the same or different axons. 12. The following statements concern the microglial cells: (a) Microglial cells resemble connective tissue mast cells. (b) Microglial cells are larger than astrocytes or oligodendrocytes. (c) Microglial cells migrate into the central nervous system during adult life. (d) In the presence of damaged neurons, microglial cells become branched. (e) In degenerative lesions of the central nervous system, the circulating blood contributes cells to the population of microglial cells. View Answer12. E is correct. In degenerative lesions of the central nervous system, the circulating blood contributes cells to the population of microglial cells. A. Microglial cells resemble connective tissue macrophages. B. Microglial cells are smaller than astrocytes or oligodendrocytes (see Fig. 2-25). C. Microglial cells migrate into the central nervous system during fetal life. D. In the presence of damaged neurons, microglial cells round off and lose their branches and increase in number. 13. The following statements concern the ependymal cells: (a) Choroidal epithelial cells do not secrete cerebrospinal fluid. (b) The ependymocytes line the ventricular system but do not permit the cerebrospinal fluid to enter the extracellular spaces of the nervous tissue. (c) Tanycytes have short, unbranched basal processes, many of which have end feet placed on the capillaries of the median eminence. (d) The ependymal cells form a single layer, and many possess microvilli and cilia. (e) Ependymal cells are incapable of absorbing substances from the cerebrospinal fluid. View Answer13. D is correct. The ependymal cells form a single layer, and many possess microvilli and cilia (see p. 58). A. Choroidal epithelial cells secrete cerebrospinal fluid. B. The ependymocytes line the ventricular system but permit the cerebrospinal fluid to enter the extracellular spaces of the nervous system. C. Tanycytes have long, branching basal processes, many of which have end feet placed on the capillaries of the median eminence. E. Ependymal cells absorb substances from the cerebrospinal fluid. 14. The following statements concern the extracellular space: (a) The space is formed by the gaps between the neurons and not the gaps between the neuroglial cells. (b) The space surrounds the lymphatic capillaries present in the brain and spinal cord. (c) The space is not in continuity with the subarachnoid space. (d) The space is filled with tissue fluid. (e) The space is not continuous with the synaptic cleft between two neurons. View Answer14. D is correct. The extracellular space is filled with tissue fluid. A. The extracellular space is formed by the gaps between the neurons and the neuroglial cells (see p. 59). B. There are no lymphatic vessels within the central nervous system. C. The extracellular space is in almost direct continuity with the subarachnoid space. E. The extracellular space is continuous with the synaptic cleft between two neurons. 15. The following statements concern tumors of neuroglia: (a) They form about 5% of all intracranial tumors. (b) Apart from the ependymomas, tumors of neuroglia grow slowly and are not highly invasive. (c) They commonly infiltrate between neurons, causing the minimum disturbance of function. (d) They are nonmalignant and easily removed surgically. (e) As they expand, they raise the intracranial pressure. View Answer15. E is correct. As neuroglial tumors expand, they raise the intracranial pressure. A. Neuroglial tumors form about 40% to 50% of all intracranial tumors. B. Apart from the ependymomas, tumors of neuroglia are highly invasive. C. Neuroglial tumors commonly infiltrate between neurons, initially causing the minimum disturbance of function; later, they completely disrupt neuronal activities. D. Neuroglial tumors, apart from ependymomas, are highly malignant and difficult to remove surgically. 16. The following statements concern neuroglial cells: (a) They tend to be larger than nerve cell bodies. (b) Heat increases the action potential in an axon and reduces the signs and symptoms in multiple sclerosis. (c) Oligodendrocytes are found some distance away from nerve cell bodies and their neurites. (d) Multiple sclerosis is a disease involving the oligodendrocyte. (e) Like Schwann cells, oligodendrocytes are surrounded by a basement membrane. View Answer16. D is correct. Multiple sclerosis is a disease involving the oligodendrocyte (see p. 63). A. Neuroglial cells tend to be smaller than nerve cell bodies. B. Heat reduces the action potential in an axon and accentuates the signs and symptoms in multiple sclerosis. C. Oligodendrocytes are found close to nerve cell bodies and their neurites. E. Unlike Schwann cells, oligodendrocytes are not surrounded by a basement membrane. 17. The following general statements concern the neuroglial cells: (a) The microglial cells have straight processes with spinelike projections. (b) The astrocytes form a scaffold for developing neurons. (c) Oligodendrocyte processes are not continuous with the myelin sheaths. (d) The ependymal cells have no cilia on their free borders. (e) Macroglia is the term used to distinguish the larger oligodendrocytes from the smaller astrocyte. View Answer17. B is correct. The astrocytes form a scaffold for developing neurons. A. The microglial cells have wavy processes with spinelike projections. C. Oligodendrocyte processes are continuous with the myelin sheaths. D. The ependymal cells have cilia on their free borders. E. 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Jessell (eds.), Principles of Neural Science (3rd ed., p. 95). New York: Elsevier, 1991. Koester, J. Voltage-gated ion channels and the generation of the action potential. In E. R. Kandel, J. H. Schwartz, and T. M. Jessell (eds.), Principles of Neural Science (3rd ed., p. 104). New York: Elsevier, 1991. Kukuljan, M., Labarca, P., and Latorre, R. Molecular determination of ion conduction and inactivation in K+ channels. Am. J. Physiol. 268:C535–C556, 1993. Lemke, G. The molecular genetics of myelination: An update. Glia 7:263–271, 1993. Matthews, G. Synaptic exocytosis and endocytosis: Capacitance measurements. Curr. Opin. Neurobiol. 6:358–364, 1996. McCormick, D. A. Membrane properties and neurotransmitter actions. In G. M. Shepherd (ed.), The Synaptic Organization of the Brain (3rd ed., p. 32). New York: Oxford University Press, 1990. Nicholls, J. G., Martin, A. R., and Wallace, B. G. From Neuron to Brain: A Cellular and Molecular Approach to the Function of the Nervous System (3rd ed.). Sunderland, MA: Sinauer, 1992. Perry, V. H. Microglia in the developing and mature central nervous system. In: K. R. Jessen, and W. D. Richardson (eds.), Glial Cell Development: Basic Principles and Clinical Relevance (pp. 123–140). Oxford: Biosok, 1996. Peters, A., Palay, S. L., and Webster, H. de F. The Fine Structure of the Nervous System: Neurons and Their Supporting Cells (3rd ed.). New York: Oxford University Press, 1991. Scherer, S. S., and Arroyo, E. J. Recent progress on the molecular organization of myelinated axons. J. Peripher. Nerv. Syst. 7:1–12, 2002. Siegel, G. J., Agranoff, B. W., Albers, R. W., et al. (eds.). Basic Neurochemistry: Molecular, Cellular, and Medical Aspects (6th ed.). Philadelphia: Lippincott-Raven, 1999. Standring, S. (ed.) Gray’s Anatomyok (39th Br. ed.). London: Elsevier Churchill Livingstone, 2005. Sudarsky, L. Pathophysiology of the Nervous System. Boston: Little, Brown, 1990. Von Gersdorff, H., and Matthews, G. Dynamics of synaptic fusion and membrane retrieval in synaptic terminals. Nature 367:735–739, 1994. Waxman, S. G. Demyelinating diseases—New pathological insights, new therapeutic targets. N. Engl. J. Med. 338:323–325, 1998.

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