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The Cell Biology of Neurons and Glia
The number of cells in the adult human central nervous system (CNS) has been estimated at 100 billion. All arise from a relatively small population of precursors, yet a diversity of cell types is seen in the adult. Their most basic classification is as neurons and glia (glial cells).
Overview
Nerve cells ( neurons ) manipulate information. Doing so involves changes in the bioelectrical or biochemical properties of the cell, and these changes require a vast expenditure of energy for each cell. The nervous system, compared with other organs, is the greatest consumer of oxygen and glucose. These energy requirements arise directly from the metabolic demand placed on cells, which have large surface areas and concentrate biomolecules and ions against an energy gradient. Along with maintaining its metabolism, each neuron (1) receives information from either the environment or other nerve cells, (2) processes information, and (3) sends information to other neurons or effector tissues.
Glial cells control the CNS environment within which neurons function. They shuttle nutritive molecules from blood vessels to neurons, remove waste products, and maintain the electrochemical surroundings of neurons. Glia also communicate directly with nearby neurons through glial receptors and release mechanisms for certain neurotransmitters. During nervous system development, glia guide neuronal migration and promote synapse formation.
For neurons to carry out the three tasks of receiving, processing, and sending information, they must have specialized structures that contribute to each of these functions. The main components of a neuron are shown in Fig. 2.1 . In addition, specialized mechanisms and structures are required to solve some special problems specific to neuron function. Two such problems are immediately apparent. First, the mix of ions inside neurons is different from the mix outside the cell. Maintaining this difference requires extraordinary amounts of energy because ions must be pumped against electrical and diffusion gradients. The large surface area of neurons compounds this problem. Second, those neurons that send information over long distances must have a way to supply these distant sites with macromolecules and energy. For the cell biology of neurons to be fully appreciated, it is important to see the biochemical, anatomic, and physiologic properties of neurons as part of an integrated whole, the machinery that permits the neuron to do its specialized functions. In the following sections, we examine how specializations in neuronal architecture and chemistry contribute to meeting these special demands.
Structure of Neurons
Although the architecture of neurons is especially diverse, our focus will be on the characteristic features of an archetypical neuron bounded by a continuous plasma membrane and consisting of a cell body, or soma, from which dendrites and an axon arise ( Figs. 2.1 and 2.2 ). The cell body contains the nucleus surrounded by a mass of cytoplasm that includes the organelles necessary for protein synthesis and metabolic maintenance. Most neurons ( multipolar neurons) have several dendrites extending from the cell body ( Figs. 2.1 and 2.2 ). These are usually relatively short processes that taper from a thick base and, in doing so, branch extensively. In contrast, there is a single axon, which is a relatively long process (extending from a few millimeters to more than a meter) with a uniform diameter. The axon has few if any branches along most of its length, branching extensively only near the distal end (the terminal arbor ) ( Figs. 2.1 and 2.2 ). In most neurons, information normally flows from the dendrites to the cell body to the axon and its terminals, then to the next neuron or an effector tissue such as muscle. These components of the neuron are described in the order in which information is processed.
Dendrites
Dendrites receive signals either from other neurons through axonal contacts ( synapses ) formed on their surfaces ( Figs. 2.1 and 2.3 D ). Dendrites usually branch extensively in the vicinity of the cell body, giving the appearance of a tree or bush ( Figs. 2.1 to 2.3 A ). Small bud-like extensions ( dendritic spines, Fig. 2.3 C ) of a variety of shapes are frequently seen on the more distal dendrites ( Figs. 2.1 and 2.3 B, C ). These are sites of synaptic contacts (discussed later). The branches of dendrites increase in thickness as they coalesce and approach the cell body.
Observed in thin distal dendrites are sparse numbers of microtubules and neurofilaments along with small triangular-shaped clusters of agranular reticulum and ribosomes at some branch points. These structures are believed to be sites of protein synthesis and associated with memory formation. Often the distinction between the smallest dendrites and axons is difficult to discern. However, as dendrites begin to coalesce and become thicker, the number and type of organelles present increases until the cytoplasm of proximal (primary) dendrites appears no different from that observed in the soma ( Figs. 2.3 D, E and 2.4 ). Numerous types of endoplasmic reticulum, vesicles, mitochondria, microtubules, neurofilaments, Nissl bodies, polyribosomes, and free ribosomes can be seen in the primary dendrites.
Cell Body
The cell body of a neuron is also called the soma (plural, somata ) or perikaryon (plural, perikarya ) ( Figs. 2.2 and 2.4 ). The perikaryon is the metabolic center of the nerve cell. Abundant mitochondria reflect the high energy consumption of the cell. Active protein synthesis is indicated by the large size of the nucleus and its content of diffuse chromatin (euchromatin) and at least one prominent nucleolus (the site of ribosomal RNA synthesis). In the cytoplasm, ribosomes are abundant, and the rough endoplasmic reticulum (rER) and Golgi complex are extensive ( Fig. 2.1 ). The rER is basophilic (binds basic dyes) as a result of the large amount of ribosomal RNA attached to the endoplasmic membrane. These extensive, stacked layers of rER are seen as patches of basophilic staining (called Nissl substance ) in histologic preparations of nerve cells.
Neurons are classified into three general types on the basis of the shape of the cell body and the pattern of processes emerging from it. These types are the multipolar, pseudounipolar, and bipolar cells ( Table 2.1 ; see also Fig. 2.2 ).
Table 2.1
A Few of the Neuronal Types Found in the Nervous System
| Type of Neuron | Location of Cell Bodies |
|---|---|
| Pseudounipolar | Posterior root or cranial nerve ganglion |
| Bipolar | Retina Olfactory epithelium Vestibular ganglion Auditory (spiral) ganglion |
| Multipolar | |
| Stellate (star shaped) | Many areas of CNS |
| Fusiform (spindle shaped) | Many areas of CNS |
| Pyriform (pear shaped) | Many areas of CNS |
| Pyramidal | Hippocampus; layers II, III, V, and VI of cerebral cortex |
| Purkinje | Cerebellar cortex |
| Mitral | Olfactory bulb |
| Chandelier | Visual areas of cerebral cortex |
| Granule | Cerebral and cerebellar cortex |
| Amacrine (axonless) | Retina |
CNS, central nervous system.
The cell bodies of multipolar neurons vary widely in shape, so their profiles in tissue sections may appear fusiform, flask shaped, triangular, polygonal, or stellate ( Fig. 2.2 A-C ). Variations of a stellate polygon are most common. This shape results from the presence of multiple, tapering dendrites that emerge from the soma. Typically the cell body also emits a single axon that generally appears thin relative to the cell’s dendrites. More than 99% of all neurons are multipolar neurons, and the different kinds of these have characteristic patterns of processes, some of which are listed in Table 2.1 .
The pseudounipolar (or unipolar ) neuron has a spherical cell body with a centrally placed (concentric) nucleus. The cell body emits a single process that courses only a short distance before bifurcating into a long peripheral branch and a long central branch ( Fig. 2.2 D ). The peripheral branch courses as part of a peripheral nerve to convey sensory information from a somatic or visceral structure, such as the skin, skeletal muscle, or wall of intestine. The distal end of the peripheral process is dendrite-like in the sense that its terminal branches receive information either by functioning as sensory receptors or by contacting other structures that function as receptors. The central branch courses as part of a nerve root to convey the sensory information to the CNS. In effect, the distal and central processes function together as a single axon. The cell bodies of pseudounipolar cells are found primarily in the sensory ganglia of cranial and spinal nerves.
Bipolar neurons have a round or oval perikaryon, with a single process emanating from each end of the cell body ( Fig. 2.2 E, F ). They are commonly found in structures associated with the special senses. In the retina, bipolar cells are interposed between receptor cells and the neurons that send long axons from the retina to the thalamus (output cells). In the olfactory system, they function as both the receptors and the output neurons, with their axons projecting to the olfactory bulb; in the vestibular and auditory systems, they are the output cells that send information to the brainstem.
Unless special staining methods are used, the cell body of a neuron has the appearance of being the entire cell when it is viewed in histologic sections. However, the volume of the cell body of a neuron constitutes only a small fraction, often less than 1%, of the volume of the axon and dendrites even though the cell body synthesizes and continually replaces all structural molecules of these processes.
Axons and Axon Terminals
The axon arises from the cell body at a small elevation called the axon hillock. The proximal part of the axon, adjacent to the axon hillock, is the initial segment. The cytoplasm of the axon (axoplasm) contains dense bundles of microtubules and neurofilaments ( Figs. 2.1 and 2.5 A, B ). These function as structural elements, and the microtubules also play key roles in the transport of metabolites and organelles along the axon. Axons are typically devoid of ribosomes, a feature that distinguishes them from dendrites at the ultrastructural level.
In contrast to dendrites, axons may extend for long distances before branching and terminating. An example is the axon of a corticospinal tract neuron with a cell body in the motor cortex and an axon that reaches the caudal portion of the spinal cord. The axon of such a neuron accounts for approximately 99.8% of the total volume of the neuron. The surface area of an axon can be several thousand times the surface area of the parent cell body. Axons are sometimes referred to as nerve fibers, although strictly speaking, a nerve fiber includes both the axon and a sheath that is provided by support cells (described in a subsequent section).
Axons in the CNS often end in fine branches known as terminal arbors ( Fig. 2.5 C ). In most neurons, each axon terminal is capped with small terminal boutons ( boutons terminaux, terminal buttons) ( Figs. 2.1 and 2.3 C, E ). These correspond to functional points of contact (synapses) between nerve cells. In some cells, boutons are found along the length of the axon, where they are called boutons en passant. Other axons contain swellings, or varicosities, that are not button-like but still can represent points of cell-to-cell information transfer.
The site at which an axon terminal communicates with a second neuron, or with an effector tissue, is called a synapse (from the Greek word meaning “to clasp”). In general, the synapse can be defined as a contact between part of one neuron (usually its axon) and the dendrites, cell body, or axon of a second neuron. The contact can also be made with an effector cell such as a skeletal muscle fiber. Synapses are considered later in this chapter in the section Neurons as Information Transmitters.
Axonal Transport
Nerve cells have an elaborate transport system that moves organelles and macromolecules between the cell body and the axon and its terminals. Transport in the axon occurs in both directions ( Table 2.2 ; Fig. 2.6 ). Axonal transport from the cell body toward the terminals is called anterograde or orthograde; transport from the terminals toward the cell body is called retrograde.
Table 2.2
Characteristics of Axonal Transport
| Direction of Transport | Speed of Transport | Proposed Mechanism | Substances Carried |
|---|---|---|---|
| Anterograde | Fast (100-400 mm/day) | Kinesin, microtubules Neurotransmitters in vesicles, mitochondria |
Proteins in vesicles |
| Slow (∼1 mm/day) | Unknown | Cytoskeletal protein components (actin, myosin, tubulin)Neurotransmitter-related cytosolic enzymes | |
| Retrograde | Fast (50-250 mm/day) | Dynein, microtubules | Macromolecules in vesicles, “old” mitochondria Pinocytotic vesicles from axon terminal |
Anterograde axonal transport is classified into fast and slow components. Fast transport, at speeds of up to 400 mm/day, is based on the action of a protein called kinesin. Kinesin, an adenosine triphosphatase (ATPase), moves macromolecule-containing vesicles and mitochondria along microtubules in much the same manner as a small insect crawling along a straw. Slow transport carries important structural and metabolic components from the cell body to axon terminals; its mechanism is less well understood.
Retrograde axonal transport allows the neuron to respond to molecules, for example, growth factors, that are taken up near the axon terminal by either pinocytosis or receptor-mediated endocytosis. In addition, this form of transport functions in the continual recycling of components of the axon terminal. Retrograde transport along axonal microtubules is driven by the protein dynein rather than by kinesin.
Axonal transport is important in the pathogenesis of some human neurologic diseases. The rabies virus replicates in muscle tissue at the site of a bite by a rabid animal and is then transported in a retrograde direction to the cell bodies of neurons innervating the muscle. The neurons produce and shed copies of the rabies virus, which in turn are taken up by the terminals of adjacent cells. In this way, the infection becomes distributed throughout the CNS, causing the behavioral changes associated with this disease. From the CNS, the virus travels to the salivary glands by means of anterograde axonal transport in neurons innervating these glands. The infected salivary glands, in turn, shed the virus in the saliva.
The toxin produced by the bacterium Clostridium tetani is also transported in a retrograde direction in nerve cells whose axons terminate at the site of infection. Tetanus toxin is released from the nerve cell body and taken up by the terminals of neighboring neurons. However, unlike the rabies virus, which is replicated in the cell body, the tetanus toxin is diluted as it passes from cell to cell. In spite of this dilution effect, patients infected with C. tetani may have a range of neurologic deficits.
Axonal Transport as a Research Tool
The ability of neurons to transport intracellular materials is exploited in investigations of neuronal connections. For example, when the enzyme horseradish peroxidase (HRP) or a fluorescent substance is injected into regions containing axon terminals, it is taken up by these processes and transported in a retrograde direction to the cell body. After histologic preparation, the cell bodies containing these retrograde tracers can be visualized. The presence of the label in a cell body indicates that the neuron has axon terminals at the site of injection.
Tracer studies can also exploit the anterograde transport system of neurons. For example, if radioactively labeled amino acids are injected into a group of neuronal cell bodies, they will be incorporated into neuronal proteins and transported in an anterograde direction. The axons containing the labeled proteins can then be detected by autoradiography. Another commonly used anterograde tracer is HRP conjugated to the glycoprotein-binding molecule (lectin) wheat germ agglutinin (WGA-HRP). Anterograde tracers are used to identify the distribution patterns of axons arising from a specific population of neuronal cell bodies.
The fact that the cell body is the trophic center of the neuron provides two other methods of studying connections in the nervous system. If the cell body is destroyed, the axon undergoes anterograde ( Wallerian ) degeneration. These degenerated axons can be visualized when neural tissue is impregnated with silver nitrate. Variations on this method make it possible to conduct studies on human material obtained at autopsy. Conversely, injury to the axon will result in a set of changes in the cell body that are referred to as chromatolysis. The cell body swells, the nucleus assumes an eccentric position, and the Nissl substance disperses. (This breakup of the dye-binding parts of the cell gives chromatolysis its name.) This technique has also been used in animal experimentation and in human autopsy material.
Classification of Neurons and Groups of Neurons
Functionally related nerve cell bodies and axons are often aggregated to form distinct structures in the nervous system. Table 2.3 lists the main terms used for such structures. In the CNS, a cluster of functionally related nerve cell bodies is most commonly called a nucleus (plural, nuclei ); cell bodies that are arranged in a layer may be called a layer, lamina, or stratum, and columnar groups of cell bodies may be called columns. This last term is used for two types of structures. In the cerebral cortex, it refers to a group of cells that are related by function and by the location of the stimulus that drives them. These functional groups form columns oriented perpendicular to the plane of the cortex. The second type of column is found in the spinal cord and refers to a longitudinal group of functionally related cells that extend for part or all of the length of the brainstem or spinal cord.
Table 2.3
Terms Used to Describe Groupings of Neuronal Components
| Name | Description | Examples |
|---|---|---|
| CNS Structures | ||
| Nucleus (plural, nuclei) | A group of functionally related nerve cell bodies in the CNS | Inferior olivary nucleus, nucleus ambiguus, caudate nucleus |
| Column | In the cerebral cortex, a group of nerve cell bodies that are related in function and in the location of the stimulus that drives them and that form a column oriented perpendicular to the plane of the cortex | The ocular dominance and orientation columns of the visual cortex |
| In the spinal cord, a group of functionally related nerve cell bodies that form a longitudinal column extending through part or all of the length of the spinal cord | Clarke column | |
| Layer, lamina (laminae), stratum (strata) | A group of functionally related cells that form a layer oriented parallel to the plane of the larger neural structure that includes it | Layer IV of cerebral cortex, the stratum opticum of the superior colliculus |
| Tract, fasciculus (fasciculi), ∗ lemniscus (lemnisci) | A bundle of parallel axons in the CNS | Optic tract, corticospinal tract, medial longitudinal fasciculus, fasciculus gracilis, medial lemniscus |
| Funiculus (funiculi) † | A group of several parallel tracts or fasciculi | Anterior, posterior, and lateral funiculi of spinal cord |
| PNS Structures | ||
| Ganglion (ganglia) | A group of nerve cell bodies located in a peripheral nerve or root; it forms a visible knot | Posterior root ganglia, trigeminal ganglion |
| Nerve, ramus (rami), root | A peripheral structure consisting of parallel axons plus associated cells | Facial nerve, ventral roots of spinal nerves, gray and white rami of spinal nerve roots |
CNS, central nervous system; PNS, peripheral nervous system.
Bundles of axons in the CNS are called tracts, fasciculi, or lemnisci. These are typically composed of specific populations of functionally related nerve fibers (as in the corticospinal tract and medial lemniscus). A group of several tracts or fasciculi is called a funiculus or, in certain cases, a system.
In the peripheral nervous system (PNS), collections of cell bodies form a ganglion (plural, ganglia ), which may be either sensory (dorsal root, cranial nerve) or motor (visceromotor or autonomic); and axons make up nerves, rami, or roots.
As noted previously, neurons can be classified into multipolar, pseudounipolar, or bipolar neurons on the basis of shape of the cell body and the number and arrangement of processes. Neurons may also be classified on the basis of functional characteristics. A neuron that conducts signals from the periphery toward the CNS is called afferent; one that conducts signals in the opposite direction is called efferent. Neurons with long axons that convey signals to a distant target are called projection neurons, whereas neurons that act locally (because their dendrites and axons are limited to the vicinity of the cell body) are called interneurons or local circuit cells.
Neurotransmitter specificity also can be used to describe neurons and their axons. For example, cells that contain the neurotransmitter dopamine are called dopaminergic neurons. The neurons whose axons form the corticospinal tracts produce the neurotransmitter glutamate and are called glutamatergic.
The distinctions among categories based on shape, projection type, or transmitter type are not as clear as those implied in the preceding discussion. For example, most neurons only vaguely resemble the “ideal” multipolar cell. In addition, neurons may overlap several categories of classification. In practice, references to ganglia, nuclei, and tracts commonly use a blend of these terms. For example, posterior root ganglion cells are pseudounipolar (their shape), sensory (type of input), and afferent (information conveyed toward the CNS), and many are peptidergic (they contain peptides such as substance P).
Electrical Properties of Neurons
The communicative function of neurons is carried out by fluctuations in their electrical potential. Chapter 3 explains the electrical properties of neurons in depth; at this point, only a brief introduction is needed.
Neurons carry a negative electrical charge relative to the extracellular fluid bathing them. The negative charge is required because there is a preponderance of negatively charged protein molecules within the cell and is the result of the electrochemical gradient of the relatively permanent potassium ion, with more potassium being inside the cell than outside. The uneven distribution of charged particles is maintained by the neuronal plasma membrane, which limits passage of ions, permitting them to cross only when specific ion channels open. The plasma membrane is selectively permeable because certain ions can cross at certain times, but there is not a free exchange across the membrane.
The opening and closing of specific ion channels can be controlled by chemical signals, including neurotransmitters. Channels in some sensory receptor neurons can be controlled by mechanical distortion of the membrane. Still other channels are controlled by voltage changes in the neuron. These allow an explosive feed-forward amplification from a small, chemically induced voltage change to a much larger action potential that occurs with the simultaneous opening of a large number of channels. The small, chemically induced voltage changes are restricted to tiny local areas within the neuron. They result in depolarization of the neuron if positive (sodium) ions enter the cell, reducing its net negative charge, or hyperpolarization if positive (potassium) ions exit, increasing the concentration of negative charge inside the cell.
When the sum of all tiny, local depolarizations and hyperpolarizations reaches a threshold of depolarization at the initial segment of the axon, the voltage-controlled sodium channels open, producing an action potential. The action potential is large enough that it does not remain local but is propagated anterogradely along the entire length of the axon and reaches all of the axon terminals. Arrival of the action potential at the axon terminals causes release of neurotransmitter at synapses, stimulating ion channel opening and local electrical voltage changes in the next neuron in the chain of communication, the postsynaptic neuron.
Neurons as Information Receivers
Neurons collect, transform, and transmit information. Collection of information by the nerve cell occurs when the neuron receives input either from other neurons or directly from the environment. Sensory information enters the nervous system by the latter of the two routes.
Sensory Neural Information
Neurons that receive information from the environment are called primary sensory neurons. These include photoreceptors, chemoreceptors, mechanoreceptors, thermoreceptors, and nociceptors. Further information on these receptor types is found in the chapters describing sensory systems. For most primary sensory neurons, a stimulus results in a graded depolarizing potential, called a generator potential.
The process of converting sensory input into a form interpretable by the nervous system is transduction. Each type of sensory receptor transduces an external physical or chemical stimulus into electrical or chemical changes, which then can be transmitted as signals within the nervous system.
The rod and cone photoreceptors of the retina are specialized for transducing light energy in the form of photons. As few as three photons (possibly even a single photon) can be detected by a trained human observer. As a photon strikes the photoreceptor, it sets in motion a complex chain of events culminating in the closing of a large number of sodium channels that normally are open. As a result, the photoreceptor cell becomes hyperpolarized. This makes the photoreceptor unique among sensory cells in that the membrane potential becomes more negative on application of the stimulus rather than more positive.
In humans, the taste and olfactory receptor cells mediate the two primary types of chemoreception. Both receptor types respond to the presence of specific chemicals dissolved in a solution. Also included in this category are receptors in the hypothalamus, which sense low blood glucose concentration, low oxygen tension, or changes in blood pH; oxygen and pH receptors are also found in the aortic sinus and the carotid body.
Mechanoreceptors transduce various qualities of physical force into electrical signals that are transmitted by sensory neurons. Such receptors are found in the vestibular, auditory, and somatosensory systems.
Other types of sensory receptors include thermoreceptors, which sense temperature changes in the skin and viscera, and nociceptors, which transduce noxious (potentially harmful) stimuli. These receptors mediate what is commonly called pain; this is one of the most common complaints in clinical medicine.
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