OBJECTIVES

This chapter should help you to:

· List the structural and functional features that distinguish nerve tissue from the other basic tissue types.
· List the cell types that make up nerve tissue and describe the structure, function, location, and embryonic origin of each.
· Describe in detail how neurons receive, propagate, and transmit signals.
· Describe the organelles of neurons in terms of their intracellular location and their roles in transmitting nerve impulses and in repairing neuronal damage.
· Describe synapses in terms of their structural components, function, and classification.
· Describe the organization of the nervous system in terms of the structure, function, distribution, and any distinguishing features of its subsystems.
· Describe the structure and function of the meninges.
· Describe the response of nerve tissue to injury.
· Recognize the type of nerve tissue and identify the individual cells and cell processes in a photomicrograph or slide of a tissue or organ.

SYNOPSIS

I. GENERAL FEATURES OF NERVE TISSUE & THE NERVOUS SYSTEM

A. Two Classes of Cells: Nerve tissue consists of the neurons that transmit clcctrochemical impulses and the supporting cells that surround them. It contains little extracellular material.


1. Neurons(see section II for more detail). These cells are highly specialized to carry out nerve tissue functions. Neurons receive, integrate, and transmit electrochemical messages. Each has a cell body, also called the soma ("body") or perikaryon ("around the nucleus"), comprising the nucleus and the surrounding cytopiasm and plasma membrane. Each neuron has a variable number of dendrites, cytoplasmic processes that collect incoming messages and carry them toward the soma, and a single axon, a cytoplasmic process that transmits messages to the target cell. Axons of most neurons have a myelin sheath formed by supporting cells and interrupted by gaps called nodes of Ranvier. Myelinated axon segments between the gaps are called internodes.
2. Supporting cells (see section III for more detail). These cells are called neuroglia ("nerve glue") or glial cells. Their functions include structural and nutritional support of neurons, electrical insulation, and enhancement of impulse conduction velocity along axons (VII.B).

B. Impulse Conduction: Within a neuron, signals (impulses) are propagated as a wave of depolarization along the plasma membrane of the dendrites, soma, and axon. Depolarization involves channels (ionophores) in the membrane, which allow ions leg, Na+, K-) to enter or exit the cell. In unmyelinated axons, depolarization is continuous. In myelinated axons, depolar ization occurs only at nodes of Ranvier, jumping from node to node (saltatory conduction). Impulse conduction is thus faster in myelinated axons.

C. Synapses: Signals pass from neuron to target cell by specialized connections called syn apses. The target may be another neuron or a cell in the end organ leg, gland or muscle) it supplies. At chemical synapses (IV), the signal is transmitted by exocytosis of neurotransmit ters, chemicals such as acetylcholine that cross the narrow gap (synaptic cleft) between the cells to initiate depolarization of the target cell. At the less common electrical synapses, the signal is transmitted by ions flowing through a gap junction-like complex.

D. Subsystems of the Nervous System: The nervous system is divisible into 2 overlapping pairs of subsystems:


1. The central and peripheral nervous systems are defined mainly by location. The central nervous system (CNS) includes the brain and spinal cord. The peripheral nervous system (PNS) includes all other nerve tissue. Terminology associated with the CNS and PNS, as well as structural comparisons, is shown in Table 9-1.
2. The autonomic and somatic nervous systems are defined according to function, but have distinctive anatomic features as well. Each has CNS and PNS components. The autonomic nervous system (ANS; Fig 9-1) controls involuntary visceral functions leg, glandular secretions, smooth muscle contraction) and has both motor and sensory pathways, although some authors exclude visceral sensory pathways from the ANS. As shown in Fig 9-1, each motor pathway consists of 2 neurons that synapse in a peripheral autonomic ganglion (V). The cell body of the first (preganglionic) neuron is in the CNS; the cell body of the second (postganglionic) neuron is in the autonomic ganglion. The cell bodies of the sensory neurons are located in craniospinal ganglia (V) and have processes that extend peripherally. The ANS is subdivided into the sympathetic and parasympathetic nervous systems, whose structure and functions are compared in Table 9-2. When they innervate the same end organ, sympathetic and parasympathetic nerves usually have opposing effects. The somatic ner vous system includes all nerve tissue except the ANS. It controls somatosensory perception leg, touch, heat, cold) and somatomotor (voluntary) functions (eg, skeletal muscle contraction). Acetylcholine is the most common somatic neurotransmitter.

E. Embryonic Development of Nerve Tissue: All neurons and supporting cells derive from embryonic ectoderm. Cells of the midline dorsal ectoderm of the early embryo are induced by the underlying notochord to form a thickened neural plate, The lateral border of the plate thickens and the center invaginates, forming a troughlike neural groove. As the groove deepens, the lateral borders contact each other to close the groove and form the neural tube, Cells lining the tube elongate to form a mitotically active pseudostratified columnar epithelium (neuroepithelium), and they eventually form the layers that generate the entire CNS. As the neural groove is closing, cells at its lateral borders proliferate to form 2 columnar masses that come to lie dorsal to the neural tube and form the neural crest. Neural crest cells migrate away from the neural tube and form much of the peripheral nervous system, including the sensory neurons of the craniospinal ganglia (V), the postganglionic neurons of the autonomic nervous system, the Schwann cells of peripheral nerves, and the satellite cells of ganglia. Neural crest cells also form the meninges (I.G) and much of the mcsenchyme of the head and neck. Neural crest derivatives covered in other chapters include the odontoblasts of developing teeth (Chapter 15), the melanocytes of the skin (Chapter 18), and the chromaffin cells and ganglion cells of the adrenal medulla (Chapter 21).

F. Aging and Repair: Mature neurons are incapable of mitosis and are often used as examples of terminally differentiated cells. Neurons of the elderly may contain abundant lipofuscin pig ment. The inability of neurons to divide makes repair of injured nerve tissue more difficult than for most other tissues. Neuron cell bodies lost through injury or surgery cannot be replaced, but if an axon is severed or crushed and the cell body remains intact, regeneration of the injured axon is possible (VIII). Supporting cells, unlike neurons, can divide if stimulated by injury.

G. Meninges: The brain and spinal cord are separated from the bony compartments that house them (skull and vertebral canal) by 3 connective tissue layers termed the meninges. The outer layer, or dura mater, is dense connective tissue bound tightly to the periosteum of the surround ing bone. The middle layer, or arachnoid, has 2 components: (1) a layer of loose connective tissue in contact with the dura mater, and (2) many connective tissue trabeculae (strands) that attach the arachnoid to the underlying pia mater. The spaces between the arachnoid trabeculae contain cerebrospinal fluid. Projections of the arachnoid into sinuses in the dura are called arachnoid villi. The innermost layer, or pia mater, is a thin, richly vascularized layer of loose connective tissue that is firmly attached to the surface of the brain or spinal cord but separated from the neurons by neuroglial cells processes. Ramified, cuboidal epithelium-covered projections of the pia matter into the ventricles of the brain are collectively termed the choroid plexus; they produce the cerebrospinal fluid by selective ultrafiltration of the blood plasma.

H. Blood-Brain Barrier: Nerve tissue of the CNS receives oxygen and nutrients from capillaries in the pia mater. These capillaries are relatively impermeable because (1) their endothelial cells lack fenestrations and are joined at their borders by tight junctions, and (2) they are partly surrounded by the cytoplasmic processes of neuroglia called astrocytes (III.A. i). These features contribute to a structural and functional barrier that protects CNS neurons from many extraneous influences and prevents certain antibiotics and chemotherapeutic agents from reaching the CNS.

II. NEURONS

A. Cell Body: The cell body (soma, perikaryon) is the synthetic and trophic center of the neuron. It can receive signals from axons of other neurons through synaptic contacts on its plasma membrane and relay them to its axon. The nucleus is usually large, central, and euchromatic. It has a prominent nucleolus and heterochromatin around the inner surface of the nuclear envelope. The cytoplasm of the soma contains many organelles, including mitochondria, lysosomes, and centrioles. The abundant free and RER-associated polyribosomes appear as clumps of basophilic material collectively called Nissl bodies. The Goigi complex is well developed. It packages (and in some cases glycosylates) neurotransmitters in neurosecretory, or synaptic, vesicles. Once packaged, the vesicles are transported down the axon to the terminal bouton (II.C). Neurotubules (microtubules) and bundles of neurofilaments (intermediate filaments) are found throughout the perikaryon and extend into the axon and dendrites.

B. Dendrites: These extensions of the soma are specialized to increase the surface available for incoming signals. The farther they are from the soma, the thinner they are owing to successive branching. They are often covered over much of their surface with synaptic contacts, and some have numerous sharp projections, termed dendritic spines or gemmules, that act as synaptic sites. Dendrites lack Golgi complexes but may contain small amounts of other organelles found in perikaryon.

C. Axon: Each neuron has one axon, a complex cell process that carries impulses away from the soma. An axon is divisible into several regions. The axon billock, the part of the soma leading into the axon, differs from the rest of the perikaryon in that it lacks Nissl bodies. Although the entire axon is usually not visible in sectioned material, its origin is distinguishable from that of the dendrites by the absence of Nissl-related basophilia. The initial segment is the part of a myelinated axon between the apex of the axon hillock and the beginning of the myelin sheath. It is characterized by a thin layer of electron-dense material, termed the dense undercoating, beneath the plasma membrane and contains neurotubule and neurofilament bundles originating in the axon hillock. The axon proper is the main trunk of the axon. Unlike dendrites, axons tend to have a constant diameter along their entire length. The larger the diameter of the axon, the more likely it is to be myelinated and the higher its rate of impulse conduction. Some axons have branches, termed collaterals, which may contact other neurons or even return to the cell body of origin to modulate their own subsequent depolarization. The axoplasm (cytoplasm) contains few organelles but usually has some mitochondria and parallel bundles of neurotubules and neurofilaments. It has limited metabolic activity, but it conveys metabolic products to and from the axon terminals (VII.A). Signal transmission (VII.B) relies heavily on the asymmetric dis tribution of ionic charges (potential differences) on either side of the axolemma, the axonal plasma membrane. Many axons undergo branching (arborization) near their terminations. The degree of terminal arborization depends on the size and function of the axon. Each terminal branch of an axon ends in a bulblike enlargement called a terminal end-bulb or terminal bouten. Swellings in the wall of an axon before its termination are termed beutons en passage. Each bouton typically contains many mitochondria and neurosecretory vesicles. A specialized region of its plasma membrane, the presynaptic membrane, forms part of a synapse (IV).

D. Classification of Neurons: Table 9-3 shows a number of the overlapping classifications that describe the wide variety of neuron types In terms of their structure and function.

III. SUPPORTING CELLS

By providing neurons with structural and functional support, these cells play a passive role in neural activity. Positioned between the blood and the neurons, they establish compartments and monitor the passage of materials from one compartment to another. It is difficult to maintain neurons in tissue culture without adding supporting cells. As indicated in Table 9-1, different supporting cell types are found in the CNS and PNS.

A. Supporting Cells of the CNS: There are about 10 neuroglial cells per neuron in the CNS. Glial cells are generally smaller than neurons. Their processes, although abundant and exten sive, are indistinguishable without special stains. Identification is usually based on nuclear morphology. The major supporting cells in the CNS are the macroglia, including astrocytes and oligodendrocytes, the microglia, and the ependymal cells.


1. Astrocytes are the largest glial cells. Their nuclei, also the largest, are irregular, spheric, and pale-staining with a prominent nucleolus. Their branching cytoplasmic processes often have, at their tips, expanded pediclcs, or vascular end-feet. These surround capillaries of the pia mater and are important components of the blood-brain barrier (I.H). Proteplasmic astro cytes (messy cells) are more common in gray matter. They have ample granular cytoplasm and short, thick, highly branched processes. Fibrens astrecytes are more common in white matter. Silver stains show their cytoplasm to be full of fibrous material. Their long, thin processes are less branched than those of protoplasmic astrocytes.
2. Oligedendroglia or oligodendrocytes, the most numerous glial cells, are found in both gray and white matter. Their spheric nuclei fall between those of astrocytes and microglia in terms of size and staining intensity. Like the Schwann cells of the PNS, oligodendrocytes form myelin and occur in long rows as required to myelinate entire axons. Unlike a Schwann cell, each may have several cell processes and may provide myelin for segments of several axons. Unmyelinated axons of the CNS are not sheathed.
3. Microglia, the smallest and rarest of the glia, are found in both gray and white matter. Their nuclei are small and elongate (often bean-shaped), and their chromatin is so condensed that they often appear black in H&E-stained sections. Their processes are shorter than those of astrocytes and are covered with thorny branches. Microglial cells may derive from mes enchyme, or they may be glioblasts (immature oligodendrocytes) of neuroepithelial origin. Some microglia may be components of the mononuclear phagocyte system and have phago cytic capabilities. When neural injury is unaccompanied by vascular injury, phagocytic cells in the lesioned area appear to derive from macroglia.
4. Ependymal cells derive from ciliated neuroepithelial cells of the internal lining of the neural tube (1.E). In adults, they retain their epithelial nature and some cilia, and they line the remnants of the neural tube (ventricles and aqueducts of the brain and the central canal of the spinal cord). The lining resembles a simple columnar epithelium, but epcndymal cells have basal cell processes that extend deep into the gray matter. The ependymal lining is con tinuous with the cuboidal epithelium of the choroid plexus (I.G).

B. Supporting Cells of the PNS:

1. Schwann cells are the supporting cells of the peripheral nerves. One Schwann cell may envelop segments of several unmyelinated axons or provide a segment of a single myeli nated axon with its myelin sheath. Each myelinated axon segment is surrounded by multiple layers of a Schwann cell process with most of its cytoplasm squeezed out; the remaining multilayered Schwann cell plasma membrane, called myelin, consists mainly of phospho lipid. The gaps between the myelin sheath Se8ments are the nodes of Ranvier. Ovoid or flattened Schwann cell nuclei lie peripheral to the axon they support. They are usually more euchromatic than the nuclei of the fibrocytes scattered among the axons.

2. Satellite cells are specialized Schwann cells in craniospinal and autonomic ganglia (V), where they form a one-cell-thick covering over the cell bodies of the neurons (ganglion cells). Their nuclei are spheric with mottled chromatin. In sections, the nuclei typically appear as a "string of pearls" surrounding the much larger ganglion cell bodies.

IV. SYNAPSES (CHEMICAL)

Synapses are specialized junctions by which a stimulus is transmitted from a neuron to its target cell. Artificially stimulated axons can propagate a wave of depolarization in either direction, but the signal can travel in only one direction across a synapse, which functions as a unidirectional signal valve. Synapses are named according to the structures they connect, eg, axodendritic, axosomatic, axoaxonic, and dendrodendritic synapses. The 3 major structural components of each synapse are the pre and postsynaptic membranes and the synaptic cleft that separates them (Pig 9-2).

A. Presynaptic Membrane: This is the part of the terminal bouton membrane closest to the target cell. It consists of an electron-dense thickening into which insert many short intermediate filaments, as in a hemidesmosome. On stimulation, neurosecretory vesicles in the bouton fuse with the presynaptic membrane and exocytose their neurotransmitters into the synaptic cleft. Neurosecretory vesicles are present only in the presynaptic component of the junction. The vesicle membrane added to the presynaptic membrane is recycled by endocytosis of the mem brane lateral to the synaptic cleft. Intact vesicles do not cross the synaptic cleft.

B. Synaptic Cleft (Synaptic Gap): This is a fluid-filled space, generally 20 nm wide, between the pre- and postsynaptic membranes. It is shielded from the rest of the extracellular space by supporting cell processes and basal lamina material that binds the pre- and postsynaptic mem branes together. Some clefts are traversed by dense filaments that link the membranes and perhaps guide neurotransmitters across the gap.

C. Postsynaptic Membrane: This is a thickening of the plasma membrane of the next neuron or target cell leg, muscle). It resembles the presynaptic membrane but also contains receptors for neurotransmitters. When enough receptors are occupied, hydrophilic channels open, resulting in depolarization of the postsynaptic membrane (VII.B.2). Neurotransmitter leg, acetylcholine) remaining in the cleft after stimulation of the postsynaptic neuron (or other target cell) is degraded by enzyme leg, acetylcholinesterase) in the cleft. Degradation products are endo cytosed by coated pits (3.II.C.3.c) in the membrane of the bouton, lateral to the presynaptic thickening. Removal of excess transmitter allows the postsynaptic membrane to reestablish its resting potential and prevents continuous firing of the postsynaptic neuron in response to a single stimulus.

V. GANGLIA

Peripheral clusters of neuron cell bodies, called ganglia, are of 2 major types: the craniospinal ganglia and the autonomic ganglia. Each ganglion contains large ganglion (neuron) cell bodies

surrounded by satellite cells. Cell processes are supported by Schwann cells with smaller, elongated, pale-staining nuclei. Condensed fibroblast nuclei occur in the capsule and scattered through the ganglion itself. Table 9-4 provides a comparison of the key structural and functional features of the 2 main ganglion types.

VI. PERIPHERAL NERVES

Peripheral nerves contain myelinated and unmyelinated axons, Schwann cells, and fibmblasts, but no neuron cell bodies. Nuclei seen in cross sections ofperipheral nerves belong to Schwann cells (larger and paler-staining) or to fibroblasts (mature fibroblasts; smaller and darker-staining). Each peripheral nerve (Fig 9-3) is surrounded by a dense connective tissue sheath or epineurium branches of which penetrate the nerve and divide the nerve fibers into bundles or fascicles. The sheath surrounding each fascicle is called the perineurium. Fine slips of reticular connective tissue from the perineurium penetrate the fascicles to surround each nerve fiber, forming the endoneurium, Branches of blood vessels in the epineurium penetrate the nerve along With the connective tissue, providing the tissue with its vascular supply. The 3 main nerve fiber types in peripheral nerves (A, B, and C) are compared in Table 9-5.

VII. HISTOPHYSIOLOGY OF NERVE TISSUE

A. Axoplasmlc(Axonal) Transport: Movement of metabolic products through the axoplasm Can be fast (up to 400 mm/d) or slow (eg, 1 mm/d), and it involves neurotubules and neurofilaments. Anterograde or Orthograde axoplasmic transport moves newly synthesized products and synaptic vesicles toward the axon's terminal arborization and can be fast or slow. Retrograde axoplasmic transport, the return of worn materials to the perikaryon for degradation or reutilization, is usually relatively fast.

B. Signal Generation and Transmission: The basic function of nerve tissue is to generate and transmit signals, in the form of nerve impulses or action potentials, from one part of the body to another. The arrangement of neurons in chains and circuits allows integration of simple on-off Signals into complex information. The microscopic structure of nerve tissue (axon diameter, presence or absence of myelin, etc) exploits physicochemical phenomena to regulate the rate and sequence of signal transmission.

1. Resting membrane potential. The K+ concentration is 20-fold higher inside neurons than outside, whereas the Na+ concentration is I0-fold higher outside than inside. Since the plasma membrane is much more permeable to KS than to other ions, K+ ions tend to leak out until the accumulated positive charge outside the cell inhibits further K+ movement. In this state of equilibrium, the inside of the cell is negatively charged (-40 to --100 mV) relative to the outside; this potential difference (voltage) across the membrane is the resting membrane potential. Energy-requiring pumps in the plasma membrane help maintain the resting potential, keeping the neuron ready to receive and transmit signals. The best known is Na+/K+-ATPase, which can exchange internal Na+ for escaped K+ when ATP is available.
2. Firing and propagation of action potentials. Binding of excitatory neurotransmitters leg, acetylcholine) to receptors in the postsynaptic membrane allows positive ions to enter the cell, reducing the potential difference across the membrane. When this membrane depolar ization reaches a critical level, or threshold, integral membrane proteins acting as voltage sensitive Na+ channels (voltage-gated channels) open, allowing Na+ ions to rush in and reverse the membrane potential in one region of the membrane. This is the firing of the action potential. Incoming Na+ ions diffuse to nearby sites, causing threshold depolarization and opening the Na+ channels in these areas as well; thus, a wave of depolarization spreads along the neuron surface. Spread of the wave of depolarization is termed propagation of the action potential. The firing of an action potential is an "all-or-none" event and will not occur unless the threshold is reached.
3. Refractory period. Reversal of the membrane potential at threshold opens voltage-gated K+ channels and K+ ions exit the cell, returning the membrane to its resting potential (repolarization). An even greater potential difference (hyperpolarization) may be achieved before stabilizing at normal resting levels. The refractory period is the 1- to 2-ms interval between the firing of the action potential and restoration of the resting potential during which another impulse cannot be generated. Na+/Kt-ATPase helps restore the normal balance of ions across the membrane during this period.
4. Direction of signal transmission. For action potentials fired by neurotransmitters crossing a synapse, the sequence of depolarization is usually dendrites --, soma --> axon --> synapse --> next neuron or end organ). This is termed orthodromic spread, Two factors normally prevent antiaromic spread along the axon toward the soma: (1) directly behind the newly depolarized region the axon is refractory, and (2) the signal cannot be propagated in a reverse direction across a synapse. For action potentials fired artificially by electrical stimulation of an axon, both orthodromic and antidromic spread occur but the antidrornic spread has no effect because it cannot cross a synapse.
5. Saltatory conduction. Depolarization of rnyelinated axons occurs only at nodes of Ranvier where insulation is reduced and Nat and K - channels are concentrated. The action potential must therefore jump from node to node along the axons, a phenomenon called saltatory co"duction. The result is faster impulse conduction, less change in ion concentration, and thus a lower energy requirement for recovery of resting potential.
6. Blocking signal transmission, Cold, heat, and pressure on a nerve can block impulse conduction. Local anesthetics allow more complete and reversible impulse blocking by disturbing the resting potential. Some poisons block ion channels and prevent propagation of the action potential.

VIII. RESPONSE OF NERVE TISSUE TO INJURY

A. Damage to the Cell Body: Because mature neurons cannot divide, dead neurons cannot be replaced. Neurons not connected with otherfunctioning neurons or end organs are useless, and mechanisms have evolved to dispose of them. Thus, if a neuron makes synaptic contact with Only one other neuron and the latter is destroyed, the former undergoes autolysis, a process termed transneuronal degeneration. Most neurons, however, have multiple connections.

B. Damage to the Axon: Regeneration can occur in axons injured or severed Far enough from the soma to spare the cell. Such injuries are followed by partial degeneration and then regeneration.

1. Degeneration. A crushed or severed axon degenerates both distal and proximal to the injury. Distal to the site Of injury, both the axon and myelin sheath undergo complete degeneration connection with the soma has been lost. During this Wallerian, descendent, or secondary degeneration, whichusually lakes about 2-3 days, nearby Schwann cells proliferate, phagocytose degenerated tissue, and invade the remaining endoneurial channel. Proximal to the site of injury, degeneration of the axon and myelin sheath is similar but incomplete. This retrograde, ascendent, orprimary degeneration proceeds for about 2 internodes before the injured axon is sealed. The cell body also changes in response to injury. The perikaryon enlarges; chromatolysis, or dispersion of Nissl substance, occurs; and the nucleus moves to an eccentric position. Proximal degeneration and cell body changes fake about 2 weeks.
2. Regeneration. This begins in the third week after the injury. As the perikaryon gears up for increased protein synthesis, the Nissl bodies 'eappear. The axon's proximal stump gives off a profusion of smaller processes called neurites; one of these encounters and grows into the endoneurial channel, while the others degenerate. In the channel, the neurite grows 3-4 mm/d, guided and then myelinated by the Schwann cells. Growth is maintained by orthograde axoplasmic transport of material synthesized in the soma. When the tip of the neurite reaches its termination, it connects with its end organ or another neuron in the chain. If the cut ends of a severed nerve are matched by by fascicle size and arrangement and sutured together by their epineurial sheaths within 34 weeks after injury, sensory and motor innervation can often be restored. If the gap between the cut ends is too wide, the neurites may fail to find endoneurial sheaths to grow into and may grow out in a potentially painful disorganized swelling called a neuroma. Target organs deprived of innervation often atrophy.