General organization of the nervous system

Anatomically, the nervous system can be divided into (1) the central nervous system (CNS) (the brain, spinal cord, and neural parts of the eye) and (2) the peripheral nervous system (PNS) (peripheral ganglia, nerves, and nerve endings connecting ganglia with the CNS and receptors and effectors of the body). The CNS and PNS are morphologically and physiologically different, and these differences are significant in areas such as neuropharmacology.

The basic cell components of the CNS are neurons and glia. The PNS contains supporting cells called satellite cells and Schwann cells, analogous to the glial cells of the CNS.

We start the study of the nervous tissue by reviewing the highlights of the development of the nervous system.

Neuron

The functional unit of the nervous system is a highly specialized, excitable cell, the nerve cell or neuron. Neurons usually consist of three principal components (Figures 8-3 and 8-4): (1) soma or cell body, (2) dendrites, and (3) axon.

Figure 8-3 Components of a neuron

Figure 8-4 Components of a neuron

The soma contains the nucleus and its surrounding cytoplasm (also called perikaryon; Greek peri, around; karyon, nucleus).

The dendrites are processes that arise as multiple treelike branches of the soma, forming a dendritic tree collectively. The entire surface of the dendritic branches is covered by small protrusions called dendritic spines. Dendritic spines establish numerous axonal synaptic connections, as we will see later (see Figure 8-7).

Figure 8-5 Types of neurons: Bipolar, pseudounipolar, and multipolar neurons

Figure 8-6 Synaptic transmission

Figure 8-7 Axonal transport

Neurons have a single axon originating from the soma at the axon hillock and ending in a terminal arborization, the telodendron. Each terminal branch of the telodendron has an enlarged ending, the synaptic terminal or synaptic bouton.

Note that although dendrites and axons branch extensively, axons branch at their distal end (the telodendron), whereas dendrites are multiple extensions of the soma or cell body.

The surface membrane of the soma and the dendritic tree are specialized for the reception and integration of information, whereas the axon is specialized for the transmission of information in the form of an action potential or a nerve impulse.

Types of neurons

Different types of neurons can be identified on the basis of the number and length of processes emerging from the soma (Figure 8-5):

According to the number of processes, neurons can be classified as:

Based on the length of the axon relative to the dendritic tree, multipolar neurons can be subclassified into (1) Golgi type I neurons, when the axon extends beyond the limits of the dendritic tree and (2) Golgi type II neurons, when an axon terminates in the immediate area of the cell body and does not extend beyond the limits of the dendritic tree. Small stellate cells of the cerebral cortex are Golgi type II cells.

Designation of groups of neurons and axons

In the CNS, functionally and structurally related neurons form aggregates called nuclei. An area called the neuropil can be found within a nucleus and between the neuronal cell bodies. The term neuropil designates an area with packed dendrites, axonal branches with abundant synapses, and glial cells.

Clusters of neurons arranged in a layer form a stratum or lamina (cerebral cortex). When neurons form longitudinal groups, these groups are designated columns.

Bundles of axons in the CNS are called tracts, fasciculi (bundles), or lemnisci (for example, the optic tract).

In the PNS, a cluster of neurons forms a ganglion (plural ganglia). A ganglion can be sensory—dorsal root ganglia and trigeminal ganglion—or motor—visceromotor or autonomic ganglia. Axons derived from a ganglion are organized as nerves, rami (singular ramus), or roots.

Synaptic terminals and synapses

The synaptic terminal (Figure 8-6) is specialized for the transmission of a chemical message in response to an action potential. The synapse is the junction between the presynaptic terminal of an axon and a postsynaptic membrane receptor surface, generally a dendrite.

The prefixes pre- and post- refer to the direction of synaptic transmission: (1) Presynaptic refers to the transmitting side (usually axonal). (2) Postsynaptic identifies the receiving side (usually dendritic or somatic, sometimes axonal). The presynaptic and postsynaptic membranes are separated by a space: the synaptic cleft. A dense material coats the inner surface of these membranes: the presynaptic and postsynaptic densities.

Presynaptic terminals contain a large number of membrane-bound vesicles (40 to 100 nm in diameter), the synaptic vesicles. Synaptic vesicles originate in the neuronal soma and are transported by molecular motor proteins along the axon (axonal transport) (Figure 8-7). Each vesicle contains a neurotransmitter. Presynaptic terminals contain mitochondria, components of the smooth endoplasmic reticulum, microtubules, and a few neurofilaments.

Synapses are classified by their location on the postsynaptic neuron (Figure 8-8) as follows:

Figure 8-8 Types of synapses

Clinical significance: Axonal transport of rabies virus

The role of the axonal cytoskeleton and motor proteins (kinesin and cytoplasmic dynein; see Figure 8-7) was discussed in the Cytoskeleton section of Chapter 1, Epithelium. We emphasize once more the bidirectional transport of molecules along the axon: kinesin-mediated anterograde axonal transport of neurotransmitters—from the cell body toward the axon terminals, and the cytoplasmic dynein-mediated retrograde axonal transport of growth factors and recycling of axon terminal components—from the axon terminals to the cell body (see Box 8-D).

Axonal transport is important in the pathogenesis of neurologic infectious diseases. For example, the rabies virus introduced by the bite of a rabid animal replicates in the muscle tissue from as little as 2 to 16 weeks or longer. After binding to the acetylcholine receptor, the viral particles are mobilized by retrograde axonal transport to the cell body of neurons supplying the affected muscle. The rabies virus continues to replicate within infected neurons and after the shedding of the virions by budding, they are internalized by the terminals of adjacent neurons. Further dissemination of the rabies virus occurs in the CNS. From the CNS, the rabies virus is transported by anterograde axonal transport by the peripheral nerves to the salivary glands. The virus enters the saliva to be transmitted by the bite. Painful spasm of the throat muscles on swallowing accounts for hydrophobia (aversion to swallowing water).

The retrograde axonal transport to the CNS of tetanus toxin—a protease produced by the vegetative spore form of Clostridium tetani bacteria after entering at a wound site—blocks the release of inhibitory mediators at spinal synapses. Spasm contraction of the jaw muscles (known as trismus), exaggerated reflexes, and respiratory failure are characteristic clinical findings.

Glia: The “connective tissue” of the CNS

Glial cells (Greek glia, glue) are more numerous than neurons and retain the capacity to proliferate. Most brain tumors, benign or malignant, are of glial origin. When the CNS is injured, glial cells mobilize, clean up the debris, and seal off the local area, leaving behind a “glial scar” (gliosis), which interferes with neuronal regeneration.

Glial cells include (1) astrocytes, derived from the neuroectoderm; (2) oligodendrocytes, derived from the neuroectoderm; and (3) microglia, derived from the mesoderm.

Unlike neurons, glial cells do not propagate action potentials and their processes do not receive or transmit electrical signals. The function of glial cells is to provide neurons with structural support and maintain local conditions for neuronal function.

Astrocytes

Astrocytes are observed in the CNS and are divided into two categories: (1) fibrous astrocytes, and (2) protoplasmic astrocytes.

Fibrous astrocytes are found predominantly in white matter and have long thin processes with few branches. Protoplasmic astrocytes reside predominantly in gray matter and have shorter processes with many short branches. Astrocytic processes end in expansions called end-feet (Figure 8-9).

Figure 8-9 Astrocytes

One of the distinctive features of astrocytes is the presence of a large number of glial filaments (glial fibrillary acidic protein, a class of intermediate filament studied in Chapter 1, Epithelium). Glial fibrillary acidic protein is a valuable marker for the identification of astrocytes by immunohistochemistry. Nuclei of astrocytes are large, ovoid, and lightly stained.

Most brain capillaries and the inner surface of the pia mater are completely surrounded by astrocytic end-feet (see Figure 8-9) forming the glia limitans (also called the glial limiting membrane). The close association of astrocytes and brain capillaries suggests a role in the regulation of brain metabolism.

Astrocytes surround neurons and neuronal processes in areas devoid of myelin sheaths and form the structural matrix for the nervous system.

Oligodendrocytes and Schwann cells: Myelinization

Oligodendrocytes are smaller than astrocytes and their nuclei are irregular and densely stained. The cytoplasm contains an extensive Golgi apparatus, many mitochondria, and a large number of microtubules. One function of oligodendrocytes is axonal myelination.

Processes of oligodendrocytes envelop axons and form a sheathlike covering (Figure 8-10). The formation of this sheath is similar to that of Schwann cells in peripheral nerves.

Figure 8-10 Oligodendrocytes and nodes of Ranvier in the CNS and PNS

Myelin sheaths extend from the initial segments of axons to their terminal branches. The segments of myelin formed by individual oligodendrocyte processes are internodes. The periodic gaps between the internodes are the nodes of Ranvier.

A single oligodendrocyte has many processes and may form 40 to 50 internodes. The nodes of Ranvier are naked segments of axon between the internodal segments of myelin. This region contains a high concentration of voltage-gated sodium channels, essential for the saltatory conduction of the action potential. During saltatory conduction in the myelinated axons, the action potential “jumps” from one node to the next.

During the formation of the myelin sheath, a cytoplasmic process of the oligodendrocyte wraps around the axon and, after one full turn, the external surface of the glial membrane makes contact with itself, forming the inner mesaxon (Figure 8-11).

Figure 8-11 Myelinization

As the oligodendrocyte process continues to spiral around the axon, the external surfaces fuse to form the first intraperiod line. At the same time, the cytoplasm is squeezed off from the intracellular space (like toothpaste from a tube), and the cytoplasmic surfaces fuse to form the first dense line.

Spiraling continues until the axon is invested with a number of wrappings. The alternate fusion of both the cytoplasmic and external surfaces of the membrane results in an interdigitated double spiral (see Figure 8-11), one of intraperiod lines (fused external surfaces with remnant extracellular space), and one of major dense lines (fused cytoplasmic surfaces).

The dense line terminates when the membrane surfaces separate to enclose the cytoplasm at the surface of the sheath (the tongue), and the intraperiod line terminates as the tongue turns away from the sheath. The incisures of Schmidt-Lanterman are seen in longitudinal sections of myelinated nerve fibers in the CNS and PNS. They correspond to areas of residual cytoplasm.

As the myelin sheath approaches the node of Ranvier region, an additional ring of cytoplasm separates the cytoplasmic surfaces of the cell membrane. These tongues make contact with the axolemma, or surface membrane of the axon, in the paranodal region. Axons branch to form collaterals at a node of Ranvier.

The apposed interdigitating processes of myelinating Schwann cells and the incisures of Schmidt-Lanterman are linked by tight junctions. They are called autotypic tight junctions because they link plasma membranes of the same cell. Heterotypic tight junctions are seen between the axolemma (surrounding the axon) and the Schwann cell paranodal cytoplasmic loops adjacent to the node of Ranvier.

Tight junctions contain claudins (claudin-1, claudin-2, and claudin-5) and zonula occludens (ZO) proteins (ZO-1 and ZO-2) (see Figure 8-10). Tight junctions (1) stabilize newly formed wraps of myelin during nerve development, (2) act as a selective permeability barrier, and (3) restrict the movement of lipids and proteins from specific membrane domains.

Connexin 32 (Cx32) is found in Schwann cells. Cx32 does not form gap junctions with other Schwann cells. Instead, Cx32 predominates in the para-nodal membranes and incisures of Schmidt-Lanterman and forms intercellular channels linking portions of the same cell. Mutations in the Cx32 gene causes X-linked Charcot-Marie-Tooth disease, a demyelinating disorder of the PNS characterized by the progressive loss of both motor and sensory functions of the distal legs (see Box 8-E).

Myelin: Protein and lipid components

Myelin in the CNS and PNS is similar in overall protein and lipid composition, except that myelin in the PNS contains more sphingomyelin and glycoproteins. Three proteins are particularly relevant (Figure 8-12): myelin basic protein (MBP), proteolipid protein (PLP), and myelin protein zero (MPZ).

Figure 8-12 Structure of myelin

MBP is a cytosolic plasma membrane–bound protein present in both the myelin of the PNS and CNS. PLP is a tetraspanin protein found only in the myelin of the CNS. PLP plays a significant role in neural development and is a structural component of myelin. A mutation of the PLP gene and its alternatively transcribed DM20 protein causes Pelizaeus-Merzbacher disease, an X-linked dysmyelinating neuropathty in which affected males have a reduction of white matter and a reduction in the number of oligodendrocytes. The most common characteristics of Pelizaeus-Merzbacher disease are flickering eyes, and physical and mental retardation.

The predominant protein in myelin of the PNS is MPZ, a functional equivalent to PLP in the CNS. The extracellular domain of two MPZ proteins extends into the extracellular space to establish homophilic interaction with a similar pair of MPZ molecules on an opposite membrane. The homotetrameric structure provides intermembrane adhesion essential for the compactation of myelin (see Figure 8-13). The intracellular domain of MPZ participates in a signaling cascade that regulates myelinogenesis. In the CNS, plasma membrane–associated PLPs interact with each other and have a similar stabilizing function.

Figure 8-13 Development of myelinated and unmyelinated nerves

Proteins of myelin are strong antigens with a role in autoimmune diseases such as multiple sclerosis in the CNS and Guillain-Barré syndrome in the PNS.

Some axons of the PNS are unmyelinated (see Figure 8-13). A Schwann cell can accommodate several axons in individual cytoplasmic invaginations and no myelin is produced.

Clinical significance: Demyelinating diseases

The integrity of myelin, but not the axon, is disturbed in demyelinating diseases affecting the survival of oligodendrocytes or the integrity of the myelin sheath.

Demyelinating diseases can be (1) immune-mediated, (2) inherited, (3) metabolic, and (4) virus-induced.

Immune-mediated demyelinating diseases include multiple sclerosis and monophasic demyelinating diseases (for example, optic neuritis).

Multiple sclerosis (Figure 8-14) is characterized by clinically recurrent or chronically progressive neurologic dysfunction caused by multiple areas of demyelination in the CNS, in particular the brain, optic nerves, and spinal cord. An immune-mediated origin of multiple sclerosis is supported by an increase of immunoglobulin G (IgG) in the cerebrospinal fluid (CSF), and abnormalities of T cell function. A characteristic pathologic finding is the multiple sclerosis plaque, a demyelination lesion of the white matter, where the primary target is the myelin sheath and oligodendrocytes.

Figure 8-14 Pathogenesis of multiple sclerosis

An inherited demyelination disorder is adrenoleukodystrophy, in which progressive demyelination is associated with dysfunction of the adrenal cortex. The X-linked form of this disease is caused by a mutation of a gene encoding a membrane protein of peroxisomes. A defect in this gene leads to the accumulation of very-long-chain fatty acids (VLCFAs) in serum (discussed under Peroxisomes in Chapter 2, Epithelial Glands).

Metabolic demyelination disorders include central pontine myelinolysis, a syndrome in which neurologic dysfunction is observed following rapid correction of hyponatremia in individuals with alcohol abuse or malnutrition. A typical pathologic finding is the presence of symmetrical demyelinated lesions in the central pons.

Vitamin B₁₂ deficiency results in demyelination of axons in the CNS (the spinal cord, in particular) and the PNS.

Virus-induced demyelination can be observed in progressive multifocal encephalopathy caused by an opportunistic viral infection of oligodendrocytes in patients with immunodeficiency.

Clinical significance: Neurodegenerative diseases

Degenerative processes of specific groups of neurons of the brain cause movement disorders, dementia syndromes, and autonomic perturbations. Neurodegenerative diseases include:

2. Alzheimer’s disease, the most common neurodegenerative disease, is a progressive cortical dementia affecting language, memory, and vision, as well as emotion or personality. The predominant lesions are: (1) the accumulation of plaques containing β-amyloid (Aβ) peptide in the extracellular space, (2) neurofibrillary tangles in the cytoplasm of aging neurons, and (3) progressive hyppocampal synaptic failure in correlation with cognitive decline in Alzheimer’s disease. In addition, vascular injury (ischemia) and parenchymal inflammation (activated microglia and reactive astrocytes) enhance the effects of Aβ peptide-containing plaques in the brain.

Figure 8-15 Amyotrophic lateral sclerosis

Plaques and tangles lead to neuronal and white matter loss. Figure 8-16 and Box 8-F summarize and highlight the major molecular events observed in the brains of patients with Alzheimer’s disease, in particular the formation of amyloid plaques. A disproportion between production and clearance, and accumulation of Aβ peptides may be the initiation factor in Alzheimer’s disease.

Figure 8-16 Alzheimer’s disease

Box 8-F Amyloid precursor protein: Secretases and ADAM family proteins are sheddases

• Amyloid-β protein is produced by endoproteolysis of the amyloid precursor protein (APP), a single-transmembrane, receptor-like protein. This is achieved by the sequential cleavage of APP by enzyme complexes designated α-, β- and γ-secretases (see Figure 8-16).

• Three enzymes with α-secretase activity are ADAM9, ADAM10 and ADAM17 (also known as tumor necrosis factor converting enzyme). In Chapter I, Epithelium, we discuss the structure and function of the ADAM family (a disintegrin and metalloproteinase family enzyme).

• The γ-secretase consists of a complex of enzymes composed of presenilin 1 or 2, nicastrin, anterior pharynx defective and presenilin enhancer 2.

• Secretases and ADAMs are sheddases. They are involved in regulated intramembrane proteolysis: membrane proteins first shed their ectodomains by membrane-anchored proteases (sheddases), releasing the extracellular domains. Then, the membrane-retained fragment can be cleaved within the transmembrane domains to release hydrophobic peptides (such as amyloid-β) into the extracellular space. α-Secretase (consisting of members of the ADAM family) or β-secretase (also called β-site APP-cleaving enzyme, BACE, see Figure 8-16) are involved in ectodomain shedding of APR

Neurofibrillary tangles in pyramidal neurons are typical of Alzheimer’s disease and other neurodegenerative disorders called tauopathies. Alterations in the stabilizing function of tau, a microtubule-associated protein, result in the accumulation of twisted pairs of tau in neurons. In normal neurons, soluble tau promotes the assembly and stability of microtubules and axonal vesicle transport. Hyperphosphorylated tau is insoluble, lacks affinity for microtubules, and self-associates into paired helical filaments (see Figure 8-16). Figure 8-17 stresses the role of microtubules in axonal transport, a function affected by abnormal tau.

3. Parkinson’s disease, the second most common neurodegenerative disease, after Alzheimer’s disease. It is characterized clinically by parkinsonism, defined by resting tremor, slow voluntary movements (hypokinetic disorders), and movements with rigidity. This disease is pathologically defined by a loss of dopaminergic neurons from the substantia nigra and elsewhere. A characteristic pathologic aspect is the presence of α-synuclein-containing deposits in the cytoplasm of neurons (Lewy bodies) and threadlike inclusions in axons (Lewy neurites).

Figure 8-17 Microglial cells

Autosomal recessive juvenile parkinsonism is a relatively rare syndrome characterized by a mutation in a gene encoding the protein parkin. Parkin is detected primarily in the nervous system and is a member of the family of E3 ubiquitin ligases. Ubiquitin ligases attach ubiquitin protein chains to proteins, a process called ubiquination, thereby targeting them for degradation by the 26S proteasome (see Figure 3-14, Chapter 3, Cell Signaling). The ubiquination by parkin may be important for the normal turnover of α-synuclein. Aggregation of abnormal proteins and defective ubiquination may be important in the pathogenesis of Parkinson’s disease. A routine clinical test of the α-synuclein and parkin genes is currently not available. Essentially, the common neurodegenerative diseases are idiopathic (unknown cause) disorders of undefined pathogenesis.

Microglial cells

Microglia comprise about 12% of cells in the brain. They predominate in the grey matter, with higher concentrations in the hippocampus, olfactory telencephalon, basal ganglia, and substantia nigra. Microglial cells exist in a resting state characterized by a branching cytoplasmic morphology. In response to brain injury or immunologic activity, microglial cells change into an activated state characterized by an ameboidal morphology accompanied by the up-regulation of cell surface molecules, such as CD14, major histocompatibility complex (MHC) recptors and chemokine receptors.

Activated microglial cells participate in brain development by supporting the clearance of neural cells undergoing apoptosis, eliminating toxic debris and enhancing neuronal survival through the release of trophic and anti-inflammatory factors. In the mature brain, microglia facilitate repair by steering the migration of stem cells to the site of inflammation and injury.

Microglial cells may become overactivated and exert neurotoxic effects by the excessive production of cytotoxic substances such as superoxide, nitric oxide, and tumor necrosis factor–α (TNF-α). Activated microglial cells are present in large numbers in neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease), causing a generalized microglial hyperactivity, a condition called reactive microgliosis. Figure 8-17 provides a summary of the structural and functional aspects of resting, activated and hyperactivated microglial cells.

The distinction between microglia, astrocytes, and oligodendrocytes is difficult in routine histologic techniques. Immunocytochemical and silver impregnation procedures are commonly used for the identification of glial cells.

Cerebrospinal fluid

The choroid plexuses of the lateral, third, and fourth ventricles produce CSF.

CSF flows from the fourth ventricle into the brain and spinal subarachnoid space through median and lateral apertures. After entering the subarachnoid space, CSF flows outside the CNS into the blood, at the superior sagittal sinus (see Figure 8-18). The epithelium of the choroid plexus represents a barrier between the blood and the CSF. Several substances can leave the capillaries of the choroid plexus but cannot enter the CSF.

CSF protects and supports the brain and spinal cord from external forces applied to the skull or vertebral column (cushioning effect). In addition, the CSF allows the removal of metabolic wastes by continual drainage of the ventricular cavities and subarachnoid space. The volume of CSF varies with the intracranial blood volume. The free communication of CSF among compartments protects against pressure differences.

Lumbar puncture is a procedure to collect—with a needle inserted between the third and fourth and fourth and fifth lumbar vertebrae—a sample of CSF for biochemical analysis and pressure measurement. The total volume of CSF in an adult is 120 mL.

Clinical significance: Brain permeability barriers

The brain is supplied with blood from major arteries forming an anastomotic network around the base of the brain. From this region, arteries project into the subarachnoid space before entering the brain tissue.

In the brain, the perivascular space is surrounded by a basal lamina derived from both glial and endothelial cells: the glia limitans. Nonfenestrated endothelial cells, linked by tight junctions, prevent the diffusion of substances from the blood to the brain.

Tight junctions represent the structural basis of the blood-brain barrier. This barrier offers free passage to glucose and other selected molecules but excludes most substances, in particular potent drugs required for the treatment of an infection or tumor. If the blood-brain barrier breaks down, tissue fluid accumulates in the nervous tissue, a condition known as cerebral edema.

External to the capillary endothelial cell lining is a basal lamina and external to this lamina are the end-feet of the astrocytes. Although the pericapillary end-feet of astrocytes are not part of the blood-brain barrier, they contribute to its maintenance by transporting fluid and ions from the perineuronal extracellular space to the blood vessels.

Figure 8-20 illustrates details of three brain permeability barriers: (1) the arachnoid-CSF barrier, represented by arachnoid villi distributed along the venous sinus, in particular the arachnoid barrier cells linked by tight junctions. Arachnoid villi transfer CSF to the venous system (superior sagittal sinus). Fluid in the subarachnoid space operates like a shock absorber, which prevents the mass of the brain from compressing nerve roots and blood vessels. (2) The blood-CSF barrier. It involves tight junctions in the choroidal epithelium, responsible for the production of the CSF. (3) The blood-brain barrier, represented by tight junctions sealing the endothelial intercellular space.

Figure 8-20 Brain permeability barriers

Obstruction of CSF movement or defective absorption causes an accumulation of fluid in the ventricular spaces and around the brain. Hydrocephalus is a pathologic condition characterized by an increase in CSF volume and pressure and enlargement of the ventricular space.

Structure of a peripheral nerve

In addition to Schwann cells, peripheral nerves have three additional connective tissue coverings (see Figures 8-21 and 8-22): (1) the epineurium, (2) the perineurium, and (3) the endoneurium.

Figure 8-22 Peripheral nerve

The epineurium is formed by type I collagen and fibroblasts and covers the entire nerve. Within the nerve, the perineurium segregates axons into fascicles. Several concentric layers of fibroblasts with two unusual characteristics form the perineurium: (1) A basal lamina surrounds the layers of fibroblasts. (2) Fibroblasts are joined to each other by tight junctions to form a protective barrier: the blood-nerve barrier.

The endoneurium surrounds individual axons and their associated Schwann cells. It consists of type III collagen fibrils and a few fibroblasts between individual nerve fibers. Additional components of the blood-nerve barrier are the endothelial cells of the endoneurial capillaries. Endoneurial capillaries derive from the vasa nervorum and are lined by continuous endothelial cells joined by tight junctions.

Clinical significance: Segmental demyelination and axonal degeneration

Diseases affecting Schwann cells lead to a loss of myelin, or segmental demyelination. Damage to the neuron and its axon leads to axonal degeneration (wallerian degeneration, first described by the English physiologist Augustus Volney Waller, 1816-1870).

Axonal degeneration (Figure 8-23) may be followed by axonal regeneration. Recall from our discussion in Chapter 7, Muscle Tissue, that the motor unit is the functional unit of the neuromuscular system. Therefore, segmental demyelination and axonal degeneration affect the motor unit and cause muscle paralysis and atrophy. Physiotherapy for the paralyzed muscles is necessary to prevent muscle degeneration before regenerating motor axons can reach the motor unit. Neurotrophins play a significant role in the survival of neurons uncoupled from a peripheral target (see Box 8-G).

Figure 8-23 Degeneration and regeneration of a peripheral nerve

Segmental demyelination occurs when the function of the Schwann cell is abnormal or there is damage to the myelin sheath, for example, a crush nerve injury. If the nerve fiber is completely severed, the chances of recovery decrease unless a nerve segment is grafted. The presence of the endoneurium is essential for the proliferation of Schwann cells. Schwann cells guide an axonal sprout, derived from the proximal axonal stump, to reach the end organ (for example, a muscle).

Several sprouts can grow into the connective tissue and, together with proliferative Schwann cells, form a mass called an amputation neuroma. Amputation neuromas prevent regrowth of the axon after trauma and must be surgically removed to allow reinnervation of the peripheral end organ.

Axonal regeneration is a very slow process. It starts 2 weeks after injury and is completed, if successful, after several months. Schwann cells remyelinate the denuded portion of the axon, but the length of internodal myelin is shorter.

Axonal degeneration results from the primary destruction of the axon by metabolic or toxic damage and is followed by demyelination and degeneration of the neuronal cell body. This process is known as a “dying back” neuropathy.

Regeneration of nerve fibers in the CNS is not possible at present because of the following factors: (1) An endoneurium is not present; (2) oligodendrocytes do not proliferate in contrast to Schwann cells, and a single oligodendrocyte serves a large number of axons; and (3) astrocytes deposit scar tissue (the astrocytic plaque).

Neurohistochemistry

The nervous tissue has specialized features not observed in other basic tissues stained with routine staining methods such as hematoxylin-eosin. For example, basic dyes can demonstrate the cytoplasmic Nissl substance (ribonucleoproteins) in the cytoplasm of neurons (Figure 8-25).

Figure 8-25 Neurohistochemistry

Reduced silver methods produce dark deposits in various structures of neurons and glial cells. The Golgi method is particularly valuable for the study of dendrites. A variant of the Golgi method enables the identification of the cytomembranes and vesicles of the Golgi apparatus.

Myelin stains are based on the use of dyes with binding affinity for proteins bound to phospholipids. They are useful for the identification of tracts of fibers. Combined Nissl and myelin stains are used in neuropathology.

A tracer, such as horseradish peroxidase, injected into a neuron using a micropipet, has been used for anterograde transport studies. Similarly, tracers injected into nerve terminals can identify the putative neuron by its retrograde transport. Histochemical techniques are available for the localization of substances (for example, catecholamines, enzymes, and others) present in specific populations of neurons.

Concept mapping

Nervous Tissue