Nervous System

Andrew D Miller; James F Zachary

doi:10.1016/B978-0-323-35775-3.00014-X

. 2017 Feb 17:805–907.e1. doi: 10.1016/B978-0-323-35775-3.00014-X

Nervous System¹

Andrew D Miller, James F Zachary

Editor: James F Zachary¹

PMCID: PMC7158194

Key Readings Index

Central Nervous System
Structure and Function, 806
Dysfunction/Responses to Injury, 815
Portals of Entry/Pathways of Spread, 827
Defense Mechanisms/Barrier Systems, 828
Disorders of Domestic Animals, 830
Disorders of Horses, 876
Disorders of Ruminants (Cattle, Sheep, and Goats), 881
Disorders of Pigs, 888
Disorders of Dogs, 890
Disorders of Cats, 896
Peripheral Nervous System
Structure and Function, 898
Dysfunction/Responses to Injury, 899
Responses of the Axon to Injury, 899
Portals of Entry/Pathways of Spread, 899
Defense Mechanisms/Barrier Systems, 899
Disorders of Domestic Animals, 899
Disorders of Horses, 904
Disorders of Dogs, 906

E-Glossary 14-1 Glossary of Abbreviations and Terms

Astrocytosis—Increased numbers of astrocytes.
Astrogliosis—Reactive astrocytic response with increased number (variable), length, and complexity of cell processes. In the CNS, reparative processes after injury, such as inflammation and necrosis, are facilitated by astrogliosis.
Axonopathy, distal of the CNS and PNS—Degeneration of axons involving distal portions of peripheral nerves and distal portions of long axons in the CNS (spinal cord).
Axonopathy, distal, of the PNS—A neuropathy with degeneration of the terminal and preterminal axon of peripheral nerves.
Axonotmesis—Axonal injury of a peripheral nerve in which there is degeneration of the part distal to the site of trauma, leaving the supporting framework intact and allowing for improved potential for regeneration and effective reinnervation.
Blood-brain barrier of the CNS—A barrier to free movement of certain substances from cerebral capillaries into CNS tissue. Relies on tight junctions between capillary endothelial cells and selective transport systems in these cells. Endothelial cell basement membrane and foot processes of astrocytes abutting the basement membrane may play a role in barrier function.
Blood-CSF barrier of the CNS—A barrier that consists of tight junctions located between epithelial cells of the choroid plexus and the cells of the arachnoid membrane that respectively separate fenestrated blood vessels of the choroid plexus stroma and dura mater from the CSF.
Blood-nerve barrier—A barrier to free movement of certain substances from the blood to the endoneurium of peripheral nerves. Barrier properties are conferred by tight junctions between capillary endothelial cells of the endoneurium and between perineurial cells and selective transport systems in the endothelial cells.
Brain edema—Increase in tissue water within the brain that results in an increase in brain volume. The fluid may be present in the intracellular or extracellular compartments or both. The term also is used to include the accumulation of plasma, especially in association with severe injury to the vasculature.
Brain swelling—Marked, rapidly developing, sometimes unexplained increase in cerebral blood volume and brain volume because of relaxation (dilation) of the arterioles that occurs after brain injury.
Büngner, cell bands of—A column of proliferating Schwann cells that forms within the space previously occupied by an axon following Wallerian degeneration. The proliferating column of cells is surrounded by the persisting basement membrane of the original Schwann cells.
CAE—Caprine arthritis encephalitis.
CCD—Canine cognitive dysfunction.
Central chromatolysis—Dissolution of cytoplasmic Nissl substance (arrays of rough endoplasmic reticulum and polysomes) in the central part of the neuronal cell body that results from injury to the neuron (often involving the axon). The cell body is swollen, and the nucleus frequently is displaced peripherally to the cell membrane. These structural changes functionally represent a response to injury that can be found (if the cell survives) by axonal regeneration with protein synthesis to produce components of the axon required for fast and slow axonal transport.
CNS—Central nervous system.
Cranium bifidum—A dorsal midline cranial defect through which meninges alone or meninges and brain tissue may protrude into a sac (-cele), covered by skin.
CSF—Cerebrospinal fluid.
Demyelination—A disease process in which demyelination (destruction of the myelin sheath) is the primary lesion, although some degree of axonal injury may occur. Primary demyelination is caused by injury to myelin sheaths and/or myelinating cells and their cell processes. Secondary demyelination occurs with axonal injury, as in Wallerian degeneration.
Dysraphism—Dysraphia, which literally means an abnormal seam, refers to a defective closure of the neural tube during development. This defect, which may occur at any point along the neural tube, is exemplified by anencephaly, prosencephalic hypoplasia, cranium bifidum, spina bifida, and myeloschisis.
Encephalitis—Inflammation of the brain.
Encephalo-—A combining form that refers to the brain.
Encephalopathy—A degenerative disease process of the brain.
Ganglionitis—Inflammation of peripheral (sensory or autonomic or both) ganglia.
Gemistocyte—Reactive, hypertrophied astrocyte that develops in response to injury of the CNS. The cell body and processes of gemistocytes become visible with conventional staining (e.g., H&E stain). The cell bodies and processes of normal astrocytes are not visible with H&E staining.
Gitter cell—Macrophage that accumulates in areas of necrosis of CNS tissue. The cytoplasm is typically distended, with abundant lipid-containing material derived from the lipid-rich nervous tissue. Gitter cell nuclei are often displaced peripherally to the cell membrane. These cells are often referred to as “foamy” macrophages.
H&E stain—Hematoxylin and eosin stain.
Hydranencephaly—A large, fluid-filled cavity in the area normally occupied by CNS tissue of the cerebral hemispheres resulting from abnormal development. The nervous tissue may be so reduced in thickness that the meninges form the outer part of a thin-walled sac. The lateral ventricles are variably enlarged because of their expansion into the area normally occupied by tissue.
Hydrocephalus—Accumulation of excess CSF resulting from obstruction within the ventricular system (noncommunicating form) associated with enlargement of any or all of the following: lateral ventricles, third ventricle, mesencephalic aqueduct, and fourth ventricle. Hydrocephalus can also occur with communication of the CSF between the ventricular system and the subarachnoid space (communicating form). Hydrocephalus ex vacuo (compensatory hydrocephalus) is characterized by an expansion of the lateral ventricle (or ventricles) that follows loss of brain tissue.
Joest-Degen bodies—Intranuclear inclusion bodies (rarely intracytoplasmic) found in neurons in the brains of animals with Borna disease.
Leuko-—Combining form referring to white matter of the brain or spinal cord.
Leukoencephalitis—Inflammation of the white matter of the brain.
Macroglia—A collective term referring to astrocytes and oligodendrocytes. Has also been variously used to refer solely to astrocytes or to astrocytes, oligodendrocytes, and ependymal cells of the CNS, and Müller cells of the retina.
Malacia—Grossly detectable (macroscopic lesion) softening of CNS tissue, usually the result of necrosis.
Meningo-—Combining form referring to meninges.
Meningomyelocele—A form of spina bifida in which meninges and spinal cord herniate through a defect in the vertebral column into a sac (-cele) covered by skin.
Microglia—Resident macrophages of the CNS that arise from mesodermal stem cells of the yolk sac.
Motor neuron, lower—Large multipolar neurons in the brainstem and ventral horns of the spinal cord with axons extending into the PNS.
Motor neuron, upper—Motor neurons with axons residing solely in the CNS that control lower motor neurons.
MVV—Maedi-visna virus.
Myelitis—Inflammation of the spinal cord.
Myelo-—Combining form referring to spinal cord.
Myelopathy—A degenerative disease process of the spinal cord.
Myeloschisis—Similar to spina bifida, except in its severe form is characterized by complete failure of the spinal neural tube to close, therefore a lack of development of the entire dorsal vertebral column.
Nageotte nodule—An aggregate of proliferating satellite cells (see later) in a ganglion in which there has been degeneration of neuronal cell bodies.
Neuroglial cells—Astrocytes, oligodendroglia, ependymal cells, and microglia of the CNS.
Neuronophagia—Accumulation of microglial cells around a dead neuron.
Neuropil—The gray matter feltwork that consists of intermingled and interconnected processes of neurons (axons and dendrites) and their synaptic junctions, plus processes of oligodendroglia, astrocytes, and microglia.
Neurapraxia—Traumatic injury to a peripheral nerve with temporary conduction block but with no permanent axonal damage.
Neurotmesis—Complete transection of a nerve and supporting framework with little potential for normal reinnervation.
Onion bulb—Concentric arrays of Schwann cell cytoplasm around an axon signifying multiple episodes of demyelination and remyelination.
PNS—Peripheral nervous system.
Polio—Combining form referring to gray matter of the CNS.
Polioencephalomalacia—Softening (usually the result of necrosis) of the gray matter of the brain.
Polioencephalomyelitis—Inflammation of the gray matter of the brain and spinal cord.
Poliomyelomalacia—Softening (usually the result of necrosis) of the gray matter of the spinal cord.
Porencephaly—A cleft or cystic defect in the cerebral hemisphere that communicates with the subarachnoid space and also may communicate with the ventricular system. The defect may contain CSF.
Radiculoneuritis (polyradiculoneuritis)—Inflammation of a spinal nerve rootlet (or rootlets).
Rarefaction—Reduction in density of CNS tissue that may result from edema, necrosis, and the like. This lesion is usually observed microscopically.
Satellite cells—Glial cells that cover the surface of nerve cell bodies in sensorimotor, autonomic, and enteric ganglia.
Satellitosis—An accumulation of oligodendroglia around neuronal cell bodies. Although this feature can be seen in normal brains, some consider that it may also be associated with neuronal injury.
Sclerosis—Literally means induration or hardening and, when used in describing lesions of the CNS, often refers to induration or hardening of the brain or spinal cord resulting from astrogliosis (astrocytic scar formation).
Spina bifida—A dorsal midline defect involving one to several vertebrae of the spinal column caused by failure of the neural tube to close, permitting exposure of the underlying meninges and spinal cord. The lesion may be associated with herniation of meninges alone or meninges and spinal cord tissue into a sac (-cele) covered by skin, or there may be no herniation (spina bifida occulta).
Status spongiosus—An encompassing term meaning the presence of small focal, ovoid to round “clear (unstained or poorly stained [H&E stain])” spaces in the CNS. The lesion can result from several different tissue alterations, which include splitting of the myelin sheath, accumulation of extracellular fluid, swelling of cellular (e.g., astrocytic and neuronal) processes, and axonal injury (Wallerian degeneration) when swollen axons are no longer detectable within distended spaces.
Syringomyelia—A tubular cavitation (syrinx) in the spinal cord that is not lined by ependyma and may extend over several segments.
Wallerian degeneration—Degeneration of the distal component of an injured (compressed or severed) axon. Although the term originally referred to injury of axons in the PNS, current usage also includes the CNS. This process also results in functional and structural alterations in the cell body (central chromatolysis) and proximal internode segment of the axon, and in secondary demyelination.

Nervous System

Development of the Adult Nervous System

The vertebrate embryo is formed by three layers of cells—the ectoderm (outermost layer), the mesoderm (middle layer), and the endoderm (innermost layer). Nervous tissues are derived from the ectoderm and eventually form all central nervous system (CNS) and peripheral nervous system (PNS) tissues of the adult animal. In the developing embryo, neurogenesis begins with a locally extensive, elongate proliferation of cells known as the neural plate, located along the cranial surface of the neuroectoderm (E-Fig. 14-1). The neural plate is bordered on either side by neural folds, which eventually fuse dorsally to form the neural tube (i.e., the eventual brain, spinal cord, and ventricular system). Immature neuroepithelial cells that line the neural tube ultimately become the source of neurons, astrocytes, ependymal cells, and oligodendrocytes. Resident microglial cells arise from mesodermal stem cells in the yolk sac that migrate to the neural tube during development, whereas the development and maturation of the brain and spinal cord proceed through a series of coordinated mechanisms characterized by cellular proliferation and subsequent remodeling (e.g., apoptosis) to produce the final morphologic features of the adult brain and spinal cord.

E-Figure 14-1 — Neurogenesis of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) in the Developing Embryo.

Neuroectoderm differentiates from ectoderm and forms the neural plate. The neural plate gives rise to neural crest cells and the neural tube, which in turn differentiate into PNS (spinal ganglion, peripheral nerves) and CNS (brain and spinal cord), respectively. The notochord eventually regresses, and portions remain as the nucleus pulposus of intervertebral disks.

(Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Neuroepithelial cells, which form the spinal cord, reorganize during neurogenesis to produce centrally located gray matter (shaped like a butterfly with paired dorsal and ventral horns) and peripherally enveloping white matter (also see later section on gray and white matter). The white matter tracts of the spinal cord are further subdivided into funiculi, which contain variable numbers of ascending axons (i.e., action potential travels in the direction of the brain) and descending axons (i.e., action potential travels in the direction of the cauda equina). Segmentation (i.e., formation of the general regions of the brain and spinal cord) and stratification (i.e., formation of the lamina of the cerebral cortex) of the neural tube during embryologic development require a great deal more remodeling. Initial expansion of the neural tube results in a developing brain that is segmented into sections called the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain) (E-Box 14-1; E-Fig. 14-2). With further development the brain divides into the five segments: telencephalon, diencephalon (both derived from the prosencephalon), mesencephalon, and the metencephalon and myelencephalon (both derived from the rhombencephalon) (see E-Box 14-1). The telencephalon in the adult animal becomes paired cerebral hemispheres. The diencephalon becomes the thalamus and its associated structures. The mesencephalon gives rise to the corpora quadrigemina (superior and inferior colliculi) and the cerebral peduncles. The pons and cerebellum arise from the metencephalon, and lastly the medulla oblongata arises from the myelencephalon (see E-Fig 14-1). Concurrently, the spinal cord is segmented into cervical, thoracic, lumbar, and sacral sections, which are further subdivided into individual spinal nerves.

E-Box 14-1. Embryologic Development and Maturation of the Neural Tube.

Neural tube	Prosencephalon (forebrain)	Telencephalon	Paired cerebral hemispheres
	Prosencephalon (forebrain)	Diencephalon	Thalamus and related structures
	Mesencephalon (midbrain)	Mesencephalon	Corpora quadrigemina (superior and inferior colliculi)
	Mesencephalon (midbrain)	Mesencephalon	Cerebral peduncles
	Rhombencephalon (hindbrain)	Metencephalon	Pons and cerebellum
	Rhombencephalon (hindbrain)	Myelencephalon	Medulla oblongata
	Spinal cord	Spinal cord	Cervical, thoracic, lumbar, and sacral spinal nerve levels

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E-Figure 14-2 — Segmentation and Stratification of the Neural Tube.

A, Formation of the central nervous system (CNS). B, Formation of the ventricular system.

(Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

The ventricular system develops in parallel with the brain and spinal cord. It originates from the space formed by the closing of the neural folds to form the neural tube and thus gives rise to the lateral ventricles, the third ventricle, the mesencephalic (cerebral) aqueduct, the fourth ventricle, and the central canal of the spinal cord. The dispersal of agents in the cerebrospinal fluid (CSF) to seemingly disparate regions of the CNS is explained by the interconnectedness of the ventricular system.

Following the development and differentiation of the brain into the five segments listed earlier, there is differential growth (i.e., occurs at different extents, rates, and times) in each of these parts of the developing brain. For example, the brainstem (pons and medulla) undergoes marked reorganization to form numerous specific nuclei that are the source of not only the majority of the cranial nerves, but also a neural relay network for the majority of neural impulses that arise in the prosencephalon (e.g., cerebral hemispheres and thalamus). It is also during this period of embryologic differentiation that stratification occurs within the cerebral cortex resulting in the formation of cerebral lamina. Lamina are distinct topographic layers of neuron cell bodies that have similar functions and innervate specific areas of the body as designated by these similar functions. They serve as topographic maps for specific activities within the CNS such as sensory, motor, and associative functions. Additionally, these activities are spread out into distinct “functional” lamina within lobes within the cerebral cortex, such as the frontal lobe (cognitive functions), parietal lobe (motor and sensory functions), occipital lobe (vision), and the temporal lobe (auditory functions). Lastly, the cerebellum undergoes significant reorganization with the development of multiple integrated layers of neurons, including the granule cell layer, the molecular cell layer, and the Purkinje cell layer.

The adult CNS is arranged to form two basic parts: the gray and white matter (Figs. 14-1 and 14-2 ). In the CNS, gray matter is found in the cerebral cortex, in the cerebellar cortex and cerebellar nuclei, around the base of the cerebral hemispheres (basal nuclei [often called basal ganglia]: caudate nucleus, lentiform nucleus [putamen, globus pallidus], amygdaloid nucleus, claustrum), and throughout the brainstem, often in nuclei. The gray matter is typified by numerous neuronal cell bodies, plus a feltwork of intermingled thinly myelinated axons and dendrites, their synaptic junctions, and processes of oligodendroglia, astrocytes, and microglia. This network of processes and synapses in the gray matter is referred to as the neuropil. The white matter consists of well-myelinated axons that arise from neuronal cell bodies in the gray matter and terminate distally in synapses or myoneural junctions, plus oligodendroglia, astrocytes, and microglia. In the cerebral hemispheres, white matter is located centrally, whereas in the brainstem, white matter is intermingled with gray matter (nuclei). In the spinal cord, white matter is located peripherally surrounding the gray matter.

Figure 14-1 — Organization of the Brain, Gray Matter, and White Matter.

A, Transverse section at the level of the thalamus, dog. Gray matter *(darker areas)* of the cerebral cortex lies beneath the leptomeninges on the external surface of the brain, whereas in the thalamus there is a mixture of gray and white matter. Major white matter areas *(light areas)* include corona radiata, centrum semiovale, and corpus callosum of the cerebrum, and internal capsule and optic tracts bordering the lateral and ventral surfaces of the thalamus, respectively. B, Gray matter consists primarily of the cell bodies of neurons *(arrows)* and a network of intermingled thinly myelinated axons, dendrites, and glial cell processes. This network is referred to as the neuropil *(N)*. Other components include oligodendroglia *(arrowheads)*, astrocytes, and microglia. H&E stain. C, White matter primarily consists of well-myelinated axons *(arrows)* plus oligodendroglia *(arrowheads)* and astrocytes. The clear spaces surrounding large axons are artifacts formed when the lipid components of myelin lamellae are dissolved away by solvents in the process of embedding tissue in paraffin for sectioning. H&E stain. D, Immunohistochemical (IHC) stain for ionized calcium binding adapter molecule 1 (Iba1). This IHC stain identifies microglia within a section of brain *(arrows)*. Their ramified processes are similarly highlighted *(arrowheads)*. DAB IHC stain. E, IHC stain for Olig2, a transcription factor that is expressed in the nucleus of oligodendrocytes *(arrows)*. DAB IHC stain.

(A, B, and C courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois. D and E courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University.)

Figure 14-2 — Organization of the Spinal Cord, Gray Matter, and White Matter.

A, White matter in the spinal cord is located peripherally and divided into dorsal, lateral, and ventral funiculi. As a general rule, dorsal funiculi *(D)* consist of ascending sensory axons, lateral funiculi *(L)* have a mixture of sensory and motor axons, and ventral funiculi consist of descending motor axons *(V)*. Histologically, the right side is a mirror image of the left side. The areas labeled B and C and contained within the boxes correspond to the areas illustrated in B and C. B, Transverse section of spinal cord, ventral gray horn, horse. The cell bodies of large motor neurons *(arrows)* are those of lower motor neurons, and their axons extend in peripheral nerves to myoneural junctions that innervate skeletal muscle. H&E stain. C, Transverse section of spinal cord, ventral funiculus, horse. Because most axons course up and down the length of the spinal cord, in a transverse section, axons *(arrows)* are cut in cross section. They are surrounded by myelin sheaths whose lipid components are dissolved out during the preparation of paraffin-embedded sections, resulting in clear spaces that are an artifact. H&E stain. D, Efferent spinal nerve (longitudinal section shown here), transverse section of spinal cord, ventral funiculus, dog. Axons of lower motor neurons leave funiculi *(F)* and assemble as nerve rootlets *(arrow)* eventually forming peripheral nerves that innervate skeletal muscle. H&E stain. *DGH,* Dorsal gray horn; *VGH,* ventral gray horn.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

The embryologic development of the PNS is as complex as the CNS and is also dependent on the normal development of the neural tube. A population of neural crest cells that form bilaterally in the dorsal regions of the neural tube is the origin of the majority of cells that populate the PNS, such as neurons and Schwann cells. These neural crest cells also migrate peripherally in developing tissues and organ systems within the mesoderm and endoderm to form structures such as spinal ganglia, enteric plexuses, and the adrenal medullas. Neurons of the PNS are divided into afferent and efferent types based on whether they conduct impulses to or from the CNS, respectively. Cell bodies for somatic efferent neurons, such as those in cranial or spinal nerves, are located in nuclei of the brain or the ventral horns of the gray matter of the spinal cord and project ventrolaterally long distances to innervate peripheral tissues, such as skeletal muscle. The cell bodies for somatic afferent neurons are located bilaterally within spinal ganglia (dorsal root ganglia) that are developmentally associated with specific spinal cord segments. The neurogenic control of visceral tissues and organ systems such as the alimentary system is complex; involves at a minimum two neurons, a preganglionic neuron and a postganglionic neuron; and is facilitated by the sympathetic, parasympathetic, and enteric nervous systems (i.e., visceral nervous systems). As a basic rule, for all three visceral nervous systems the preganglionic neuron cell body is located in the intermediate gray matter between the dorsal and ventral horns of the spinal cord or brain nucleus.

As noted earlier, during the development of the CNS a variety of differing cell types populate the brain and spinal cord, including the neurons, glia, ependyma, endothelial cells, pericytes and smooth muscle cells of blood vessels, and various cells in the meninges (Fig. 14-3 ; Box 14-1 ). Neurons vary in size, shape, and function, and their cell bodies are organized into functional groups such as nuclei, horns of gray matter in the spinal cord, and cerebral lamina. Neuronal processes called axons and dendrites traverse through the brain and spinal cord, the former often as organized bundles (tracts, fasciculi) forming synapses on cell bodies, dendrites, and axons of other functionally related neurons. It is estimated that there are 1 × 10¹¹ neurons in the human brain. Each neuron makes approximately 10,000 synapses with other neurons; therefore there are approximately 1 × 10¹⁵ synapses in the human brain. The neurons maintain a close association with various glial cells, including microglia, astrocytes, and oligodendrocytes. The glia are responsible for helping to maintain CNS homeostasis and play an important role in the immune response and healing. Astrocytes, oligodendrocytes, and ependymal cells are derived from neuroectoderm, whereas microglia, part of the monocyte-macrophage system, are derived from progenitors in the embryonic yolk sac that populate the CNS during development. In the mammalian CNS, glia outnumber neurons 10 to 1. Ependymal cells line the ventricular system, whereas choroid plexus epithelial cells form the outer covering of the choroid plexuses. Lastly, the exterior of the CNS is covered by the meninges. The meninges consist of three layers named, from outermost to innermost layers, the dura mater, arachnoid, and pia mater. The arachnoid and pia enclose the subarachnoid space.

Figure 14-3 — Cell Types in the Central Nervous System Include Neurons, Astrocytes, Oligodendroglia, Microglia, Ependymal Cells, Choroid Plexus Epithelial Cells, and Vascular Endothelial Cells.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Box 14-1. Cells of the Central Nervous System and Their Primary Functions.

Neurons

Transmission of electric and chemical impulses
Spatial and temporal interpretation of impulses
Inhibitory and stimulatory regulation of impulses

Astroglia (Protoplasmic [Type I] and Fibrous [Type II])

Regulation of extracellular neurotransmitter concentrations and fluid/electrolyte imbalances
Repair of injury by proliferation of astrocytic cellular processes
Support and bundling of functionally related axons traversing through the CNS
Participation in barrier systems
Glia limitans
Blood-brain barrier

Oligodendroglia

Myelination of axons within the CNS
Proposed neuronal cell body homeostasis within the CNS

Ependyma

Movement of CSF through the ventricular system

Choroid Plexus Epithelial Cells

Secretion of CSF
Barrier function (blood-CSF barrier)

Microglia

Immunosurveillance, immunoregulation, phagocytosis
Monocyte-macrophage system

Meninges

Arachnoid-CSF barrier
Subarachnoid CSF cushioning of head trauma

Endothelia

Barrier function (blood-brain barrier)
Selective molecule transport systems

CNS, Central nervous system; CSF, cerebrospinal fluid.

Central Nervous System

Structure2 and Function

Cells of the Central Nervous System

Neurons.

The structure and basic cellular biology of neurons is similar to that of other cells (Fig. 14-4 ); however, there are, as discussed later, some notable differences. The neuron consists of three structural components: dendrites, a cell body, and a single axon. The length of the axon varies, depending on the function of the neuron. The length of axons of motor or sensory neurons can be 10,000 to 15,000 times the diameter of the neuronal cell body, which results in these axons being several meters in length. The axon terminates in synaptic processes or neuromuscular junctions.

Figure 14-4 — Neuron Structure.

A, Basic cell biology and structure of neurons are similar to other cells in the body. Additionally, neurons have dendritic arborizations and an axon, specializations for the initiation, propagation, and transmission of impulses that underlie the basic function of these cells. B, The cytoplasm of the neuronal cell body has blue (basophilic [H&E stain]) granular material (rough endoplasmic reticulum) called Nissl substance *(arrows)*. Nissl substance synthesizes proteins, including precursor neurotransmitter proteins and the structural proteins (neurofilaments), active in maintaining the integrity (length and diameter) of the axon. H&E stain. *rER,* Rough endoplasmic reticulum.

(A courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois. B courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Neuronal cell bodies vary considerably in size and shape, from the large neurons of the lateral vestibular nucleus, Purkinje cell layer of the cerebellum, and the ventral gray matter of the spinal cord to the very small lymphocyte-like granule cells of the cerebellar cortex (Fig. 14-5 ). Neuronal nuclei tend to be vesicular to spherical in shape, are usually centrally located, and often, particularly in large neurons, tend to contain a prominent central nucleolus. Neurons contain focal arrays of rough endoplasmic reticulum and polysomes, termed Nissl substance, that are responsible for the synthesis of proteins involved in many of the neuron's vital cellular processes such as axonal transport. Nissl substance is present in all neurons, regardless of the size of the cell body, but tends to be more prominent in those cells with voluminous cytoplasm such as motor neurons.

Figure 14-5 — Variations in Neuronal Morphologic Features, Cerebellum, Granule Cells, and Purkinje Neurons, Normal Animal.

The granule cell neurons of the cerebellar cortex *(arrowheads)* are very small basophilic cells that have relatively little demonstrable Nissl substance when compared with Purkinje neurons *(arrows)* and large motor neurons (depicted in Fig. 14-4, B). H&E stain.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Axonal Transport (Axoplasmic Transport).

Axonal transport is a cellular mechanism used to move synaptic vesicles, proteins such as neurotransmitters, mitochondria, lipids, and other cell organelles from the neuron cell body through the axon to the synapses and then bring their degradation products back to the cell body.

As a result of structural differences between neurons and other cells, neurons have developed axonal transport systems to efficiently move molecules and cellular organelles from the cell body through the axon to the synapses and bring their degradation products back to the cell body (E-Fig. 14-3). Axons can be longer than a meter in length, especially in an animal such as a giraffe. Lower motor neurons, whose cell bodies lie in the ventral gray horn of the spinal cord, and lumbar dorsal root ganglia, whose axons extend both from the distal limb and the caudal medulla, have the longest axons in the body. The neuron expends considerable energy and materials to move biologic materials up and down the axon. Alterations in the function of these transport systems can lead to neuronal dysfunction.

E-Figure 14-3 — Axonal Transport Systems.

Neurotransmitter vesicles and neurofilament proteins, synthesized in the rough endoplasmic reticulum (rER) and packaged in the Golgi apparatus (1) are transported through the length of the axon (2) and to synapses by kinesin (3). Kinesin is a microtubule motor protein that uses chemical energy from adenosine triphosphate hydrolysis to generate mechanical force and thus bind to and move attached to microtubules. Used vesicles and effete neurofilament proteins (4) are returned along a microtubule (recycled) (5) to the neuron cell body (6) by cytoplasmic dynein, another microtubule motor protein. These transport systems are used by some pathogens (rabies virus, *Listeria monocytogenes*) to enter and spread within the central nervous system.

(Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

These transport systems are divided into “fast axonal transport” and “slow axonal transport.” The fast axonal transport system has an anterograde component (toward the synapse) and a retrograde component (toward the cell body). The slow axonal transport system has only an anterograde component (toward the synapse).

Fast anterograde axonal transport (up to 400 mm per day) moves materials not intended for use in the cytoplasm of the neuron cell body. These materials formed from the Golgi apparatus are principally membrane-bound vesicles. They include mitochondria and membranous vesicles that contain peptide neurotransmitters, small transmitter molecules, and the enzymes necessary for their activation. These materials are moved down the axon on microtubules by specialized protein motors composed of kinesin and kinesin-related proteins using adenosine triphosphate (ATP) as an energy source.

Fast retrograde axonal transport (200 to 300 mm per day) returns endosomes, mitochondria, and catabolized proteins to the cell body of the neuron for degradation in lysosomes and reuse. This transported material is returned on microtubules, by dynein and microtubule-associated adenosine triphosphatase (ATPase) in the axon. This system will also transport certain toxins, such as tetanus toxin, and viruses, such as rabies virus, from the periphery via the PNS into the CNS.

Slow anterograde axonal transport (0.2 to 5 mm per day) transfers throughout the axon via microtubules, the major cytoskeletal proteins, such as microtubule and neurofilament proteins, which are necessary to maintain the structural integrity and transport systems within the axon.

Diseases of the axon that result directly or indirectly from alterations in axonal transport systems are discussed later. The character of the histologic lesions affecting injured nerve fibers can often be related to alterations in specific transport systems. Neurofilament proteins are synthesized in the neuronal cell body and are assembled and transported into axons. If neurofilaments accumulate in neuronal cell bodies and proximal axons, this lesion is called an axonopathy and is characterized by alterations in slow transport systems, which result in axonal swelling or atrophy and perikaryal neurofibrillary accumulations. Axonal injury and alterations in neurofilament transport can also cause secondary demyelination.

Membrane Potentials and Transmitter/Receptor Systems.

A fundamental activity of neurons is to modulate and effectively transmit chemical and electric signals from one neuron to another via synapses in the CNS or from one neuron to a muscle cell via junctional complexes, myoneural junctions, or motor end plates in the PNS. The process of nerve impulse conduction is made possible by the establishment and maintenance of an electric potential across the cell membrane of the neuron/axon.

A fundamental activity of neurons is to modulate and effectively transmit chemical and electric signals from one neuron to another via synapses in the CNS or from one neuron to a muscle cell via junctional complexes, myoneural junctions, or motor end plates in the PNS. The process of nerve impulse conduction is made possible by the establishment and maintenance of an electric potential across the cell membrane of the neuron/axon. Membrane potential is the difference in voltage between the inside and outside of the neuronal/axonal cell membrane and is called the resting potential. This potential is established and maintained by a membrane sodium ion (Na⁺)/potassium ion (K⁺)-ATPase (Na⁺/K⁺-ATPase) pump. The pump keeps the concentration of sodium ions outside the cell approximately 10 times greater than inside the cell, and the concentration of potassium ions inside the cell 20 times greater than outside the cell. The differences in concentrations of sodium ions outside and potassium ions inside of the cell membrane keep the membrane resting potential at approximately −70 mV. Thus the inside of the neuron/axon is 70 mV less than the outside. Sodium and potassium ions will leak across the cell membrane, and therefore concentration gradients are maintained by the Na⁺/K⁺-ATPase pump in the cell membrane. This established equilibrium and the membrane potential places the neuron in a “resting” condition, ready to generate an action potential.

An action potential arises when a neuron transmits information down an axon, away from the neuronal cell body. An action potential is initiated by an event that depolarizes the cell membrane and causes the resting potential to move toward 0 mV. When depolarization reaches a threshold level of approximately −50 mV, an action potential will occur. Once initiated, the strength of an action potential is always the same because the action potential is an intrinsic property of the neuron cell body and its axon.

Action potentials are caused by the movement of sodium and potassium ions across the neuron cell body/axon cell membrane. With an initiating event, sodium channels are first to open, and large concentrations of sodium ions enter the intracellular microenvironment (E-Fig. 14-4). Because sodium ions are positively charged, the polarity becomes more positive (−70 mV to −50 mV), and the neuron/axon becomes depolarized. Potassium channels open later in the depolarization process, concurrently with the closing of sodium channels. Potassium ions leave the cell and enter the extracellular fluid. These events cause repolarization of the neuron/axon and a return to a resting potential (−70 mV) via the membrane Na⁺/K⁺-ATPase pump. Alterations in these ion channels have been correlated with epilepsy in human beings and are starting to be discovered in animals.

E-Figure 14-4 — Resting and Action Potentials.

A, An action potential most commonly arises via neurotransmitter-induced chemical messages (depolarization) at synapses between presynaptic and postsynaptic neurons. It travels through dendrites, the cell body, and then down the axon to axon terminals of the postsynaptic neuron. B, Nerve impulse conduction occurs because of an electric potential sustained across the cell membrane of the dendrite/neuron cell body/axon. A resting membrane potential is maintained by differences in concentrations of potassium ions inside and sodium ions outside the cell membrane. When a neurotransmitter or other stimulus depolarizes the cell membrane to a threshold of approximately −50 mV, an action potential will occur. Sodium and potassium ions leak across the cell membrane, and therefore concentration gradients and thus the electric potential are maintained by sodium-potassium pumps in the cell membrane. C, When sodium channels are opened, an action potential occurs locally in the cell membrane. It is propagated down the cell membrane by the successive opening of voltage-gated sodium channels in adjacent sections of the membrane. Depolarized segments repolarize as sodium channels close and potassium ions move out of the cell.

(Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Action potentials are most commonly initiated by neurotransmitters, such as acetylcholine, acting through synapses, but they also occur as a result of mechanical stimuli, such as stretching and sound waves. There are two main classes of synapses: inhibitory and excitatory. Stimulation of inhibitory synapses results in inhibitory postsynaptic potentials that cause hyperpolarization of dendrites and cell bodies. Hyperpolarization decreases the membrane potential (more negative, −80 mV), thus making the neuron less likely to reach the threshold for an action potential. Inhibitory neurotransmitters include γ-aminobutyric acid (GABA), glycine, dopamine, serotonin, norepinephrine (in the CNS), and acetylcholine (in heart muscle).

Stimulation of excitatory synapses results in excitatory postsynaptic potentials that cause depolarization of the dendrites and cell bodies. Depolarization increases the membrane potential (more positive, −50 mV), thus making the neuron more likely to reach the threshold for an action potential. Excitatory neurotransmitters include glutamate, norepinephrine in the PNS, and acetylcholine in skeletal muscle.

The generation of an action potential is a complicated process requiring depolarization of the cell membrane (−50 mV). Inhibitory and excitatory synapses and their inhibitory and excitatory postsynaptic potentials, respectively, are “summed” through processes, termed spatial and temporal summation, occurring in the dendritic network of the neuron. Spatial summation reflects additive input from different parts of the dendritic network, whereas temporal summation reflects additive input from stimuli that occur closely in time. This summation process is a graded potential and ultimately determines if the threshold for an action potential will occur.

The action potential is a flow of depolarization that travels down the axon to synapses at the distal axon. When the axon lacks myelin, the flow of depolarization down the axon is called continuous conduction. When the axon is myelinated, the speed of conduction is determined by the degree of myelination of the axon and is called saltatory conduction. The diameter of unmyelinated axons can range from 0.2 to 1 mm with action potential velocities ranging from 0.2 to 2 m/sec, whereas the diameter of myelinated axons can range from 2 to 20 mm with action potential velocities ranging from 12 to 120 m/sec. The greater the degree of myelination, the faster the speed of impulse conduction down the axon. In unmyelinated axons, action potentials are conducted at a relatively “slower” velocity by the process of ion exchange (continuous conduction). In myelinated axons, action potentials are conducted at a relatively “faster” velocity by a mechanism called saltatory conduction. In this process, action potentials move down the myelinated axon using cable properties, like electric current flow in insulated copper wires. This method is fast, efficient, and requires less energy than ion exchange. However, the action potential would decay if axons were myelinated continuously along their length and likely would not reach synapses at full strength or at all. This decay is caused by loss of current across the cell membrane and capacitance properties of the cell membrane as the action potential travels down the axon. To minimize the decay of action potentials, axons are myelinated in segments called internodes. A gap, called the node of Ranvier, is formed between consecutive internodes and measures between 0.2 and 2 mm in length. At this gap the action potential is restored to full strength by ion exchange. The node of Ranvier is highly enriched in sodium channels, and these channels are essential for impulse propagation via rapid action potential current restoration. Disease processes that disrupt myelination of axons will interfere with saltatory conduction, slow the action potential, and result in clinical dysfunction of the nervous system (see Fig. 14-21).

Figure 14-21 — Axonal Action Potential Conduction and the Effect of Demyelination.

The speed of the conduction process is determined by the diameter of the axon and the degree of myelination. As axons increase in diameter, the resistance to ion flow decreases, allowing the action potential to flow faster. In addition, the degree of myelination is directly proportional to the diameter of the axon. Thus the concept that the more myelin the faster the speed of the impulse is true up to the point in which the myelin is normal in thickness. For an axon whose myelin is reduced, conduction of the action potential is slower. Under normal conditions, locomotion is a well-coordinated event that requires precise timing (speed) of impulse conduction to get coordinated movements. If the speed of the action potential is altered by disease, especially demyelination, then the conduction of the action potential will be delayed, and what are normally coordinated movements become uncoordinated. A, In unmyelinated axons, action potentials are conducted at a relatively “slower” velocity by the process of ion exchange continuous conduction (see E-Fig. 14-4). B, In myelinated axons, action potentials are conducted at a relatively “faster” velocity by a mechanism called saltatory conduction. Optimal function of saltatory conduction is dependent on having the proper degree of myelination of the axon (as determined by axonal diameter) throughout the full length of the axon. C, In axons that have lost some but not all of their myelin lamellae from one or more internodes so that there is a “thinner” covering of myelin, the speed of saltatory conduction is reduced because of leakage of the action potential across this thinner myelin sheath, resulting in clinical dysfunction of the nervous system. D, In axons that have lost all of their myelin from one or more internodes (complete primary demyelination of the internode), the speed of saltatory conduction is reduced because of the conversion from saltatory conduction to ion exchange continuous conduction in the areas where internodes have lost their myelin. Thus the speed and timing of the action potential is substantially reduced, leading to clinical dysfunction of the nervous system.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

The axon can be a very long extension of the neuron cell body extending, for example, up to 2 m from the lumbar dorsal root ganglion in a giraffe. At its distal end the axon splits into several branches that end as specialized structures called axon terminals/terminal buttons/synaptic bulbs. Synapses present at these axon terminals are functional, and structural points of contact between “networked” neurons and these synapses convert the action potential into chemical signals that stimulate the next neuron in the conduction pathway. The cell membrane that releases chemical neurotransmitters is called the presynaptic membrane, and the cell membrane that has neurotransmitter receptors for the chemical neurotransmitters is called the postsynaptic membrane. These membranes are found on dendrites and cell bodies of the next neuron in the neural conduction pathway. The gap between the presynaptic and postsynaptic membranes that chemical neurotransmitters must cross is called the synaptic cleft. The mechanism of diseases, such as tetanus and botulism, is manifested through presynaptic and postsynaptic membrane receptors.

When an action potential reaches the axon terminal, it causes the release of chemical neurotransmitters from the presynaptic membrane by opening voltage-gated calcium channels, leading to membrane depolarization. The amount of chemical neurotransmitter released into the synaptic cleft is determined by the number of action potentials that reach the axon terminal over time. Chemical neurotransmitters traverse the synaptic cleft and bind to neurotransmitter receptors on dendrites and cell bodies of a new neuron in the neural conduction pathway.

There are two types of chemical neurotransmitter receptors, ionotropic and metabotropic, on the membrane of postsynaptic neurons. Functionally these receptor types differ in latency and duration of action. Ionotropic receptors have a fast response and short duration of effect, whereas metabotropic receptors have a slower response and a longer duration of effect. In addition, ionotropic receptors are localized to specific sites on the postsynaptic membrane, whereas metabotropic receptors are distributed diffusely and at random.

Chemical neurotransmitter stimulation of ionotropic receptors results in the opening of ion gates or channels, resulting in depolarization of the postsynaptic membrane. Excitatory neurotransmitters, such as glutamate, open postsynaptic membrane sodium channels. Inhibitory neurotransmitters, such as GABA, open postsynaptic membrane chloride channels.

Chemical neurotransmitter stimulation of metabotropic receptors results in the generation of a second messenger such as in the cyclic adenosine monophosphate (cAMP) pathway, which initiates a sequence of metabolic changes in the neuron. Metabotropic receptors are composed of protein subunits that span the postsynaptic cell membrane. An extracellular component of this protein has a high affinity for neurotransmitters and functions as a binding site. After binding the neurotransmitter, the receptor undergoes a configurational change that directly or indirectly activates a cell membrane enzyme, such as intracellular G proteins, leading to the formation of the second messenger. cAMP can activate protein kinase A–induced phosphorylation, leading to functional changes in ion channels and protein transcription. Dopamine is an example of a chemical neurotransmitter that uses metabotropic receptor pathways.

Astrocytes.

The functions of astrocytes in the CNS are regulation, repair, and support, as depicted in Figure 14-6 . All regions of the CNS contain astrocytes, and they are derived from pluripotential neuroepithelial progenitor cells during the development of the CNS. Astrocytes are the most numerous cell type in the CNS and have traditionally been classified into two types based on morphologic features. Protoplasmic astrocytes are located primarily in gray matter, whereas fibrous astrocytes occur chiefly in white matter. Microscopically, astrocytes have relatively large vesicular nuclei, indistinct or inapparent nucleoli, and no discernible cytoplasm with routine hematoxylin and eosin (H&E) staining (Fig. 14-7 ). With suitable histochemical stains, silver impregnation, or immunohistochemical staining for glial fibrillary acidic protein (GFAP [the major intermediate filament in astrocytes]), the cell body and the extensive arborization and interconnections of astrocytic processes can be demonstrated. Processes vary from short and brushlike to long branching processes in protoplasmic and fibrous astrocytes, respectively (Fig. 14-8 ). Expression of GFAP is the standard immunohistochemical marker for tumors of astrocyte origin and can also be used to qualitatively or quantitatively characterize disorders in which astrocytes are proliferative or reactive. However, caution should be taken when assessing astrocyte numbers and/or the extent of ramification of their processes because GFAP immunoreactivity can be diminished in terminal processes and/or cell bodies, and therefore the total GFAP immunoreactivity in any given section of brain may not be representative of the overall astrocytic response in the disorder.

Figure 14-7 — Histologic Features of Glial Cells, Ventral Gray Horn, Spinal Cord, Horse.

A neuronal cell body and its processes are in the center of the illustration. To the inexperienced, identifying specific types of glial cells in H&E-stained histologic sections can be challenging. Astrocytes *(arrows)* have larger vesicular nuclei (dispersed chromatin), and the cell membrane and cytoplasm are rarely seen in nondiseased conditions. Thus these nuclei just seem to “sit” in the midst of the neuropil. The majority of nuclei in the neuropil here are astrocytic. Oligodendroglial cells *(arrowheads)* have smaller and dense round nuclei (condensed chromatin) often surrounded by a clear zone indicative of cell cytoplasm and a cell membrane. Oligodendroglial cells in gray matter are called perineuronal satellite cells; those in white matter are called interfascicular oligodendrocytes. Microglial cells can be difficult to identify in H&E-stained sections of the central nervous system (CNS) but are often identified by their small, dense elongated nuclei *(dashed arrow)*. The light pink homogeneous tissue distributed in large quantities between these cell types is the neuropil. V, Blood vessels. H&E stain.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Figure 14-8 — Astrocytic Processes, Brain, Cerebral Cortex, Normal Animal.

Processes of astrocytes arborize extensively throughout the central nervous system *(structures stained purple)*. Note that some of the processes are on the outside of blood capillaries (end feet) *(arrows)*. Holzer's stain. A, Cell body of astrocyte.

(Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.)

Functions of Astrocytes

Regulation of the Microenvironment.

The microenvironment of the CNS must be under strict control to maintain normal function. Astrocytes are involved in homeostasis of the CNS and regulate ionic and water balance, antioxidant concentrations, uptake and metabolism of neurotransmitters, and metabolism or sequestration of potential neurotoxins, including ammonia, heavy metals, and excitatory amino acid neurotransmitters such as glutamate and aspartate. Structurally, the homeostatic role of astrocytes is illustrated by the morphologic characteristics of the neuropil, where astrocytic processes surround synapses and maintain a microenvironment that is adequate for normal synaptic transmission.

Additionally, interactions between astrocytes, microglia, and neurons orchestrate immune reactions in the brain. In this regard, astrocytes can express major histocompatibility complex (MHC) class I and II antigens, a variety of cytokines and chemokines, and adhesion molecules that modulate inflammatory events in the CNS. Astrocytes also secrete growth factors and extracellular matrix molecules that play a role not only in embryonic development but also in repair of the CNS following injury. In this latter role, astrocytes can fuse with adjacent astrocytes via a variety of gap junctions, and the coupling of multiple astrocytes together can play an important role in normal CNS function and repair (see next section). The gap junctions between various astrocytes are mediated by connexins. Astrocytes also play an integral role in CNS metabolism and can accumulate glycogen that can later be used to sustain neurons, especially during periods of hypoglycemia.

Repair of Injured Nervous Tissue.

In the CNS, reparative processes that occur after injury, such as inflammation and necrosis, are chiefly the responsibility of astrocytes. In these reparative processes, astrocytes are analogous to fibroblasts in the rest of the body. Astrocytes do not synthesize collagen fibers, as do fibroblasts. Instead, repair is accomplished by astrocytic swelling and division, and abundant proliferation of astrocytic cell processes containing intermediate filaments composed of GFAP, a process called astrogliosis. As an example, neuronal necrosis occurs in some viral diseases of the CNS. When neurons die, the spaces left by the loss of the neuronal cell bodies are filled, and such spaces (<1 mm in diameter) are filled by processes of astrocytes. Larger spaces that form after injury, such as an infarct, are often too large to be filled and therefore exist in the CNS as fluid-filled spaces (cysts) surrounded by a capsule of astrocytic processes. Astrocytes will also attempt to wall off abscesses, but they are not as effective as fibroblasts, and the capsule can be incomplete or weak (Fig. 14-9 ). In the case of direct extension of bacteria from the meninges or meningeal blood vessels, which contain or are surrounded by fibroblasts, respectively, fibroblasts play a larger role in isolating the inflammatory process.

Figure 14-9 — Astrocytic Repair, Bacterial Abscess, Brainstem, Sheep.

The abscess has a central core of necrotic debris *(D)* surrounded by a layer of inflammatory cells *(I)* and a less dense pink-staining zone representing an attempt by astrocytes and fibroblasts to form a capsule *(A)*. This capsule is formed by fibrous tissue on the ventral and right sides, those sides closest to the pia, which contains fibroblasts. A fibrous capsule is absent from the dorsal and left sides of the abscess, adjacent to brain parenchyma. Here, there is no population of resident fibroblasts, and the capsule is formed by astrocytes and their processes, which are often delicate and do not form an effective capsule *(A)*. H&E stain.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Structural Support of the Central Nervous System.

Structurally, astrocytic processes provide support for other cellular elements and ensheathe and insulate synapses. Astrocytes also provide guidance and support of neuronal migration during development; thus tracts and fasciculi of axons with similar functions are arranged and structurally supported by astrocytic processes. Processes of astrocytes (foot processes) also terminate on blood vessels throughout the CNS, forming a component of the blood-brain barrier. Astrocytes influence the induction of tight junctions between endothelial cells that serve as the structural basis for the blood-brain barrier. A dense meshwork of astrocytic processes also forms the glia limitans beneath the pia mater and is variably prominent in subependymal areas. During CNS development, cells termed radial glia provide a scaffold and guidance for migrating neurons. When development is completed, radial glia mature into astrocytes. Some of these radial glia (also known as radial neural stem cells) remain active throughout life in the subventricular zone of the lateral ventricles, where they can repopulate lost populations of glial cells.

Oligodendroglia.

There are two types of oligodendroglia: (1) interfascicular oligodendrocytes and (2) satellite oligodendrocytes (satellite cells). The function of interfascicular oligodendroglia is myelination of axons, whereas the function of satellite oligodendroglia is thought to be regulation of the perineuronal microenvironment. Oligodendroglia have been compared with neurons with regard to their total cell size in that their processes occupy much more space than the cell body. Neurons have very long axons, which account for their size; oligodendroglia have extensive myelin sheaths, which account for their size. In H&E-stained sections, oligodendroglia are often confused with lymphocytes because of the similarity of the morphologic features of their nuclei and cytoplasmic volume. Interfascicular oligodendroglia and perineuronal satellite oligodendroglia are located primarily in white and gray matter of the CNS, respectively (Fig. 14-10 ); however, interfascicular oligodendroglia can also be found along axons that traverse through the gray matter. The mature, small oligodendrocyte has a spherical, hyperchromatic nucleus (see Figs. 14-7 and 14-10). As with astrocytes, the cell body and processes of this cell do not stain with conventional H&E staining methods and can only be demonstrated following special procedures that include metallic (silver) impregnation and immunohistochemical methods, including CNPase and Olig2.

Figure 14-10 — Responses of Glial Cells to Injury in H&E-Stained Central Nervous System (CNS) Sections.

A, White matter. In nondiseased states, oligodendroglia in white matter are often arranged linearly (interfascicular oligodendroglia) *(arrow)* and are responsible for the formation of myelin around axons. In gray matter (not shown; see Fig. 14-17), oligodendroglia are dispersed as individual cells around neuronal cell bodies as perineuronal satellite cells **(B)**. H&E stain. B, Gray matter. When neurons are injured or there exists some perturbation of the perineuronal microenvironment, oligodendroglia around neurons can hypertrophy and proliferate in a process referred to as satellitosis. Perineuronal satellite oligodendroglia *(arrows)* surround a small degenerate neuron with condensed chromatin and little cytoplasm. H&E stain. C, White matter. Astrocytes *(arrows)* and oligodendroglia *(arrowheads)* have a limited repertoire of responses to injury in the CNS. Astrocytic proliferation can occur but is very difficult to determine in sections stained with H&E. Here, astrocyte nuclei are somewhat enlarged and appear more numerous than expected. H&E stain. D, Gray matter. Astrocytes respond to injury in hyperammonemia, such as occurs with hepatic encephalopathy, by forming astrocytes with enlarged, markedly vesicular (“watery”), often elongated nuclei called Alzheimer's type II astrocytes *(arrows)*. This type of astrocyte may occur in pairs that are surrounded by a clear space indicative of cellular swelling. H&E stain.

(A courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee. B to D courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Most interfascicular oligodendroglia (see Fig. 14-10) are aligned in rows parallel to myelinated axons and are responsible for the formation and maintenance of segments (internodes) of myelin sheaths. One oligodendroglial cell can form as many as 50 different internodes of myelin, each of which can be located on many different axons (Fig. 14-11 ). Altered function of oligodendroglial cells, as occurs in infectious canine distemper virus (CDV) infection, can cause primary demyelination of these segments, resulting in severe neurologic dysfunction. Oligodendroglia also influence maturation and maintenance of axons and inhibit regeneration of established myelinated axons.

Figure 14-11 — Central Nervous System (CNS) Myelin.

Oligodendroglia myelinate axons within the CNS (also see Fig. 14-3). A, As depicted in this illustration, each oligodendrocyte sends out numerous cytoplasmic processes that repetitively encircle (myelinate) the portion of an axon between two nodes of Ranvier (internode) on the same and several different axons. Direct or indirect injury to an oligodendrocyte can result in “demyelination” of those internodes myelinated by that oligodendrocyte. This injury will slow the rate of conduction of an action potential and depending on the site of the lesion, may lead to clinical signs of neural dysfunction (ataxia, proprioception deficits). B, CNS nerves, longitudinal section. Axons and their neurofilaments *(brown stain)* and myelin *(red stain)* are demonstrated by this immunohistochemical stain for neurofilament and myelin basic protein.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Perineuronal satellite oligodendroglia (see Fig. 14-10) are adjacent to neuronal cell bodies and are also located around blood vessels in the gray matter. They are thought by some investigators to regulate the perineuronal microenvironment and respond to perturbation by proliferation. When the perineuronal microenvironment is altered or neuron cell bodies are injured, perineuronal satellite oligodendroglia, in an attempt to regulate the environmental perturbation, hypertrophy and proliferate in a process referred to as satellitosis. However, this term is imprecise as other glial cells can also contribute to sattelitosis. Similarly, alterations in the microenvironment of gray and white matter away from areas surrounding neuron cell bodies result in hypertrophy of oligodendroglia (see Fig. 14-10). It should be noted that in some sections of the normal CNS there are increased numbers of oligodendrocytes that surround neurons, giving a false impression of pathologic satellitosis. This arrangement is especially true for interstitial white matter neurons found in the cerebral cortices.

Microglia.

The basic functions of microglia are immunosurveillance, immunoregulation, and reparative (phagocytic) activities after neural cell injury and death. Resident microglia originate from mesodermal stem cells in the yolk sac and enter and populate the CNS during embryonic development and early postnatal life, analogous to the formation of the monocyte-macrophage system in other organs. Microglia can become amoeboid by phagocytosing dead cells and cellular debris during remodeling and maturation of the CNS. Amoeboid cells then enter a quiescent stage and transform into ramified microglia. Ramified microglia constitute up to 20% of the glial cells and are present throughout the mature CNS, serving as sentinels of brain injury. Ramified microglia, also called resting cells, are most numerous in perineuronal and perivascular areas and in interfascicular locations in white matter. Evidence of pinocytosis in ramified cells suggests some role in maintaining the neural microenvironment. The principal function of microglia is phagocytosis, the initiation of and participation in the innate and adaptive immune responses, and in degenerative and inflammatory diseases of the CNS.

Microscopically, ramified microglia have small, hyperchromatic ovoid-, rod-, or comma-shaped nuclei and no appreciable cytoplasm with routine H&E staining; thus the term rod cell is sometimes used to describe them (see Fig. 14-7). With special labeling techniques or metallic impregnation, ramified cells have delicate branching processes. The small hyperchromatic nuclei and nuclear shape distinguish microglia from astrocytes and oligodendroglia. However, microglia are often difficult to identify in H&E-stained sections without some expertise in neuropathology.

Activated microglial cells are not the major source of active macrophages in inflammation of the CNS. Blood monocytes recruited from the circulation account for up to 70% of the macrophages in inflammatory and degenerative diseases of the CNS. These macrophages differentiate from blood monocytes involved in normal “leukocytic trafficking” through the CNS and can be involved in immunologic and phagocytic responses (gitter cells) to disease processes and infectious microbes. These macrophage populations are found mainly in the leptomeninges, choroid plexus, and perivascular areas.

Ependyma (Including Choroid Plexus Epithelial Cells).

The basic functions of ependymal cells, which line the ventricular system, are to help move CSF through the ventricular system via movement of their cilia and to regulate the flow of materials between the CNS and the CSF. The ependyma is a single-layered, cuboidal to columnar epithelium that lines the ventricles and mesencephalic aqueduct of the brain and central canal of the spinal cord (Fig. 14-12 ). This layer of cells is therefore situated between the CSF and nervous tissue. Ependymal cells have cilia that project into the CSF and beat in a coordinated manner in the direction of CSF flow. Other structures, referred to as circumventricular organs, which include the choroid plexuses, are covered by highly specialized ependymal cells. The surface of ependymal cells that form the choroid plexus have microvilli (microvillus border) and cilia that occur singly or more often in groups of three or more. The choroid plexus epithelial cells also have specialized tight junctions (zonulae occludens) that are a functional part of the blood-CSF barrier. In contrast to the choroid plexus, junctions between the conventional ependymal cells include gap junctions (transmembrane proteins form a pore, allowing communication between adjacent cells) and zonulae and fasciae adherentes, which permit movement of materials, such as proteins from the CSF, into the extracellular space of the brain. This cellular lining, however, is not a static membrane in that it regulates several processes that involve interaction between the CSF and brain. The functions include regulation of fluid homeostasis between the ventricular cavities and the brain, secretion and absorption of CSF, endocytosis, phagocytosis, and metabolism of substances such as iron resulting from the lysis of erythrocytes after hemorrhage into the ventricular system. Finally, ependymal cells have the structural and enzymatic characteristics necessary for scavenging and detoxifying a wide variety of substances in the CSF.

Figure 14-12 — Ependymal and Choroid Plexus Epithelial Cells.

A, Ependymal cells are ciliated *(arrows)* and assist with the flow of cerebrospinal fluid (CSF) through the ventricular system. H&E stain. B, Choroid plexus epithelial cells *(arrows)* produce CSF from a brush border (microvilli) on the luminal surface. The surface of the choroid plexus also has cilia that occur singly or more often in groups of three or more on a single cell. H&E stain.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

During embryonic development the medial wall of the lateral ventricle (choroid fissure), the roof of the third ventricle, and the rostral part of the roof of the fourth ventricle consist of a single layer of neuroectoderm that is adherent on its outer surface to the pia mater. This neuroectoderm-pia union forms the tela choroidea, providing an anchor for the choroid plexuses, which is formed by an invagination of this bilayer membrane into the ventricular spaces.

Choroid plexus epithelial cells are modified ependymal cells. The choroid plexus epithelium is a single-layered, cuboidal to columnar epithelium with a microvillus border (see Fig. 14-12). CSF is secreted from the microvillus border. Choroid plexus epithelial cells, along with capillaries and the pia mater, form the choroid plexuses that project into the lateral, third, and fourth ventricles. The basic function of choroid plexuses is to produce the CSF that fills the ventricular system and the subarachnoid space. CSF has two important functions: (1) to act as a “shock absorber” to mitigate the effects of trauma to the brain and spinal cord and (2) to deliver nutrients to and remove wastes from the CNS.

The normal flow pattern of CSF is regulated by an intraventricular biologic pressure gradient in which the pressure created by secretion of CSF exceeds the pressure created by its absorption in arachnoid villi (arachnoid granulations). Arachnoid villi are focal extensions of the arachnoid and subarachnoid space that extend into the dorsal sagittal venous sinus of the brain. CSF is secreted by the choroid plexuses in the lateral, third, and fourth ventricles. It should be noted, however, that fluid from other sources, such as secretion by the ependyma, interstitial fluid of the brain, and ultrafiltrate of the blood, has also been reported to contribute to the formation of CSF. It moves from the lateral ventricles into the third ventricle, from the third ventricle through the mesencephalic aqueduct (aqueduct of Sylvius in human beings), and then to the fourth ventricle. Once in the fourth ventricle, the CSF exits through the two lateral apertures of the fourth ventricle to enter the subarachnoid space. Lateral apertures are the two openings in the caudal medullary velum that forms the roof of the fourth ventricle into the subarachnoid space, one at each side of the cerebellopontine angle. Although the central canal of the spinal cord is connected to the ventricular system at the caudal end of the fourth ventricle, there apparently is little active movement of CSF within the central canal. CSF in the subarachnoid space is reabsorbed by the arachnoid villi in the meninges. Recent evidence indicates that other routes of CSF drainage, in addition to arachnoid granulations, also exist and vary in different species. Venous sinuses, lymphatic drainage, and the cribriform plate appear to play important roles in CSF drainage and the maintenance of normal interventricular CSF pressure. In fact, experimental evidence suggests that the cribriform plate route may be the most important of the four. In human beings the entire volume of CSF is circulated approximately four times a day; however, with aging, the entire volume of CSF circulates less than two times a day.

Meninges.

The meninges, which enclose the CNS, consist of three layers: the dura mater (outermost layer), the arachnoid membrane, and the pia mater (innermost layer) (Fig. 14-13 ). Together, the arachnoid membrane and pia mater are frequently referred to as the leptomeninges, pia-arachnoid layer, or pia-arachnoid. The arachnoid membrane and pia mater are held together by bands of fibrous tissue called arachnoid trabeculae. This arrangement forms a compartment called the subarachnoid space in which CSF flows and which also contains blood vessels and nerves. The leptomeninges form a protective covering for the CNS and provide an external envelope filled with CSF that provides additional protection.

Figure 14-13 — Organization of the Meninges.

The meninges, from outside to inside, are the dura mater, arachnoid mater, and pia mater as illustrated in the diagram. The arachnoid mater and the pia mater form the leptomeninges. These two layers of the leptomeninges also enclose the subarachnoid space, which contains the arteries, veins, and nerves and is filled with cerebrospinal fluid. The pia mater is attached to the surface of the central nervous system (CNS). Astrocytes and their foot processes underlie the pia mater and form the glia limitans *(inset 1)* and surround the endothelial cells that form the blood-brain barrier. As arterioles penetrate the cortex to supply the tissue with blood, they carry the pia and glia limitans with them for 1 to 3 mm until the arteriole structurally becomes a capillary. At this transition site within the cortex, the capillary penetrates the pia and is surrounded by the glia limitans, and the end feet of the astrocytes become part of the blood-brain barrier *(inset 2)*. Components of the blood-brain barrier are capillary endothelial cells, basement membrane, and astrocytic foot processes, but the barrier is formed structurally by tight junctions between endothelial cells and functionally by specialized transport systems in these cells.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

The dura mater, once referred to as the pachymeninx (thick meninges), is a strong and dense collagenous membrane (Fig. 14-14 ). In the cranium the dura consists of two layers that are fused with each other. The outer layer serves as the periosteum of the cranial bone, except in the areas of the venous sinuses (surrounded by dura) and falx cerebri, which is the longitudinal layer that extends ventrally between the two cerebral hemispheres. At the level of the foramen magnum, the two layers become separated; the outer layer continues to function as the periosteum of the vertebral (spinal) canal, and the inner layer forms the free dural membrane that surrounds the spinal cord. The inner aspect of dura mater is lined by elongated, flattened mesothelial-like cells. Except in neonates, there is no epidural (extradural) space in the cranial vault as there is in the spinal cord. There can be a “potential” epidural or extradural space in mature animals from hemorrhage caused by trauma.

Figure 14-14 — Layers of the Meninges.

A, Brain, dog. The dura matter is a thick opaque layer. Here it covers the rostral (cranial) half of the brain and has been dissected away from the caudal half of the brain to expose the underlying leptomeninges. In old animals the dura mater often fuses with the periosteum of the calvaria, and at necropsy to expose the brain, it is usually removed attached to the calvaria. The leptomeninges are present, but because they are so transparent, they are barely visible on the surface of the caudal half of the brain between gyri. B, Spinal cord, horse. The dura mater is the thick opaque layer dissected from and lying to the right of the spinal cord. The leptomeninges (pia-arachnoid layer) are present (but not readily visible in this photograph) on the exposed surface of the spinal cord. Arrows indicate spinal nerve roots.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

The arachnoid consists of both the multilayered membrane composed of cells that overlap one another and the trabeculae that join it to the pia. The arachnoid has tight junctions between its cells, although other junctions have also been described. It contains no blood vessels and has an outer smooth surface formed by mesothelial-like cells that abut similar cells in the dura mater. The mesothelium-like surfaces of the dura and arachnoid oppose and slide over each other, analogous to the parietal and visceral surfaces of other serous membranes.

The pia mater is closely adherent to the surface of the brain and spinal cord and is penetrated by a large number of blood vessels that supply the underlying nervous tissue (Fig. 14-15 ). The pia mater consists of flat, thin, overlapping connective tissue cells (fibroblasts) that are separated from the underlying neural tissue by variable amounts of loose collagen fibers and the glia limitans. In many areas the pia, which lacks a basal lamina, is only one-cell-layer thick and has fenestrations, so that the glia limitans is exposed directly to the subarachnoid space. Pial and arachnoid cells also ensheathe blood vessels, collagen bundles, and nerves that are within or cross the subarachnoid space and also are around arteries that penetrate into the CNS up to 1 to 2 mm in depth. Macrophages including dendritic cells also are present throughout the leptomeninges.

Figure 14-15 — Histologic Section of Spinal Cord and Meninges.

A, Low magnification of a cross-section of the spinal cord and meninges with spinal nerve rootlets and a dorsal root ganglion from which B was selected *(box)*. H&E stain. B, The inner surface of the dura mater and the outer surface of the arachnoid mater are covered with mesothelial cells, and the space between them is the subdural space. Blood vessels and nerves of the dorsal and ventral roots traverse in the subarachnoid space. H&E stain.

(Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Endothelium.

The basic functions of endothelium in the CNS are to line luminal surfaces of blood vessels; form the blood-brain barrier; regulate thrombosis, thrombolysis, and platelet adherence; and maintain a nonthrombogenic boundary between coagulation cascade molecules and luminal surfaces of endothelial cells. Additionally, endothelial cells function as regulatory barriers to small and large molecules crossing the endothelium, and they control the adherence of leukocytes to their luminal surfaces. The endothelial cells of the blood-brain barrier actively transport those molecules that the brain consumes rapidly and in large quantities such as glucose, amino acids, lactate, and ribonucleosides.

Dysfunction/Responses to Injury

Ground Rules for Understanding Injury in the Central Nervous System

Before the responses of the CNS to injury are discussed, some fundamental concepts are reviewed in Box 14-2 .

Box 14-2. Concepts in Understanding Responses of the Central Nervous System to Injury.

The cells of the CNS vary in their susceptibility to injury (neurons > oligodendroglia > astrocytes > microglia > blood vessels). Neurons are the most sensitive to injury, whereas glial and other cells are more resistant to injury.

1.
Neurons have only small energy stores; therefore they depend on an intact blood flow to supply oxygen and nutrients, particularly glucose. Neurons with the highest metabolic rate, such as some neurons in the cerebral cortex, will die 6 to 10 minutes after the cessation of blood flow after cardiac arrest.
2.
There is no regeneration of neurons. The neurons you have now are the ones you were born with; however, their metabolism is dynamic, and metabolites are continually turned over and replaced.
3.
If nerve fibers in the CNS are cut by transection of the cord, no or little regeneration of nerve fibers results. Therefore if sufficient motor nerve fibers are cut, there is paralysis; if not, there is a neurologic deficit.
4.
If fibers in the PNS are cut, they can regenerate under certain circumstances. This outcome depends on axoplasmic flow, alignment of the proximal and distal portions of the nerve, and the preservation and alignment of the proximal and distal portions of the endoneurial tube (the structure in which the axon lies).
5.
Healing in the CNS is different than in the rest of the body. There are few fibroblasts in the CNS, and they are principally found only in the leptomeninges and in the outer few millimeters of the CNS, where they are pulled into the cerebral cortex with blood vessels. Therefore wounds deep in the CNS heal by proliferation of astrocyte processes. Astrocytic processes fill small dead spaces of less than a few millimeters and encapsulate large dead spaces and abscesses. Superficial wounds or wounds that extend through the leptomeninges heal by synthesis and deposition of collagen by fibroblasts (fibrous connective tissue) and by proliferation of astrocytic processes. However, in contrast to the fibroblast, astrocytic processes produce a very poor capsule, which can break down easily.
6.
The cranial cavity is nearly filled by the brain, its coverings, and fluids. Therefore many lesions, such as tumors, abscesses, hemorrhages, and hydrocephalus in the brain, produce clinical signs because they are space-occupying lesions, which in neuropathology implies that they cause atrophy or displacement of portions of the brain or cord, depending on the duration of the injury.
7.
The blood-brain barrier can exert control over drugs and antibodies and prevent them from entering the intact brain. It is also a barrier to infection and is formed by the tight junctions of the endothelial cells, aided by basement membrane, and the end feet of the astrocytes, which lie on the outside of the capillary.
8.
Although the CNS has the ability to resist infection and injury, once the CNS is infected, it has a low degree of resistance when compared with other tissues of the body. Microbes, such as Cryptococcus neoformans, which normally would be relatively nonpathogenic in other organs, may produce death if the CNS is infected. This outcome in part is attributable to the complexity of the CNS and the fact that it is the most vital organ in the body. Any disease process will often cause catastrophic results in the CNS, as opposed to tissues such as the lung, liver, and kidney.

CNS, Central nervous system; PNS, peripheral nervous system.