Nervous Introduction PDF

CHAPTER 13 Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System 891 Thymus See the section on Lymphoid/Lymphatic System, Diseases Affecting Multiple Species of Domestic Animals, Thymus. * * Figure 13.93 Alimentary Lymphoma, Stomach, Cat. The stomach mucosa is markedly thickened by the neoplastic cells (gray-white areas in the right half of the image); focal ulcers are also noted (asterisks). (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) Mucosa-Associated Lymphoid Tissue (MALT) See the section on Lymphoid/Lymphatic System, Diseases Affecting Multiple Species of Domestic Animals, Mucosa-Associated Lymphoid Tissue (MALT) and Table 13.5. Hemal Nodes No disorders have been reported that specifically affect hemal nodes. See the sections on Lymphoid/Lymphatic System, Diseases Affecting Multiple Species of Domestic Animals, Lymph Nodes, and on Lymphoid/Lymphatic System, Diseases of Cats, Lymph Nodes. 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Valli VE: Veterinary comparative hematopathology, Ames, 2007, Blackwell Publishing. 891.e1 891.e2 SECTION II Pathology of Organ Systems Valli VE, Jacobs RM, Parodi AL, et al.: Histologic classification of hematopoietic tumors of domestic animals. In World Health Organization international histological classification of tumors in domestic animals, second series, Washington, DC, 2002, Armed Forces Institute of Pathology. Valli VE, Kass PH, Myint MS, et al.: Canine lymphomas: association of classification type, disease stage, tumor subtype, mitotic rate, and treatment with survival, Vet Pathol 50:738–748, 2013. Valli VE, Myint MS, Barthel A, et al.: Classification of canine malignant lymphomas according to the World Health Organization criteria, Vet Pathol 48:198–211, 2011. Valli VE, Vernau W, De Lorimier LP, et al.: Canine indolent nodular lymphoma, Vet Pathol 43:241–256, 2006. 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Porter Key Readings Index Central Nervous System (CNS), 893 Structure and Function, 893 Dysfunction/Responses to Injury, 902 Portals of Entry/Pathways of Spread, 914 Defense Mechanisms/Barrier Systems, 915 Diseases Affecting Multiple Species of Domestic Animals, 916 Diseases of Horses, 960 Diseases of Ruminants (Cattle, Sheep, and Goats), 966 Diseases of Pigs, 975 Diseases of Dogs, 975 Diseases of Cats, 982 Peripheral Nervous System (PNS), 983 Structure and Function, 983 Dysfunction/Responses to Injury, 985 Responses of the Axon to Injury, 985 Portals of Entry/Pathways of Spread, 985 The Nervous System The nervous system consists of the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS is made up of the brain, spinal cord, olfactory and optic cranial nerves, and proximal segments of cranial and spinal nerve roots. The PNS is divided into sensorimotor, autonomic, and enteric divisions, with each division having specific functions that will be discussed later in this chapter. The nervous system functions to initiate, interpret, coordinate, monitor, and modulate a wide array of physiologic activities in all of the organ systems (i.e., establish and maintain physiologic homeostasisb). Additionally, the nervous system monitors, interprets, and responds to environmental stimuli that directly or indirectly affect these organ systems. Development of the 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 structures of the CNS and the PNS 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. The development and maturation of the brain and spinal cord proceed through a aFor a glossary of abbreviations and terms used in this chapter, see E-Glossary 14.1. bA condition of “normalcy” in which the concentrations of ions, metabolites, gases, and other molecules are maintained in blood plasma within a stable “predetermined” range and thus cellular function is normal. 892 Defense Mechanisms/Barrier Systems, 985 Diseases Affecting Multiple Species of Domestic Animals, 985 Diseases of Horses, 989 Diseases of Ruminants (Cattle, Sheep, and Goats), 991 Diseases of Pigs, 991 Diseases of Dogs, 991 Diseases of Cats, 991 series of coordinated steps characterized by cellular proliferation and subsequent remodeling (e.g., apoptosis) to produce the final morphologic features of the adult brain and spinal cord. 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 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 and 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 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 gives rise to individual spinal nerves. After the development and differentiation of the brain into the five segments listed earlier, there is differential growth (i.e., it occurs at different extents, rates, and times) in each of these parts of the developing brain. For example, the brainstem 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. CHAPTER 14 Nervous System 892.e1 E-Glossary 14.1 Glossary of Abbreviations and Terms Astrocytosis Axonopathy, distal, of the CNS and PNS Axonopathy, distal, of the PNS Axonotmesis Blood-brain barrier of the CNS Blood-CSF (cerebrospinal fluid) barrier of the CNS Blood-nerve barrier Brain edema Brain swelling Büngner, cell bands of CAE CCD Increased size and number of astrocytes, generally accompanied by and used synonymously with astrogliosis Degeneration of axons involving distal portions of peripheral nerves and distal portions of long axons in the central nervous system (spinal cord) A neuropathy with degeneration of the terminal and preterminal axon of peripheral nerves 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 A barrier to free movement of certain substances from cerebral capillaries into central nervous system (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. 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 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. 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. 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 A column of proliferating Schwann cells that forms within the space previously occupied by an axon after Wallerian degeneration. The proliferating column of cells is surrounded by the persisting basement membrane of the original Schwann cells. Caprine arthritis encephalitis Canine cognitive dysfunction Central chromatolysis CNS Cranium bifidum CSF Demyelination Dysraphism Encephalitis EncephaloEncephalopathy Ganglionitis Gemistocyte Gitter cell H&E stain Hydranencephaly 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. Central nervous system A dorsal midline cranial defect through which meninges alone or meninges and brain tissue may protrude into a sac (-cele) covered by skin Cerebrospinal fluid 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. 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. Inflammation of the brain A combining form that refers to the brain A disease process of the brain Inflammation of peripheral (sensory or autonomic or both) ganglia Reactive, hypertrophied astrocyte that develops in response to injury of the central nervous system. 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. Macrophage that accumulates in areas of necrosis of central nervous system (CNS) tissue. The cytoplasm is typically distended, with abundant lipidcontaining material derived from the lipidrich nervous tissue. Gitter cell nuclei are often displaced peripherally to the cell membrane. These cells are often referred to as “foamy” macrophages. Hematoxylin and eosin stain A large, fluid-filled cavity in the area normally occupied by central nervous system (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. (Continued) 892.e2 SECTION II Pathology of Organ Systems E-Glossary 14.1 Glossary of Abbreviations and Terms—cont’d Hydrocephalus Joest-Degen bodies LeukoLeukoencephalitis Macroglia Malacia MeningoMeningomyelocele Microglia Motor neuron, lower Motor neuron, upper MVV Myelitis MyeloMyelopathy Myeloschisis Nageotte nodule Neuroglial cells Neuronophagia Neuropil Neurotmesis Neurapraxia Accumulation of excess cerebrospinal fluid (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. Intranuclear inclusion bodies (rarely intracytoplasmic) found in neurons in the brains of animals with Borna disease Combining form referring to white matter of the brain or spinal cord Inflammation of the white matter of the brain A collective term referring to astrocytes and oligodendrocytes. It has also been variously used to refer solely to astrocytes or to astrocytes, oligodendrocytes, and ependymal cells of the central nervous system (CNS) and Müller cells of the retina. Grossly detectable (macroscopic lesion) softening of central nervous system (CNS) tissue, usually the result of necrosis Combining form referring to meninges 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 Resident macrophages of the central nervous system (CNS) that arise from mesodermal stem cells of the yolk sac Large multipolar neurons in the brainstem and ventral horns of the spinal cord with axons extending into the peripheral nervous system (PNS) Motor neurons with axons residing solely in the central nervous system (CNS) that control lower motor neurons Maedi-visna virus Inflammation of the spinal cord Combining form referring to spinal cord A disease process of the spinal cord Similar to spina bifida, except in its severe form it is characterized by complete failure of the spinal neural tube to close and therefore a lack of development of the entire dorsal vertebral column An aggregate of proliferating satellite cells associated with a degenerating ganglionic neuronal cell body Astrocytes, oligodendrocytes, ependymal cells, and microglia of the central nervous system (CNS) Accumulation of microglia around a dead neuron The gray matter feltwork that consists of intermingled and interconnected processes of neurons (axons and dendrites) and their synaptic junctions, plus processes of oligodendrocytes, astrocytes, and microglia Complete transection of a nerve and supporting framework with little potential for normal reinnervation Traumatic injury to a peripheral nerve with temporary conduction block but with no permanent axonal damage Onion bulb PNS Polio Polioencephalomalacia Polioencephalomyelitis Poliomyelomalacia Porencephaly Radiculoneuritis (polyradiculoneuritis) Rarefaction Satellite cells Satellitosis Sclerosis Spina bifida Status spongiosus Syringomyelia Wallerian degeneration Concentric arrays of Schwann cell cytoplasm around an axon signifying multiple episodes of demyelination and remyelination Peripheral nervous system Combining form referring to gray matter of the central nervous system (CNS) Softening (usually the result of necrosis) of the gray matter of the brain Inflammation of the gray matter of the brain and spinal cord Softening (usually the result of necrosis) of the gray matter of the spinal cord A cleft or cyst-like defect in the cerebral hemisphere that communicates with the subarachnoid space and also may communicate with the ventricular system. The defect may contain cerebrospinal fluid (CSF) Inflammation of a spinal nerve rootlet (or rootlets) Reduction in density of central nervous system (CNS) tissue resulting from edema and/or necrosis Glial cells that cover the surface of nerve cell bodies in sensorimotor, autonomic, and enteric ganglia An accumulation of oligodendrocytes around neuronal cell bodies. Although this feature can be seen in normal brains, some consider that it may also be associated with neuronal injury Literally means induration or hardening and, when used in describing lesions of the central nervous system (CNS), often refers to induration or hardening of the brain or spinal cord resulting from astrocytosis (astrocytic scar formation) 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). An encompassing term meaning the presence of small, focal, ovoid to round, clear (unstained or poorly stained) spaces in the central nervous system (CNS). The lesion can result from 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. The presence of a tubular cavitation (syrinx) in the spinal cord that is not lined by ependyma and may extend over several segments Degeneration of the distal component of an injured (compressed or severed) axon. Although the term originally referred to injury of axons in the peripheral nervous system (PNS), current usage also includes the central nervous system (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. Neural plate transition zone Neural plate Ectoderm Mesoderm Notocord Convergence of neural plate transition zones Neural crest Concave invagination of neural plate Convergence of neural plate transition zones Neural crest Ectoderm (pre-epidermis) Convergence of neural plate transition zones Eventual spinal ganglion Early neural tube Epidermis (skin) Spinal ganglion Somite (muscle and bone precursors) Neural tube Epidermis (skin) Neurocele Spinal ganglion (eventual PNS) Somite (muscle and bone precursors) Neural tube (eventual CNS) 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.) 892.e4 SECTION II Pathology of Organ Systems E-Box 14.1 Embryologic Development and Maturation of the Neural Tube Neural tube Prosencephalon (forebrain) Mesencephalon (midbrain) Rhombencephalon (hindbrain) Spinal cord Telencephalon Diencephalon Mesencephalon Metencephalon Myelencephalon Spinal cord Paired cerebral hemispheres Thalamus and related structures Corpora quadrigemina (superior and inferior colliculi) Cerebral peduncles Pons and cerebellum Medulla oblongata Cervical, thoracic, lumbar, and sacral spinal nerve levels Cranial Forebrain Neural tube Midbrain Telencephalon Cerebrum Diencephalon Cerebellum Mesencephalon Hindbrain Brainstem Metencephalon Myelencephalon Spinal cord Early development Spinal cord Lateral view Later development Caudal A Segmentation of the CNS during embryologic development Cranial Lateral ventricles Neural tube See Fig. 14.2, A for detail 3rd ventricle Mesencephalic aqueduct 3rd ventricle Lateral ventricle 4th ventricle 4th ventricle Neurocele Central canal Mesencephalic aqueduct Early development Later development Central canal Lateral view Caudal B Segmentation of the ventricular system during embryologic development 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.) CHAPTER 14 Nervous System 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. 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 cerebral lobes, 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 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 are the origin of the majority of cells that populate the PNS, such as neurons and Schwann cells. 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. It involves at least 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). In 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. 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. Central Nervous System The central nervous system (CNS) is arranged to form two basic parts: the gray and white matter (Figs. 14.1 and 14.2). 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 nuclei. It consists of numerous neuronal cell bodies and a feltwork of intermingled thinly myelinated axons and dendrites, their synaptic junctions, and processes of oligodendrocytes, astrocytes, and microglia. This network of processes and synapses in the gray matter is referred to as the neuropil. 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 and oligodendrocytes, 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. 893 As noted earlier, a variety of differing cell types populate the brain and spinal cord during development of the CNS, 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. 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, the dura mater, arachnoid, and pia mater. The arachnoid and pia enclose the subarachnoid space. Structure and Function 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. 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 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. Neurons are highly active cells and consume about 20% of an animal’s total requirement for energy. They have very limited quantities of “stored” cytosolic glycogen and thus are highly dependent on a homeostatic supply of oxygen and glucose via the arterial vasculature for oxidative phosphorylation in neuronal mitochondria and the production of adenosine triphosphate (ATP) (see Chapter 1, Mechanisms and Morphology of Cellular Injury, Adaptation, and Death). 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. More information on this topic is available at www.expertconsult. com. 893.e1 CHAPTER 14 Nervous System Because of structural differences between neurons and other cells of the body (i.e., neurons have axons of varying length), 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. 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 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 reuse and degradation in lysosomes. 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 the major cytoskeletal proteins, such as microtubule and neurofilament proteins, which are necessary to maintain the structural integrity and transport systems within the axon. Disorders 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. Neuron cell body Neurotransmitter 1 2 Nucleus 6 Golgi rER Presynaptic membrane Axon 3 5 Neurotransmitter vesicle Microtubule 4 Kinesin Dynein 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). Axons, particularly of motor neurons, can be several meters in length; thus vesicles and proteins are transported over long distances and their movement has the potential to be disrupted along the course of the axon by direct or indirect injury to the axon. 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 (CNS). Note: Axons can be longer than a meter in length, especially in an animal such as a giraffe. (Courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University; and Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) 894 SECTION II Pathology of Organ Systems A n n B D C E 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 oligodendrocytes (arrowheads), astrocytes, and microglia. Hematoxylin and eosin (H&E) stain. C, White matter primarily consists of well-myelinated axons (arrows), oligodendrocytes (arrowheads), and astrocytes. The clear space surrounding large axons is an artifact 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). Diaminobenzidine immunohistochemistry (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.) CHAPTER 14 Nervous System Left Right dgh B vgh More information on this topic is available at www.expertconsult. com. C v Astrocytes A B 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 a 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. d l 895 C f D 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 large neurons (arrows) are lower motor neurons, and their axons extend in peripheral nerves to myoneural junctions that innervate skeletal muscle. Hematoxylin and eosin (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 during the preparation of paraffin-embedded sections, resulting in artifactual clear spaces. 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 functions of astrocytes in the CNS are regulation, repair, and support, as depicted in Fig. 14.6. All regions of the CNS contain astrocytes, and they are derived from pluripotential neuroepithelial progenitor cells during CNS development. 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, and 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 (IHC) 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 IHC marker for neoplasms of astrocyte origin and can also be used to qualitatively or quantitatively characterize disorders in which astrocytes are proliferative or reactive. Nevertheless, 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. 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 after 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 CHAPTER 14 Nervous System 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 a 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. These differences in sodium and potassium ion concentrations 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 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 are called channelopathies, and many of these disorders have been recognized in people, including epilepsy, spinocerebellar ataxia, and paroxysmal extreme pain disorder. Channelopathies are also starting to be discovered in animals, and examples include the retinal disorder achromatopsia in dogs and the skeletal muscle disorder myotonia congenita in goats, horses, dogs, and cats. 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 cardiac 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 895.e1 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 whether 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 through 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. The action potential, however, 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. 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). The axon can be a very long extension of the neuron cell body (e.g., extending 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 some diseases, such as tetanus and 895.e2 SECTION II Pathology of Organ Systems 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 on the membrane of postsynaptic neurons: ionotropic and metabotropic. 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. Presynaptic neuron Postsynaptic neuron Axon terminal Synapse Cell membrane Myelinating cell Cell body Dendrite Myelin lamella Axon Nissl substance An axon can be over a meter in length. Axon hillock Axon terminal Nucleus Direction of spread for an action potential Synapse tential Action Po Action potential Dendrite Axon terminal Postsynaptic membrane Neurotransmitter vesicle Neurotransmitter receptor Presynaptic membrane A Resting state of charge on neuron cell membrane Neurotransmitter + + + + + + + + + - - - - - - - - Na ion concentration is higher outside the cell + + + + + + + + + + + - - - - - - - - - - - K+ ion concentration is higher inside the cell Axon terminal Dendrite Axoplasm - inside of neuron + + + + Synapse - - - - - - - - - + + + + + + + + + - - - - - - + + + + + + Interstitium - outside of neuron Sodium (Na+) ions Potassium (K+) ions Na+/K+ ion pump K+ channel Na+ channel Ion pumps Ion channels are unidirectional are unidirectional B 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. Continued 895.e4 SECTION II Pathology of Organ Systems Resting - normal structure Step 1 Cell membrane Axon terminal Axon terminal Synapse K+ channel (closed) Dendrite Na+ channel (closed) Neurotransmitter vesicle Neurotransmitter receptor Neurotransmitter Action potential Step 2 Na+ ion Step 3 K+ ion Axoplasm (inside of neuron) + + + - - - - - - - - - - + + + + + + + Action potential Step 4 Na+ ion K+ ion C - - - - + + + + - - - + + + + - - - - + + + Refractory status Action potential (Repolarization) (Depolarization) Resting Na+/K+ ion pump - + Na+ channel (open) Interior charge Exterior charge K+ channel (open) Step 1: The action potential facilitates the movement of the neurotransmitter vesicle to membrane of the axon terminal followed by the opening of the vesicle and release of the transmitter into the synapse. Step 2: The fusion of the transmitter with the receptor initiates a second messenger response that causes the opening of nearby Na+ ion channels. Step 3: Na+ ions rapidly enter the cell and depolarize the cell membrane thereby reversing its polarity. Additionally, K+ ion channels open and then K+ ions leave the cell. The reversal of membrane polarity causes adjacent Na+ and K+ ion channels to open. This process of membrane depolarization rapidly moves the action potential down the length of the axon to its axon terminals. Step 4: Depolarized cell membrane rapidly becomes hyperpolarized and then refractory to further depolarization. Na+/K+ ion pumps return the membrane polarity to normal and the membrane charge to resting status. E-Figure 14.4, cont’d 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.) 896 SECTION II Pathology of Organ Systems Dendrites Nucleus Nissl substance Cell body Neuron Axon Oligodendrocyte Foot processes Axon terminal Astrocyte Capillary Synaptic end bulbs Endothelial cells Cilia Microglia Brush border Ependymal cells Choroid plexus cells Figure 14.3 Cell Types in the Central Nervous System Include Neurons, Astrocytes, Oligodendrocytes, 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 CNS and Their Primary Functions NEURONS Transmission of electric and chemical impulses Spatial and temporal interpretation of impulses Inhibitory and stimulatory regulation of impulses ASTROCYTES (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 OLIGODENDROCYTES Myelination of axons within the CNS Proposed neuronal cell body homeostasis within the CNS CNS, Central nervous system; CSF, cerebrospinal fluid. 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 CHAPTER 14 Nervous System Dendrite Lysosome 897 Mitochondrion Microtubules/ microfilaments Nucleolus Myelin sheath Nucleus Axon hillock rER (Nissl substance) Golgi Neuron cell body Lipofuscin A Figure 14.5 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 compared with Purkinje neurons (arrows) and large motor neurons (depicted in Fig. 14.4, B). Hematoxylin and eosin (H&E) stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) and therefore exist in the CNS as fluid-filled spaces (cysts) surrounded by a capsule of astrocytic processes. Astrocytes will 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. B 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. B, The cytoplasm of the neuronal cell body has blue (basophilic) granular material called Nissl substance (arrows), which is composed of rough endoplasmic reticulum. Nissl substance synthesizes proteins, including precursor neurotransmitter proteins and the structural proteins (neurofilaments) that are active in maintaining the integrity (length and diameter) of the axon. Hematoxylin and eosin (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.) 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 the way that fibroblasts do. 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 astrocytosis or 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 by processes of astrocytes. Larger spaces that form after injury, such as an infarct, are often too large to be filled Structural Support of the CNS. 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 oligodendrocytes: (1) interfascicular oligodendrocytes and (2) satellite or perineuronal oligodendrocytes. The function of interfascicular oligodendrocytes is myelination of axons, whereas the function of satellite oligodendrocytes is thought to be regulation of the perineuronal microenvironment. Oligodendrocytes have been compared with neurons with regard to their total cell size in that their processes occupy much more space than the cell body, but whereas neurons have very long axons, oligodendrocytes have extensive myelin sheaths. In H&E-stained sections, oligodendrocytes are often confused with lymphocytes because of the similarity of their nuclei and cytoplasmic volume. Interfascicular oligodendrocytes and satellite oligodendrocytes are located primarily in the white and gray matter, respectively (Fig. 14.10); however, interfascicular oligodendrocytes can also be found along axons that traverse the gray matter. The mature, small oligodendrocyte has a spherical, hyperchromatic 898 SECTION II Pathology of Organ Systems 4 2 3 1 5 7 6 8 Figure 14.6 Functions of Astrocytes. Astrocytes provide structural integrity and regulatory oversight, as depicted in this diagram. They (1) monitor and regulate fluid and electrolyte balances within neurons and surrounding extracellular space; (2) form the glia limitans at the base of the pia mater; (3) interconnect with other astrocytes to provide a system to monitor and regulate fluid and electrolyte balances; (4) participate in the formation and functions of the blood-brain barrier; (5) participate in the support of axon tracts of functionally related neurons; (6) monitor for and remove excessive neurotransmitters at synapses; (7) protect and insulate nodes of Ranvier; and (8) participate in the cerebrospinal fluid–brain barrier. In addition, astrocytes are a reparative (healing) cell after central nervous system (CNS) injury with loss of tissue because nervous tissue is relatively devoid of fibroblasts. Fibroblasts exist in the meninges and around blood vessels. Everywhere else, healing depends on the astrocyte, which responds by increased length, branching, and complexity of cellular processes (astrocytosis). The astrocyte has many functions in the nervous system; one of them is to act in healing to produce a scar in attempts to isolate cavities and abscesses. Fibroblasts may also contribute to the formation of a scar, if this cell type is present, as it is in the leptomeninges. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) a bv a bv a 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. Identifying specific types of glial cells in hematoxylin and eosin (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 neuroparenchyma. The majority of nuclei in the neuropil here are astrocytic. Oligodendrocytes (arrowheads) have smaller and dense round nuclei (condensed chromatin) often surrounded by a clear zone indicative of cell cytoplasm and a cell membrane. Oligodendrocytes in gray matter are called satellite cells, and those in white matter are called interfascicular oligodendrocytes. Microglia can be difficult to identify in H&E-stained sections but are often identified by their small, dense elongated nuclei (dashed arrow). The light pink homogeneous tissue between these cell types is the neuropil. H&E stain. bv, Blood vessels. (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 (CNS) (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.) nucleus (see Figs. 14.7 and 14.10). As with astrocytes, the cell body and processes do not stain with conventional H&E staining and can only be demonstrated with special procedures involving metallic (silver) impregnation or immunohistochemistry. Most interfascicular oligodendrocytes are aligned in rows parallel to myelinated axons (see Fig. 14.10) and are responsible for the formation and maintenance of segments (internodes) of myelin sheaths. One oligodendrocyte 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 oligodendrocytes, such as that occurring in infectious canine distemper virus (CDV) infection, can cause CHAPTER 14 Nervous System A a n B d i C 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). Hematoxylin and eosin (H&E) stain. Also see Fig. 14.40. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) primary demyelination of these segments, resulting in severe neurologic dysfunction. Oligodendrocytes also influence the maturation and maintenance of axons and inhibit regeneration of established myelinated axons. Satellite oligodendrocytes are adjacent to neuronal cell bodies and are also located around blood vessels in the gray matter (see Fig. 14.10). They are believed to regulate the perineuronal microenvironment. When neuron cell bodies are injured, satellite oligodendrocytes hypertrophy and possibly proliferate (along with microglia and astrocytes), a process referred to as satellitosis (see Fig. 14.10). Microglia 899 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. Microscopically, microglia have small, hyperchromatic ovoid-, rod-, or comma-shaped nuclei and no appreciable cytoplasm with routine H&E staining (see Fig. 14.7). With special labeling techniques or metallic impregnation, microglia have delicate branching D Figure 14.10 Responses of Glial Cells to Injury in Hematoxylin and Eosin (H&E)-Stained Central Nervous System (CNS) Sections. A, White matter. In nondiseased states, oligodendrocytes in white matter are often arranged linearly (interfascicular oligodendrocytes) (arrow) and are responsible for the formation of myelin around axons. In gray matter, oligodendrocytes are dispersed as individual cells around neuronal cell bodies as satellite cells (B). H&E stain. B, Gray matter. When neurons are injured or there exists some perturbation of the perineuronal microenvironment, oligodendrocytes around neurons (n) can hypertrophy and proliferate in a process referred to as satellitosis. Satellite oligodendrocytes (arrows) surround a small degenerate neuron with condensed chromatin and little cytoplasm. H&E stain. C, White matter. Astrocytes (arrows) and oligodendrocytes (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 developing enlarged, markedly vesicular nuclei called Alzheimer’s type II astrocytes (arrows). H&E stain. (A courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee. B and D courtesy Dr. A.D. Miller, College of Veterinary Medicine, Cornell University. C courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) processes. The small hyperchromatic nuclei and nuclear shape distinguish microglia from astrocytes and oligodendrocytes; however, microglia are often difficult to identify in H&E-stained sections. Activated microglia 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 disorders. These macrophages differentiate from blood monocytes involved in normal “leukocytic trafficking” through the CNS and are involved in immunologic and phagocytic responses (gitter cells) to disease processes. 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 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. 900 SECTION II Pathology of Organ Systems Internode Node of Ranvier Oligodendrocyte A Myelin sheath Cytoplasm of the oligodendrocyte A Axon B 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. Hematoxylin and eosin (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.) B Figure 14.11 Central Nervous System (CNS) Myelin. Oligodendrocytes 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.) The choroid plexus and other structures, referred to as circumventricular organs, 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 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. It regulates several processes that involve interaction between the CSF and brain, including regulation of fluid homeostasis between the ventricular system 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. 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. The choroid plexuses that project into the lateral, third, and fourth ventricles are composed of epithelial cells, capillaries, connective tissue, and the pia mater. The basic function of choroid plexuses is to produce the CSF that fills the ventricular system and the subarachnoid space. The choroid plexus epithelium is a singlelayered, cuboidal to columnar epithelium with a microvillus border that secretes CSF (see Fig. 14.12). Fluid from other sources, such as secretion by the ependyma, interstitial fluid of the brain, and ultrafiltrate of the blood, also contributes to the formation of CSF. 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 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 CHAPTER 14 Nervous System 901 Calvaria Dural periosteum Extradural space Dura mater with dural collagen Dural border cells Interface layer Arachnoid barrier cells Arachnoid trabecula Subarachnoid space Pia mater Basic meninges Dura mater Arachnoid Pia mater Cerebral cortex Glia limitans Astrocytes Blood-brain barrier Foot process of astrocyte Basement membrane 1 Foot process of astrocyte Blood vessel Endothelial cells 2 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 enclose the subarachnoid space, which contains arteries, veins, and nerves and is filled with cerebrospinal fluid. The pia mater is attached to the surface of the brain and spinal cord. Astrocytes and their foot processes underlie the pia mater, forming 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.) ventricle, the CSF exits through the two lateral apertures to enter the subarachnoid space. Lateral apertures are the two openings in the caudal medullary velum that form 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. Other routes of CSF drainage exist, including the cribriform plate, cranial and spinal nerve sheaths, and the adventitia of cerebral arteries, all of which allow for drainage of CSF into the lymphatic system. In human beings, the entire volume of CSF is circulated approximately four times a day. Meninges The meninges 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 piaarachnoid. 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, which contains CSF, 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. 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 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 like there is in the spinal cord. There can be a “potential” epidural or extradural space in mature animals from hemorrhage caused by trauma. 902 A SECTION II Pathology of Organ Systems B Figure 14.14 Layers of the Meninges. A, Brain, dog. The dura mater 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, 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 on the exposed surface of the spinal cord but are not readily visible in this photograph. 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, allowing for direct exposure of the glia limitans 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 around arteries that penetrate into the CNS up to 1 to 2 mm. Macrophages are also present in the leptomeninges. Endothelium The basic functions of CNS endothelium are to form the bloodbrain barrier, maintain a nonthrombogenic boundary between coagulation cascade molecules and luminal surfaces of endothelial cells, regulate hemostasis, and participate in the inflammatory response. The endothelial cells of the blood-brain barrier actively transport the molecules that the brain consumes rapidly and in large quantities, such as glucose, amino acids, lactate, and ribonucleosides. Vasculature of the CNS. The arterial vasculature transports and delivers its cellular- and plasma-based components between and among organ systems. The plasma-based components include ions (e.g., Na+2, K+), molecules (e.g., glucose), gases (e.g., oxygen), hormones (e.g., thyroxine), and other substances that play important roles in neuronal function and thus are maintained in plasma at predetermined concentrations (i.e., homeostasis). The pathogeneses of many disorders of the CNS, especially of the cerebrum, reflect (1) an alteration in plasma homeostasis or (2) the fact that the arterial vasculature is simply used as a direct conduit by infectious agents, toxins, and neoplastic cells to travel to the cerebrum and directly or indirectly affect neurons and their supporting cells. Examples of such disorders include thrombotic meningoencephalitis (see Fig. 14.91), cytotoxic cerebral edema (see Fig. 14.28), ischemic encephalopathy (see Fig. 14.111), and metastatic neoplasia (see Fig. 14.77). Neurons are highly active cells and consume about 20% of an animal’s total requirement for energy. They have very limited quantities of “stored” cytosolic glycogen and thus are highly dependent on a homeostatic supply of oxygen and glucose via the arterial vasculature for oxidative phosphorylation in neuronal mitochondria and the production of ATP (see Chapter 1, Mechanisms and Morphology of Cellular Injury, Adaptation, and Death). ATP, in part, is used to establish and maintain the processes involved in the generation of action potentials, ion and water concentrations (i.e., osmolarity) across cell membranes through ion pumps, and axonal transport. Many of the disorders of the CNS that are correlated with alterations in arterial blood supply and plasma homeostasis occur in the cerebrum. The cerebrum is supplied with arterial blood via the cranial (rostral), middle, and caudal cerebral arteries. The cerebral arteries arise from the cerebral arterial circle (formally known as the circle of Willis), which, in turn, arises from a “threefold” arterial blood supply formed by the internal carotid arteries (right and left) and the single basilar-vertebral artery. Arterial blood reaches the brain and the cerebral arterial circle through an extensive network of sequentially connected arteries arising from the aorta arch (see Chapter 2, Vascular Disorders and Thrombosis and Chapter 10, Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels). In general, the brachiocephalic arteries give rise to the common carotid arteries that ascend to the head, whereas the subclavian arteries give rise to the vertebral arteries; however, there is variation in the sequential connectivity of these arteries among species. Similar sequentially connected arterial blood supplies exist for the cerebellum and brainstem. Rete mirabile. A rete mirabile (pl. retia mirabilia) is a network of blood vessels that functions as a vascular “countercurrent exchanger” that acts to maintain (1) a homeostatic temperature in specific tissues or organ systems, (2) homeostatic concentrations of specific ions and gases, or (3) blood pressure in specific tissue areas or organs within normal homeostatic ranges. See Chapter 2, Vascular Disorders and Thrombosis for a detailed discussion (see E-Figs. 2.2 to 2.5). The most common and well-characterized retia, especially in cattle and bison, are the carotid retia mirabilia (or retia mirabilia cerebri). They are located in and around the right and left internal carotid arteries as they pass by the pituitary gland (see E-Fig. 2.6) along the cranial floor where they intermingle with large venous channels (cavernous sinuses) that lie on each side of the gland. This structural arrangement (i.e., bloodstreams flowing in opposite directions) enables large volumes of arterial blood to interact with venous blood to achieve the functional purpose of maintaining temperature homeostasis in the cerebrum (see E-Fig. 2.7). Dysfunction/Responses to Injury Concepts in Understanding Injury in the CNS Before the responses of the CNS to injury are discussed, some fundamental concepts are reviewed in Box 14.2.

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