Nervous System

CHAPTER 14


Nervous System*





Central Nervous System (CNS)



Structure and Function


The CNS consists of neurons, glia, ependyma, endothelial cells and pericytes of blood vessels, and the meninges (Fig. 14-1 and Box 14-1). Neurons vary in size, shape, and function, and their cell bodies are organized into functional groups such as nuclei, gray columns, 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 about 1 × 1015 synapses in the human brain.




Exactly which cells are classified as glia has varied over the last few decades. Originally, histologists included astrocytes (astroglia), oligodendrocytes (oligodendroglia), ependymal cells (ependymocytes), and microglia as glial cells; however, they currently recognize astrocytes, oligodendrocytes, and microglia as glial cells. Some classification schemes list astrocytes and oligodendrocytes as macroglia. Astrocytes, oligodendrocytes, and ependymal cells are derived from neuroectoderm; whereas microglia, part of the monocyte-macrophage system, are derived from mesoderm (bone marrow). 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.


The CNS is arranged to form two basic parts: the gray and white matter (Figs. 14-2 and 14-3). In the CNS, gray matter is found in the cerebral cortex, in the cerebellar cortex and cerebellar roof 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.




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Fig. 14-3 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). DGH, Dorsal gray horn; VGH, ventral gray horn. 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. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)


The exterior of the CNS is covered by the meninges. The meninges consist of three layers named, from outermost to inner most layers, the dura mater, arachnoid, and pia mater. The arachnoid and pia enclose the subarachnoid space.



Cells of the CNS



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, tend to be 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.




Axonal Transport: In most cells of the body, proteins and other molecules are distributed throughout the cell by simple diffusion. In neurons, simple diffusion alone is inefficient because synapses are a considerable distance away from the cell body of the neuron. As a result, molecules cannot diffuse the length of the axon; they must be transported the length of the axon to the synapse. In addition, there are no systems in axons or synapses to catabolize molecules resulting from normal metabolic processes in these structures. Thus these molecules need to be returned to the cell body for processing. These processes are facilitated in the axon by retrograde (toward the cell body) and anterograde (toward the synapse) axonal transport systems.




As a result of these 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 their degradation products back to the cell body (Web Fig. 14-1). 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 to the distal limb and to 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 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 peripheral nervous system (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, that 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 results 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 (Web Fig. 14-2). 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 humans and will likely be discovered in animals.


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).


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 Fig. 14-6. Mature astrocytes differentiate from pluripotential 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 morphology. 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, metallic 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). These morphologic features and their corresponding histochemical and immunohistochemical staining reactions serve as important criteria for the classification of tumors of astrocyte origin.






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. 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 development but also in repair of the CNS.



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.




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.



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 morphology 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.



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Fig. 14-10 Responses of glial cells to injury in H&E stained 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 (Fig. 14-10, B). H&E stain. B, Gray matter. When neurons are injured or there exists some perturbation of the perineuronal microenvironment, a long-held belief was that oligodendroglia around neurons hypertrophy and proliferate in a process referred to as satellitosis. Currently, there is no uniform agreement that these cells respond to neuronal injury in this manner. 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.



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 cells bodies are injured, perineuronal satellite oligodendroglia, in an attempt to regulate the environmental perturbation, hypertrophy and proliferate in a process referred to as satellitosis. Similarly, alterations in the microenvironment of gray and white matter away from areas surrounding neuron cell bodies results in hypertrophy of oligodendroglia (see Fig. 14-10). Finally, satellitosis can be quite prominent in normal CNS in various areas of the gray matter.



Microglia: The basic functions of microglia are immunosurveillance, immunoregulation, and reparative (phagocytic) activities after neural cell injury and death. The origin of microglia in the CNS has been debated for years. The current consensus is that the cells originate from circulating monocytes (mesoderm-derived) that enter and populate the CNS during embryonic development and early postnatal life, analogous to the formation of the monocyte-macrophage system in other organs. After entry into the CNS, the cells become amoeboid microglia, 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 a few 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 organisms. They 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 move cerebrospinal fluid (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 occludentes) 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.



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 humans), 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 brain. 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 humans, 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 [pachymeninges]), the arachnoid membrane (mater), 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. There is also limited evidence based on studies in humans with neuro–acquired immunodeficiency syndrome that the brain has a primitive lymphatic system. 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 (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.


Sep 17, 2016 | Posted by in GENERAL | Comments Off on Nervous System
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