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Histology_Ross. myofibrils. Other myofiber nuclei (MFN) can be seen at the periphery of the myofibers. Note that they exhibit a similar chromatin pattern as the three nuclei previously described. Also present in this micrograph is a capillary (C) coursing along the center of the micrograph. In this plane of section, it is difficult to clearly distinguish between the endothelial cell nuclei and nuclei of fibroblasts in the endomysium. Perhaps the most significant feature of a longitudinal section of a muscle fiber is the striations that they exhibit. The inset shows at higher magnification the banding pattern of the myofiber. The dark staining lines represent the A-band. The light staining area is the I-band which is bisected by the dark staining Z-line.


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Histology_Ross. micrograph. They correspond to the dot-like structures seen in the inset of the cross-sectioned myofibers above. Note that adjadcent myofibrils are aligned with one another with respect to their banding pattern and also that they exhibit different widths. Each myofibril is essentially a cylindrical structure much like a dowel, thus when sectioned in a longitudinal plane, the width of each myofibril will vary depending on what portion of the cylindrical structure has been cut. The sarcoplasmic reticulum, a membrane system that is present between myofibrils and the nature of the bands in a myofibril are shown to advantage in the next plate. • KEY C, capillaries E, endomysium ECN, endothelial cell nuclei FN, fibroblast nuclei MF, muscle fibers MFN, muscle fiber nuclei M, myofibers My, myofibrils MyN, myofiber nuclei N, nucleus


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Histology_Ross. The work effected by skeletal muscle to allow body movement is through tendons to which the muscle fibers are attached. The site of attach-ment between a muscle fiber and the collagen of the tendon is referred to as the myotendinal junction. The muscle fibers at the junctional site end in numerous fingerlike cytoplasmic projections. At the ends of each projection and between these projections, the collagen fibrils of the tendon attach to the cell at its basal lamina (see electron micrograph in adjacent plate). In the light microscope, these fingerlike projections appear to merge into the tendon. The detailed relationship is seen at the electron microscope level. The last sarcomeres in the muscle fiber end where the fingerlike projections begin. At this point, the ending sarcomere lacks its Z-line and the actin filaments from the A-band con-tinue into the cytoplasmic fingers ending at the sarcolemma.


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Histology_Ross. Myotendinal junction, monkey, H&E, ×365. collagenous bundles of the tendon. Several of the muscle fibers (MF’) are seen at the point where they terminate and are attached to the tendon This light micrograph reveals a tendon (T) and adjacent to it fibers. The area in the rectangle is seen in higher magnification in the mi-several muscle fibers (MF). The tendon contains dispersed crograph below. tendinocytes whose nuclei (N) are compressed between the Myotendinal junction, monkey, H&E, ×1,560. end of the muscle fiber are clearly seen. Between the fingerlike structures are the collagen fibers of the tendon. The nuclei of the tendinocytes (T) are seen The muscle fiber (MF) in this micrograph is seen at the point in the tendon where it continues from the muscle fiber.


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Histology_Ross. where it ends. Note the banding pattern of the muscle fiber. At this magnification, the fingerlike projections (arrows) at the • MYOTE N DI NAL J U NCTION KEY MF, muscle fibers MF’, terminating muscle fibers N, nuclei S, sarcomere T, tendon Tc, tendinocytes Myotendinal junction, monkey, electron micrograph, ×24,000. This electron micrograph shows the end of part of a muscle. Note that the last sarcomere (S) lacks a Z-line. The actin filaments appear to extend from the A-band and continue along the length of the finger projections and seemingly attach to the sarcolemma. Between the finger projec-tions are the collagen fibrils (arrows) that make up the tendon. (Micrograph courtesy of Dr. Douglas Kelly.)


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Histology_Ross. Cardiac muscle consists of fibers that possess the same arrangement of contractile filaments and thus the same cross-banding patterns that are present in striated skeletal and visceral muscle. Although cardiac muscle is, therefore, also striated, it differs in many significant respects from skeletal and striated visceral muscle. Cardiac muscle consists of individual cells that are joined by complex junctions to form a functional unit (fiber). The histologically obvious differences between cardiac and the other striated muscle fibers are the presence in cardiac muscle of intercalated discs (the light microscopic representation of the complex junctions), the location of cardiac muscle cell nuclei in the center of the fiber, and the branching of the cardiac muscle fibers. All of these characteristics are evident in a well-prepared longitudinal section of the muscle. Cardiac muscle, heart, human, H&E ×160.


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Histology_Ross. Cardiac muscle, heart, human, H&E ×160. This figure shows a longitudinal section of cardiac muscle. The muscle fibers are disposed horizontally in the illustration and show cross-striations. In addition to the regular cross-striations (those of greater frequency), however, there is another group of very pronounced cross-bands, namely, the interca346 lated discs (ID). Intercalated discs most often appear as a straight band, but sometimes they are arranged in a stepwise manner (see also figure on right). These discs are not always displayed in routine H&E sections; therefore, one Cardiac muscle, heart, human, H&E ×400.


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Histology_Ross. Cardiac muscle, heart, human, H&E ×400. Like skeletal muscle, the cardiac muscle is composed of linear contractile units, the myofibrils. These are evident in this figure as the longitudinally disposed linear structures that extend through the length of the cell. The myofibrils separate to bypass the nuclei, and in doing so, they delineate a perinuclear region of cytoplasm that is free of myofibrils and their cross-striations. These perinuclear cytoplasmic areas (asterisks) contain the cytoplasmic organelles that are not directly involved in the contractile process. Many cardiac muscle cells are binucleate; both nuclei typically occupy the myofibrilfree region of cytoplasm, as shown in the cell marked by the asterisks. The third nucleus in this region appears to belong to the connective tissue either Cardiac muscle, heart, human, H&E ×160.


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Histology_Ross. This figure shows cross-sectioned cardiac muscle fibers. Many have rounded or smooth-contoured polygonal profiles. Some fibers, however, are generally more irregular and elongate in profile. These probably reflect a profile of both a fiber and a branch of the fiber. The more lightly stained region in the center of many fibers represents the myofibril-free region of the cell already re- may not be able to depend on these structures for identifying cardiac muscle. Intercalated discs are opposing cell-to-cell contacts. Thus, cardiac muscle fibers differ in a very fundamental respect from fibers of skeletal muscle. The cardiac muscle fiber consists of an end-to-end alignment of individual cells; in contrast, the skeletal muscle fiber is a single multinucleated protoplasmic unit. In examining a longitudinal section of cardiac muscle, it is useful to scan specific fibers along their long axes. By doing so, one can find places where the fibers obviously branch. Two such branchings are


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Histology_Ross. a longitudinal section of cardiac muscle, it is useful to scan specific fibers along their long axes. By doing so, one can find places where the fibers obviously branch. Two such branchings are indicated by the arrows in this figure.


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Histology_Ross. above or below the “in-focus” plane of section. Often, the staining of muscle cell nuclei in a specific specimen is very characteristic, especially when seen in face view as here. Notice, in the nucleus between the asterisks, the well-stained nucleolus and the delicate pattern of the remainder of the nucleus. Once such features have been characterized for a particular specimen, it becomes easy to identify nuclei with similar staining characteristics throughout the specimen. For example, survey the field in figure on left for nuclei with similar features. Having done this, it is substantially easier to identify nuclei of connective tissue cells (CT), which display different staining properties and are not positioned in the same relationship to the muscle cells.


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Histology_Ross. ferred to above and indicated by the asterisks in top right figure. Delicate connective tissue surrounds the individual muscle fibers. This contains capillaries and sometimes larger vessels, such as the venule (V) in the center of the bundle of muscle fibers. Larger amounts of connective tissue (CT) surround bundles of fibers, and this tissue contains larger blood vessels, such as the arteriole (A) marked in the figure. Cardiac muscle, heart, human, H&E ×400. At higher magnification, it is possible to see the cut ends of the myofibrils. These appear as the numerous red areas that give the cut face of the muscle cell a stippled appearance. The nuclei (N) occupy a central position surrounded by myofibrils.


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Histology_Ross. Remember, in contrast, that nuclei of skeletal muscle fibers are located at the periphery of the cell. Note, also, that as mentioned, the nucleus-free central area of the cell, devoid of myofibrils, shows areas of perinuclear cytoplasm similar to that marked with asterisks in figure directly above. KEY A, arteriole C, capillaries CT, connective tissue ID, intercalated discs N, nuclei of cardiac muscle cells V, venule arrows, sites where fibers branch asterisks, perinuclear cytoplasmic areas PLATE 25 Cardiac Muscle, Purkinje Fibers


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Histology_Ross. Cardiac muscle cells possess the ability for spontaneous rhythmic contractions. The contraction or beat of the heart is regulated and coordinated by specialized and modified cardiac muscle cells that are found in nodes and muscle bundles. The beat of the heart is initiated at the sinoatrial (SA) node which consists of a group of specialized cardiac muscle cells located at the junction of the superior vena cava in the right atrium. The impulse spreads from this node along the cardiac mus-cle fibers of the atria. The impulse is then received at the atrioventricular (AV) node which is lo-cated on the inner or medial wall of the right ventricle adjacent to the tricuspid valve. Specialized cardiac muscle cells then conduct impulses from the AV node along the ventricular septum and into the ventricular walls. Within the ventricular septum, the specialized cells are grouped into a bundle, the AV bundle (of His). This bundle then divides into two main branches, a left and right bundle branch,


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Histology_Ross. walls. Within the ventricular septum, the specialized cells are grouped into a bundle, the AV bundle (of His). This bundle then divides into two main branches, a left and right bundle branch, the former going to the left ventricle and the latter to the right ventricle. The specialized con-ducting fibers carry the impulse at a rate that is approximately four times faster than the cardiac muscle fibers. They are responsible for the final distribution of the electrical stimulus to the my-ocardium. While the sinoatrial node on its own exhibits a constant or inherent rhythm, it is modu-lated by the autonomic nervous system. Thus, the rate of the heartbeat can be decreased by parasympathetic fibers from the vagus nerve or increased by fibers from sympathetic ganglia. The specialized conducting cells within the ventricles are referred to as Purkinje fibers. The cells that make up the Purkinje fibers differ from cardiac muscle cells in that they are larger and have their my-ofibrils located


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Histology_Ross. cells within the ventricles are referred to as Purkinje fibers. The cells that make up the Purkinje fibers differ from cardiac muscle cells in that they are larger and have their my-ofibrils located mostly at the periphery of the cell. Their nuclei are also larger. The cytoplasm be-tween the nucleus and the peripherally located myofibrils stains poorly, a reflection, in part, of the large amount of glycogen present in this part of the cell. ORIENTATION MICROGRAPH: The specimen shown here is a saggital section revealing part of the atrial wall (A) and the ventricular wall (V). Between these two portions of the heart is the atri-oventricular septum (AS). The clear space is the interior of the atrium. AAVVASASAVAS


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Histology_Ross. PLATE 25 • CARDIAC MUSCLE, PURKINJE FIBERS KEY A, atrial wall AS, atrioventricular septum DICT, dense irregular connective tissue Ec, endocardium Ec’, deep endocardium Et, endothelium EtC, endothelial cells ID, intercalated discs M, myofibrils My, myocardium PF, Purkinje fibers SM, smooth muscle cells V, ventricular wall Purkinje fibers, heart, human, Masson, ×180. This micrograph shows the area in the rectangle of the orientation figure. At this site, the endocardium (Ec) has been separated by bundles of Purkinje fibers (bundle of His) (PF) coursing along the ventricle wall. Normally, the endocardium consists of three layers. The endothelium (Et) lining the ventricle is the most superficial, but is barely detectable at this magnification. Purkinje fibers, heart, human, Masson, ×365; inset ×600.


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Histology_Ross. Purkinje fibers, heart, human, Masson, ×365; inset ×600. This higher magnification is the boxed area in the above photomicrograph. It reveals the endothelial cells of the endocardium (EtC) and the underlying connective tissue containing smooth muscle cells (SM). Where the Purkinje fibers are cut in cross section or obliquely sectioned, the myofibrils (M) are seen at the periphery of the Beneath the endothelium is a middle layer consisting of dense connective tissue (DICT), in which elastic fibers are present as well as some smooth muscle cells. The third layer, the deepest part of the endocardium (Ec’), consists of more irregularly arranged connective tissue with blood vessels and occasional fat cells. At the bottom of the micrograph is myocardium (My). Note how darkly stained the cardiac muscle fibers are compared to those of the Purkinje fibers.


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Histology_Ross. cell. The cytoplasm in the inner portion of the cell appears unstained. Where the nuclei are included in the section of the cell, they are surrounded by the clear cytoplasm. In the lower portion of the figure, several longitudinally sectioned Purkinje fibers can be seen. Note the intercalated discs (ID) when seen in this profile. The inset reveals to advantage the intercalated discs and the myofibrils with their cross-banding. Note the clear area or unstained cytoplasm surrounding the nuclei. PLATE 25 • CARDIAC MUSCLE, PURKINJE FIBERS EtEtDICTDICTPFPFEc’Ec’EcEcDICTDICTMyMyEtDICTPFEc’EcDICTMyEtCEtCSMSMSMSMIDIDMMMMMMEtCSMSMIDMMM


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Histology_Ross. Smooth muscle is the intrinsic muscle of the alimentary canal, blood vessels, the genitourinary and respiratory tracts, and other hollow and tubular organs. It is also a component of the nipple, scrotum, skin (arrector pili muscle) and parts of the eye (iris). In most locations, smooth muscle consists of bundles or layers of elongate fusiform cells. They may range in length from 20 m in the walls of small blood vessels to about 200 m in the intestinal wall. In the case of the uterus, they may become as large as 500 m during pregnancy. The smooth muscle cells are joined by gap junctions that allow small molecules or ions to pass from cell to cell and allow regulation of contraction of the entire bundle or sheet of smooth muscle. The cytoplasm of smooth muscle cells stains uniformly with eosin in routine H&E preparations because of the concentration of actin and myosin that these cells contain. The nucleus of the cell is located in its center and is elongate with tapering ends, matching


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Histology_Ross. in routine H&E preparations because of the concentration of actin and myosin that these cells contain. The nucleus of the cell is located in its center and is elongate with tapering ends, matching the shape of the cell. When the cell is maximally contracted, the nucleus displays a corkscrew shape. During lesser degrees of contraction, the nucleus may appear to have a slight spiral shape. Often in H&E preparations, smooth muscle stains much the same as dense connective tissue. A distinguishing feature relative to smooth muscle is that nuclei are considerably more numerous and they tend to look the same, appearing as elongate profiles when smooth muscle is longitudinally sectioned and as circular profiles when smooth muscle is cross-sectioned. In contrast, the nuclei of dense connective tissue, though fewer in number per unit area, may appear in varying profiles in a given section.


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Histology_Ross. Smooth muscle, small intestine, human, H&E, ×256. This low power micrograph reveals part of the wall of the small intestine, the muscularis externa. The left side of the micrograph shows two bundles, both are longitudinally sectioned (LS), whereas on the right side, smooth muscle bundles are seen in cross section (CS). Note that the nuclei of Smooth muscle, small intestine, human, H&E, ×512.


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Histology_Ross. Smooth muscle, small intestine, human, H&E, ×512. This higher magnification photomicrograph shows a bundle of smooth muscle cells (SMC). Note how the nuclei exhibit an undulating or wavy form indicating that the cells are partially contracted. The nuclei seen in the dense connective tissue the smooth muscle cells in the longitudinally sectioned bundles are all elongate; in contrast the nuclei in the cross-sectioned smooth muscle bundles appear as circular profiles. Intermixed between the bundles is dense irregular connective tissue (DICT). While both the smooth muscle cells and the dense connective tissue stain with eosin, the dense connective tissue exhibits a paucity of nuclei compared to the smooth muscle cell bundles.


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Histology_Ross. (DCT) in contrast show a variety of shapes. The collagen fibers in this case, as in the previous micrograph, have a brighter red coloration than the cytoplasm of the smooth muscle cells, which provides further distinction between the two types of tissue. However, this is not always the case and the two may appear similarly stained. Smooth muscle, small intestine, human, H&E, ×256. dense connective tissue (DCT) and the numerous circular profiles of the smooth muscle cell nuclei. This micrograph shows at low magnification several bundles of cross-sectioned smooth muscle (SM). Again, note how the smooth muscle bundles are separated from one another by Smooth muscle, small intestine, human, H&E, ×512; inset ×1,185.


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Histology_Ross. Smooth muscle, small intestine, human, H&E, ×512; inset ×1,185. At this higher magnification, the smooth muscle is again seen in cross section. As is typically the case, the distribution of the smooth muscle cell nuclei is not uniform, thus in some areas there appears to be a crowding of nuclei (lower box), whereas in other areas, there appears to be a paucity of nuclei (upper box). This is a reflection of the side-by-side orientation of the smooth muscle cells; thus, in this area, the cells are aligned in a manner that the nucleus has not been included in the thickness of the section. The inset is a higher magnification of this area and shows the cross-sectioned smooth muscle cells as circular profiles of varying size. Where the nuclei appear more numerous, the cells simply are aligned where the section has included the nucleus.


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Histology_Ross. KEY CS, cross-sectioned bundles DCT, dense connective tissue DICT, dense irregular connective tissue LS, longitudinally sectioned bundles SM, smooth muscle SMC, smooth muscle cells


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Histology_Ross. OVERVIEW OF THE NERVOUS SYSTEM / 352 COMPOSITION OF NERVE TISSUE / 353 THE NEURON / 353 Cell Body / 355 Dendrites and Axons / 357 Synapses / 358 Axonal Transport Systems / 363 SUPPORTING CELLS OF THE NERVOUS SYSTEM: THE NEUROGLIA / 363 Peripheral Neuroglia / 363 Schwann Cells and the Myelin Sheath / 364 Satellite Cells / 366 Central Neuroglia / 367 Impulse Conduction / 371 ORIGIN OF NERVE TISSUE CELLS / 373 ORGANIZATION OF THE PERIPHERAL NERVOUS SYSTEM / 375 Peripheral Nerves / 375 Connective Tissue Components of a Peripheral Nerve / 375 Afferent (Sensory) Receptors / 377 ORGANIZATION OF THE AUTONOMIC NERVOUS SYSTEM / 378 Sympathetic and Parasympathetic Divisions of the Autonomic Nervous System / 378 Enteric Division of the Autonomic Nervous System / 378 A Summarized View of Autonomic Distribution / 381 ORGANIZATION OF THE CENTRAL NERVOUS SYSTEM / 381 Cells of the Gray Matter / 382 Organization of the Spinal Cord / 382 Connective Tissue of the Central Nervous System / 383 Blood–Brain


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Histology_Ross. / 381 ORGANIZATION OF THE CENTRAL NERVOUS SYSTEM / 381 Cells of the Gray Matter / 382 Organization of the Spinal Cord / 382 Connective Tissue of the Central Nervous System / 383 Blood–Brain Barrier / 385 RESPONSE OF NEURONS TO INJURY / 386 Degeneration / 386 Regeneration / 387 Folder 12.1 Clinical Correlation: Parkinson’s Disease / 358 Folder 12.2 Clinical Correlation: Demyelinating Diseases / 366 Folder 12.3 Clinical Correlation: Gliosis: Scar formation in the CNS / 389


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Histology_Ross. The nervous system enables the body to respond to continuous changes in its external and internal environment. It controls and integrates the functional activities of the organs and organ systems. Anatomically, the nervous system is divided into the following:  The central nervous system (CNS) consists of the brain and the spinal cord, which are located in the cranial cavity and spinal canal, respectively.


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Histology_Ross.  The peripheral nervous system (PNS) consists of cranial, spinal, and peripheral nerves that conduct impulses from (efferent or motor nerves) and to (the afferent or sensory nerves of ) the CNS, collections of nerve cell bodies outside the CNS called ganglia, and specialized nerve endings (both motor and sensory). Interactions between sensory (afferent) nerves that receive stimuli, the CNS that interprets them, and motor (efferent) nerves that initiate responses create neural pathways. These pathways mediate reflex actions called reflex arcs. In humans, most sensory neurons do not pass directly into the brain but instead communicate by specialized terminals (synapses) with motor neurons in the spinal cord.


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Histology_Ross. Functionally, the nervous system is divided into the following:  The somatic nervous system (SNS) consists of somatic [Gr. soma, body] parts of the CNS and PNS. The SNS controls functions that are under conscious voluntary control with the exception of reflex arcs. It provides sensory and motor innervation to all parts of the body except viscera, smooth and cardiac muscle, and glands.  The autonomic nervous system (ANS) consists of autonomic parts of the CNS and PNS. The ANS provides efferent involuntary motor innervation to smooth muscle, the conducting system of the heart, and glands. It also provides afferent sensory innervation from the viscera (pain and autonomic reflexes). The ANS is further subdivided into a sympathetic division and a parasympathetic division. A third division of ANS, the enteric division, serves the alimentary canal. It communicates with the CNS through the parasympathetic and sympathetic nerve fibers; however, it can also function independently of the other


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Histology_Ross. ANS, the enteric division, serves the alimentary canal. It communicates with the CNS through the parasympathetic and sympathetic nerve fibers; however, it can also function independently of the other two divisions of the ANS (see page 378).


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Histology_Ross. Nerve tissue consists of two principal types of cells: neurons and supporting cells. The neuron or nerve cell is the functional unit of the nervous system. It consists of a cell body, containing the nucleus, and several processes of varying length. Nerve cells are specialized to receive stimuli from other cells and to conduct electrical impulses to other parts of the system via their processes. Several neurons are typically involved in sending impulses from one part of the system to another. These neurons are arranged in a chainlike fashion as an integrated communications network. Specialized contacts between neurons that provide for transmission of information from one neuron to the next are called synapses.


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Histology_Ross. Supporting cells are nonconducting cells that are located close to the neurons. They are referred to as neuroglial cells or simply glia. The CNS contains four types of glial cells: oligodendrocytes, astrocytes, microglia, and ependymal cells (see page 367). Collectively, these cells are called the central neuroglia. In the PNS, supporting cells are called peripheral neuroglia and include Schwann cells, satellite cells, and a variety of other cells associated with specific structures. Schwann cells surround the processes of nerve cells and isolate them from adjacent cells and extracellular matrix. Within the ganglia of the PNS, peripheral neuroglial cells are called satellite cells. They surround the nerve cell bodies, the part of the cell that contains the nucleus, and are analogous to Schwann cells. The supporting cells of the ganglia in the wall of the alimentary canal are called enteric neuroglial cells. They are morphologically and functionally similar to central neuroglia (see


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Histology_Ross. Schwann cells. The supporting cells of the ganglia in the wall of the alimentary canal are called enteric neuroglial cells. They are morphologically and functionally similar to central neuroglia (see page 367).


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Histology_Ross. Functions of the various neuroglial cell types include:  physical support (protection) for neurons,  insulation for nerve cell bodies and processes that facilitates rapid transmission of nerve impulses,  repair of neuronal injury,  regulation of the internal fluid environment of the CNS,  clearance of neurotransmitters from synaptic clefts, and  metabolic exchange between the vascular system and the neurons of the nervous system In addition to neurons and supporting cells, an extensive vasculature is present in both the CNS and the PNS. The blood vessels are separated from the nerve tissue by the basal laminae and variable amounts of connective tissue, depending on vessel size. The boundary between blood vessels and nerve tissue in the CNS excludes many substances that normally leave blood vessels to enter other tissues. This selective restriction of blood-borne substances in the CNS is called the blood–brain barrier, which is discussed on page 385.


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Histology_Ross. The nervous system allows rapid response to external stimuli. The nervous system evolved from the simple neuroeffector system of invertebrate animals. In primitive nervous systems, only simple receptor–effector reflex loops exist to respond to external stimuli. In higher animals and humans, the SNS retains the ability to respond to stimuli from the external environment through the action of effector cells (such as skeletal muscle), but the neuronal responses are infinitely more varied. They range from simple reflexes that require only the spinal cord to complex operations of the brain, including memory and learning. The autonomic part of the nervous system regulates the function of internal organs.


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Histology_Ross. The autonomic part of the nervous system regulates the function of internal organs. The specific effectors in the internal organs that respond to the information carried by autonomic neurons include the following:  Smooth muscle. Contraction of smooth muscle modifies the diameter or shape of tubular or hollow viscera such as the blood vessels, gut, gallbladder, and urinary bladder.  Cardiac conducting cells (Purkinje fbers) located within the conductive system of the heart. The inherent frequency of Purkinje fiber depolarization regulates the rate of cardiac muscle contraction and can be modified by autonomic impulses. Glandular epithelium. The autonomic nervous system reg ulates the synthesis, composition, and release of secretions.


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Histology_Ross. The regulation of the function of internal organs involves close cooperation between the nervous system and the endocrine system. Neurons in several parts of the brain and other sites behave as secretory cells and are referred to as neuroendocrine tissue. The varied roles of neurosecretions in regulating the functions of the endocrine, digestive, respiratory, urinary, and reproductive systems are described in subsequent chapters. The neuron is the structural and functional unit of the nervous system. The human nervous system contains more than 10 billion neurons. Although neurons show the greatest variation in size and shape of any group of cells in the body, they can be grouped into three general categories.


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Histology_Ross.  Sensory neurons convey impulses from receptors to the CNS. Processes of these neurons are included in somatic afferent and visceral afferent nerve fibers. Somatic afferent fbers convey sensations of pain, temperature, touch, and pressure from the body surface. In addition, these fibers convey pain and proprioception (nonconscious sensation) from organs within the body (e.g., muscles, tendons, and joints) to provide the brain with information related to the orientation of the body and limbs. Visceral afferent fbers transmit pain impulses and other sensations from internal organs, mucous membranes, glands, and blood vessels.


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Histology_Ross.  Motor neurons convey impulses from the CNS or ganglia to effector cells. Processes of these neurons are included in somatic efferent and visceral efferent nerve fibers. Somatic efferent neurons send voluntary impulses to skeletal muscles. Visceral efferent neurons transmit involuntary impulses to smooth muscle, cardiac conducting cells (Purkinje fibers), and glands (Fig. 12.1).  Interneurons, also called intercalated neurons, form a communicating and integrating network between the node of Ranvier FIGURE 12.1 • Diagram of a motor neuron. The nerve cell body, dendrites, and proximal part of the axon are within the CNS. The axon leaves the CNS and, while in the PNS, is part of a nerve (not shown) as it courses to its effectors (striated muscle). In the CNS, the myelin for the axon is produced by, and is part of, an oligodendrocyte; in the PNS, the myelin is produced by, and is part of, a Schwann cell.


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Histology_Ross. sensory and motor neurons. It is estimated that more than 99.9% of all neurons belong to this integrating network. The functional components of a neuron include the cell body, axon, dendrites, and synaptic junctions. The cell body (perikaryon) of a neuron contains the nucleus and those organelles that maintain the cell. The processes extending from the cell body constitute the single common structural characteristic of all neurons. Most neurons have only one axon, usually the longest process extending from the cell, which transmits impulses away from the cell body to a specialized terminal (synapse). The synapse makes contact with another neuron or an effector cell (e.g., a muscle cell or glandular epithelial cell). A neuron usually has many dendrites, shorter processes that transmit impulses from the periphery (i.e., other neurons) toward the cell body. Neurons are classified on the basis of the number of processes extending from the cell body.


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Histology_Ross. Neurons are classified on the basis of the number of processes extending from the cell body. Most neurons can be anatomically characterized as the following:  Multipolar neurons have one axon and two or more dendrites (Fig. 12.2). The direction of impulses is from dendrite to cell body to axon or from cell body to axon. Functionally, the dendrites and cell body of multipolar neurons are the receptor portions of the cell, and their plasma membrane is specialized for impulse generation. The axon is the conducting portion of the cell, and its plasma membrane is specialized for impulse conduction. The terminal portion of the axon, the synaptic ending, contains various neurotransmitters—that is, small molecules released at the synapse that affect other neurons as well as muscle cells and glandular epithelium. Motor neurons and interneurons constitute most of the multipolar neurons in the nervous system.


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Histology_Ross.  Bipolar neurons have one axon and one dendrite (see Fig. 12.2). Bipolar neurons are rare. They are most often associated with the receptors for the special senses (taste, smell, hearing, sight, and equilibrium). They are generally found within the retina of the eye and the ganglia of the vestibulocochlear nerve (cranial nerve VIII) of the ear. Some neurons in this group do not fit the above generalizations. For example, amacrine cells of the retina have no axons, and olfactory receptors resemble neurons of primitive neural systems, in that they retain a surface location and regenerate at a much slower rate than other neurons.


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Histology_Ross.  Pseudounipolar (unipolar) neurons have one process, the axon, that divides close to the cell body into two long axonal branches. One branch extends to the periphery, and the other extends to the CNS (see Fig. 12.2). The two axonal branches are the conducting units. Impulses are generated in the peripheral arborizations (branches) of the neuron that are the receptor portion of the cell. Each pseudounipolar neuron develops from a bipolar neuron, as its axon and dendrite migrate around the cell body and fuse into a single process. The majority of pseudounipolar neurons are sensory neurons located close to the CNS (Fig. 12.3). Cell bodies of sensory neurons are situated in the dorsal root ganglia and cranial nerve ganglia.


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Histology_Ross. FIGURE 12.2 • Diagram illustrating different types of neurons. The cell bodies of pseudounipolar (unipolar), bipolar, and postsynaptic autonomic neurons are located outside the CNS. Purkinje and pyramidal cells are restricted to the CNS; many of them have elaborate dendritic arborizations that facilitate their identification. Central axonal branch and all axons in remaining cells are indicated in green. Cell Body surfaced endoplasmic reticulum (rER) and free ribosomes when observed with the transmission electron microscope The cell body of a neuron has characteristics of a protein (TEM), a feature consistent with its protein synthetic activity. producing cell.


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Histology_Ross. The cell body of a neuron has characteristics of a protein (TEM), a feature consistent with its protein synthetic activity. producing cell. In the light microscope, the ribosomal content appears as small The cell body is the dilated region of the neuron that contains bodies called Nissl bodies that stain intensely with basic dyes a large, euchromatic nucleus with a prominent nucleolus and and metachromatically with thionine dyes (see Fig. 12.4a). surrounding perinuclear cytoplasm (Fig.12.4a, Plate 27, Each Nissl body corresponds to a stack of rER. The perinupage 390). The perinuclear cytoplasm reveals abundant rough- clear cytoplasm also contains numerous mitochondria, a large node of Ranvier nucleus of Schwann cell spinal nerve Pacinian corpuscle cell body of motor neuron cell body of sympathetic neuron smooth muscle and striated enteroceptors of ANS muscle


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Histology_Ross. FIGURE 12.3 • Schematic diagram showing arrangement of motor and sensory neurons. The cell body of a motor neuron is located in the ventral (anterior) horn of the gray matter of the spinal cord. Its axon, surrounded by myelin, leaves the spinal cord via a ventral (anterior) root and becomes part of a spinal nerve that carries it to its destination on striated (skeletal) muscle fibers. The sensory neuron originates in the skin within a receptor (here, a Pacinian corpuscle) and continues as a component of a spinal nerve, entering the spinal cord via the dorsal (posterior) root. Note the location of its cell body in the dorsal root ganglion (sensory ganglion). A segment of the spinal nerve is enlarged to show the relationship of the nerve fibers to the surrounding connective tissue (endoneurium, perineurium, and epineurium). In addition, segments of the sensory, motor and autonomic unmyelinated neurons have been enlarged to show the relationship of the axons to the Schwann cells.


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Histology_Ross. perinuclear Golgi apparatus, lysosomes, microtubules, neurofilaments (intermediate filaments), transport vesicles, and inclusions (Fig. 12.4b). Nissl bodies, free ribosomes, and occasionally the Golgi apparatus extend into the dendrites but not into the axon. This area of the cell body, called the axon hillock, lacks large cytoplasmic organelles and serves as a landmark to distinguish between axons and dendrites in both light microscope and TEM preparations. The euchromatic nucleus, large nucleolus, prominent Golgi apparatus, and Nissl bodies indicate the high level of anabolic activity needed to maintain these large cells. Neurons do not divide; however, in some areas of the brain, neural stem cells are present and are able to differentiate and replace damaged nerve cells.


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Histology_Ross. Neurons do not divide; however, in some areas of the brain, neural stem cells are present and are able to differentiate and replace damaged nerve cells. Although neurons do not replicate, the subcellular components of the neurons turn over regularly and have life spans measured in hours, days, and weeks. The constant need to replace enzymes, neurotransmitter substances, membrane components, and other complex molecules is consistent with the morphologic features characteristic of a high level of synthetic activity. Newly synthesized protein molecules are transported to distant locations within a neuron in a process referred to as axonal transport (page 363).


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Histology_Ross. It is generally accepted that nerve cells do not divide. However, recently it has been shown that the adult brain retains some cells that exhibit the potential to regenerate. In certain regions of the brain such as olfactory bulb and dentate gyrus of the hippocampus, these neural stem cells are able to divide and generate new neurons. They are characterized by prolonged expression of a 240-kDa intermediate filament protein nestin, which is used to identify these cells by histochemical methods. Neural stem cells are also able to migrate to sites of injury and differentiate into new nerve


Histology_Ross

Histology_Ross. FIGURE 12.4 • Nerve cell bodies. a. This photomicrograph shows a region of the ventral (anterior) horn of a human spinal cord stained with toluidine blue. Typical features of the nerve cell bodies visible in this image include large, spherical, pale-stained nuclei with a single prominent nucleolus and abundant Nissl bodies within the cytoplasm of the nerve cell body. Most of the small nuclei belong to neuroglial cells. The remainder of the field consists of nerve fibers and cytoplasm of cental neuroglial cells. 640. b. Electron micrograph of a nerve cell body. The cytoplasm is occupied by aggregates of free ribosomes and profiles of rough-surfaced endoplasmic reticulum (rER) that constitute the Nissl bodies of light microscopy. The Golgi apparatus (G) appears as isolated areas containing profiles of flattened sacs and vesicles. Other characteristic organelles include mitochondria (M) and lysosomes (L). The neurofilaments and neurotubules are difficult to discern at this relatively low


Histology_Ross

Histology_Ross. of flattened sacs and vesicles. Other characteristic organelles include mitochondria (M) and lysosomes (L). The neurofilaments and neurotubules are difficult to discern at this relatively low magnification. 15,000.


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Histology_Ross. cells. Research studies on the animal model demonstrate that newly generated cells mature into functional neurons in the adult mammalian brain. These findings may lead to therapeutic strategies that use neural cells to replace nerve cells lost or damaged by neurodegenerative disorders such as Alzheimer and Parkinson diseases. Dendrites are receptor processes that receive stimuli from other neurons or from the external environment.


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Histology_Ross. Dendrites are receptor processes that receive stimuli from other neurons or from the external environment. The main function of dendrites is to receive information from other neurons or from the external environment and carry that information to the cell body. Generally, dendrites are located in the vicinity of the cell body. They have a greater diameter than axons, are unmyelinated, are usually tapered, and form extensive arborizations called dendritic trees. Dendritic trees significantly increase the receptor surface area of a neuron. Many neuron types are characterized by the extent and shape of their dendritic trees (see Fig. 12.2). In general, the contents of the perinuclear cytoplasm of the cell body and cytoplasm of dendrites are similar, with the exception of the Golgi apparatus. Other organelles characteristic of the cell body, including ribosomes and rER, are found in the dendrites, especially in the base of the dendrites.


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Histology_Ross. Axons are effector processes that transmit stimuli to other neurons or effector cells. The main function of the axon is to convey information away from the cell body to another neuron or to an effector cell, such as a muscle cell. Each neuron has only one axon, and it may be extremely long. Axons that originate from neurons in the motor nuclei of the CNS (Golgi type I neurons) may travel more than a meter to reach their effector targets, skeletal muscle. In contrast, interneurons of the CNS (Golgi type II neurons) have very short axons. Although an axon may give rise to a recurrent branch near the cell body (i.e., one that turns back toward the cell body) and to other collateral branches, the branching of the axon is most extensive in the vicinity of its targets. The axon originates from the axon hillock. The axon hillock usually lacks large cytoplasmic organelles such as Nissl  FOLDER 12.1 Clinical Correlation: Parkinson’s Disease


Histology_Ross

Histology_Ross. Parkinson’s disease is a slowly progressive neurologic disorder caused by the loss of dopamine (DA)-secreting cells in the substantia nigra and basal ganglia of the brain. DA is a neurotransmitter responsible for synaptic trans -mission in the nerve pathways coordinating smooth and focused activity of skeletal muscles. Loss of DA-secreting cells is associated with a classic pattern of symptoms, including the following:  Resting tremor in the limb, especially of the hand when in a relaxed position; tremor usually increases during stress and is often more severe on one side of the body  Rigidity or increased tone (stiffness) in all muscles  Slowness of movement (bradykinesia) and inability to initiate movement (akinesia)  Lack of spontaneous movements  Loss of postural reflexes, which leads to poor balance and abnormal walking (festinating gait)  Slurred speech, slowness of thought, and small, cramped handwriting The cause of idiopathic Parkinson’s disease, in which DA-secreting


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Histology_Ross. leads to poor balance and abnormal walking (festinating gait)  Slurred speech, slowness of thought, and small, cramped handwriting The cause of idiopathic Parkinson’s disease, in which DA-secreting neurons in the substantia nigra are damaged and lost by degeneration or apoptosis, is not known. However, some evidence suggests a hereditary predisposition; about 20% of Parkinson’s patients have a family member with similar symptoms. Symptoms that resemble idiopathic Parkinson’s dis-ease may also result from infections (e.g., encephalitis), toxins (e.g., MPTP), drugs used in the treatment of neuro-logic disorders (e.g., neuroleptics used to treat schizophre-nia), and repetitive trauma. Symptoms with these causes are called secondary parkinsonism. On the microscopic level, degeneration of neurons in the substantia nigra is very evident. This region loses its typical pigmentation, and an increase in the number of glial cells is noticeable (gliosis). In addition, nerve cells in this region


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Histology_Ross. in the substantia nigra is very evident. This region loses its typical pigmentation, and an increase in the number of glial cells is noticeable (gliosis). In addition, nerve cells in this region display characteristic intracellular inclusions called Lewy bodies, which represent accumulation of intermedi-ate neurofilaments in association with proteins -synuclein and ubiquitin. Treatment of Parkinson’s disease is primarily symp-tomatic and must strike a balance between relieving symp-toms and minimizing psychotic side effects. L-Dopa is a precursor of DA that can cross the blood–brain barrier and is then converted to DA. It is often the primary agent used to treat Parkinson’s disease. Other drugs that are used in-clude a group of cholinergic receptor blockers and aman-tadine, a drug that stimulates release of DA from neurons. If drug therapies are not effective, several surgical op-tions can be considered. Stereotactic surgery, in which nuclei in selective areas of the brain (globus


Histology_Ross

Histology_Ross. stimulates release of DA from neurons. If drug therapies are not effective, several surgical op-tions can be considered. Stereotactic surgery, in which nuclei in selective areas of the brain (globus pallidus, thalamus) are destroyed by a thermocoagulative probe in-serted into the brain, can be effective in some cases. Sev-eral new surgical procedures are being developed and are still in experimental stages. These include transplantation of DA-secreting neurons into the substantia nigra to replace lost neurons.


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Histology_Ross. bodies and Golgi cisternae. Microtubules, neurofilaments, mitochondria, and vesicles, however, pass through the axon hillock into the axon. The region of the axon between the apex of the axon hillock and the beginning of the myelin sheath (see below) is called the initial segment. The initial segment is the site at which an action potential is generated in the axon. The action potential (described in more detail below) is stimulated by impulses carried to the axon hillock on the membrane of the cell body after other impulses are received on the dendrites or the cell body itself. Some large axon terminals are capable of local protein synthesis, which may be involved in memory processes.


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Histology_Ross. Some large axon terminals are capable of local protein synthesis, which may be involved in memory processes. Almost all of the structural and functional protein molecules are synthesized in the nerve cell body. These molecules are distributed to the axons and dendrites via axonal transport systems (described on page 363). However, contrary to the common view that the nerve cell body is the only site of protein synthesis, recent studies indicate that local synthesis of axonal proteins takes place in some large nerve terminals. Some vertebral axon terminals (i.e., from the retina) contain polyribosomes with complete translational machinery for protein synthesis. These discrete areas within the axon terminals, called periaxoplasmic plaques, possess biochemical and molecular characteristics of active protein synthesis. Protein synthesis within the periaxoplasmic plaques is modulated by neuronal activity. These proteins may be involved in the processes of neuronal cell memory.


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Histology_Ross. Neurons communicate with other neurons and with effector cells by synapses. Synapses are specialized junctions between neurons that facilitate the transmission of impulses from one (presynaptic) neuron to another (postsynaptic) neuron. Synapses also occur between axons and effector (target) cells, such as muscle and gland cells. Synapses between neurons may be classified morphologically as:  axodendritic, occurring between axons and dendrites;  axosomatic, occurring between axons and the cell body; or  axoaxonic, occurring between axons and axons (Fig. 12.5).


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Histology_Ross. Synapses are not resolvable in routine hematoxylin and eosin (H&E) preparations. However, silver precipitation staining methods (e.g., Golgi method) not only demonstrate the overall shape of some neurons but also show synapses as oval bodies on the surface of the receptor neuron. Typically, an axon makes several of these buttonlike contacts with the receptor portion of the neuron. Often, the incoming neuron travels along the surface of the neuron, making several synaptic contacts called boutons en passant (Fr., buttons in passing). The axon then continues, ending finally as a terminal branch with an enlarged tip, a bouton terminal (Fr., terminal button), or end bulb. The number of synapses on a neuron or its processes, which may vary from a few to tens of thousands per neuron (Fig. 12.6), appears to be directly related to the number of impulses that a neuron is receiving and processing.


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Histology_Ross. FIGURE 12.5 • Schematic diagram of different types of synapses. a. Axodendritic or axosomatic. b. Axodendritic, in which an axon terminal synapses with a dendritic spine. c. Axoaxonic. The axoaxonic synapse may enhance or inhibit the axodendritic (or axosomatic) synapse. (Modified from Barr ML. The Human Nervous System. New York: Harper & Row, 1979.) Synapses are classified as chemical or electrical. Classification depends on the mechanism of conduction of the nerve impulses and the way the action potential is gener-ated in the target cells. Thus, synapses may also be classified as the following.


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Histology_Ross. FIGURE 12.6 • Scanning electron micrograph of the nerve cell body. This micrograph shows the cell body of a neuron. Axon endings forming synapses are visible as are numerous oval bodies with tail-like appendages. Each oval body represents axon terminal from different neuron making contact with the cell body. 76,000. (Courtesy of Dr. George Johnson.)  Chemical synapses: Conduction of impulses is achieved by the release of chemical substances (neurotransmitters) from the presynaptic neuron. Neurotransmitters then diffuse across the narrow intercellular space that separates the presynaptic neuron from the postsynaptic neuron or target cell.


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Histology_Ross.  Electrical synapses: Common in invertebrates, these synapses contain gap junctions that permit movement of ions between cells and consequently permit the direct spread of electrical current from one cell to another. These synapses do not require neurotransmitters for their function. Mammalian equivalents of electrical synapses include gap junctions in smooth muscle and cardiac muscle cells. A typical chemical synapse contains a presynaptic element, synaptic cleft, and postsynaptic membrane. Components of a typical chemical synapse include the following.


Histology_Ross

Histology_Ross. Components of a typical chemical synapse include the following.  A presynaptic element (presynaptic knob, presynaptic component, or synaptic bouton) is the end of the neuron process from which neurotransmitters are released. The presynaptic element is characterized by the presence of synaptic vesicles, membrane-bound structures that range from 30 to 100 nm in diameter and contain neurotransmitters (Fig. 12.7). The binding and fusion of synaptic vesicles to the presynaptic plasma membrane is mediated by a family of transmembrane proteins called SNAREs (which stands for “soluble NSF attachment receptors”), (see page 34). The specific SNARE proteins involved in this activity are known as v-SNARE (vesicle–bound) proteins and t-SNARE (targetmembrane–bound found in specialized areas of the presynaptic membrane). Another vesicle-bound protein called synaptotagmin 1 then replaces the SNARE complex, which is subsequently dismantled and recycled by


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Histology_Ross. FIGURE 12.7 • Diagram of a chemical axodendritic synapse. This diagram illustrates three components of a typical synapse. The presynaptic knob is located at the distal end of the axon from which neurotransmitters are released. The presynaptic element of the axon is characterized by the presence of numerous neurotransmitter-containing synaptic vesicles. The plasma membrane of the presynaptic knob is recycled by the formation of clathrin-coated endocytotic vesicles. The synaptic cleft separates the presynaptic knob of the axon from the postsynaptic membrane of the dendrite. The postsynaptic membrane of the dendrite is frequently characterized by a postsynaptic density and contains receptors with an affinity for the neurotransmitters. Note two types of receptors: Green-colored molecules represent transmitter-gated channels, and the purple-colored structure represents a G-protein–coupled receptor that, when bound to a neurotransmitter, may act on G-protein–gated ion channels or on enzymes


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Histology_Ross. transmitter-gated channels, and the purple-colored structure represents a G-protein–coupled receptor that, when bound to a neurotransmitter, may act on G-protein–gated ion channels or on enzymes producing a second messenger. a. Diagram showing the current view of neurotransmitter release from a presynaptic knob by a fusion of the synaptic vesicles with presynaptic membrane. b. Diagram showing a new proposed model of the neurotransmitter release via porocytosis. In this model, the synaptic vesicle is anchored and juxtaposed to calcium-selective channels in the presynaptic membrane. In the presence of Ca2, the bilayers of the vesicle and presynaptic membranes are reorganized to create a 1-nm transient pore connecting the lumen of the vesicle, with the synaptic cleft allowing the release of a neurotransmitter. Note the presence of the SNARE complex and the synaptotagmin that anchor the vesicle to the active zones within plasma membrane of the presynaptic element.


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Histology_Ross. presynaptic element of axon postsynaptic membrane of dendrite NSF/SNAP25 protein complexes. Dense accumulations of proteins are present on the cytoplasmic side of the presynaptic plasma membrane. These presynaptic densities represent specialized areas called active zones where synaptic vesicles are docked and where neurotransmitters are released. Active zones are rich in Rab-GTPase docking complexes (see page 35), t-SNAREs and synaptotagmin binding proteins. The vesicle membrane that is added to the presynaptic membrane is retrieved by endocytosis and reprocessed into synaptic vesicles by the smooth-surfaced endoplasmic reticulum (sER) located in the nerve ending. Numerous small mitochondria are also present in the presynaptic element.  The synaptic cleft is the 20to 30-nm space that separates the presynaptic neuron from the postsynaptic neuron or target cell, which the neurotransmitter must cross.


Histology_Ross

Histology_Ross.  The synaptic cleft is the 20to 30-nm space that separates the presynaptic neuron from the postsynaptic neuron or target cell, which the neurotransmitter must cross.  The postsynaptic membrane (postsynaptic component) contains receptor sites with which the neurotransmitter interacts. This component is formed from a portion of the plasma membrane of the postsynaptic neuron (Fig. 12.8) and is characterized by an underlying layer of dense material. This postsynaptic density represents an elaborate complex of interlinked proteins that serve numerous functions such as translation of the neurotransmitter–receptor interaction into an intracellular signal, anchoring of and trafficking neurotransmitter receptors to the plasma membrane, and anchoring various proteins that modulate receptor activity. Voltage-gated Ca2 channels in the presynaptic membrane regulate transmitter release.


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Histology_Ross. Voltage-gated Ca2 channels in the presynaptic membrane regulate transmitter release. When a nerve impulse reaches the synaptic bouton, the voltage reversal across the membrane produced by the impulse (called depolarization) causes voltage-gated Ca2


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Histology_Ross. FIGURE 12.8 • Electron micrograph of nerve processes in the cerebral cortex. A synapse can be seen in the center of the micrograph, where an axon ending is apposed to a dendrite. The ending of the axon exhibits numerous neurotransmitter-containing synaptic vesicles that appear as circular profiles. The postsynaptic membrane of the dendrite shows a postsynaptic density. A substance of similar density is also present in the synaptic cleft (intercellular space) at the synapse. 76,000. (Courtesy of Drs. George D. Pappas and Virginia Kriho.) channels to open in the plasma membrane of the bouton. The influx of Ca2 from the extracellular space causes the synaptic vesicles to migrate, anchor, and fuse with the presynaptic membrane, thereby releasing the neurotransmitter into the synaptic cleft by exocytosis. Vesicle docking and fusion is mainly driven by the actions of SNARE and synaptotagmin proteins. Alternative to the massive release of neurotransmitter following vesicle fusion is the


Histology_Ross

Histology_Ross. by exocytosis. Vesicle docking and fusion is mainly driven by the actions of SNARE and synaptotagmin proteins. Alternative to the massive release of neurotransmitter following vesicle fusion is the process of porocytosis, in which vesicles anchored at the active zones release neurotransmitters through a transient pore connecting the lumen of the vesicle with the synaptic cleft. The neurotransmitter then diffuses across the synaptic cleft. At the same time, the presynaptic membrane of the synaptic bouton that released the neurotransmitter quickly forms endocytotic vesicles that return to the endosomal compartment of the bouton for recycling or reloading with neurotransmitter.


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Histology_Ross. The neurotransmitter binds to either transmitter-gated channels or G-protein–coupled receptors on the postsynaptic membrane. The released neurotransmitter molecules bind to the extracellular part of postsynaptic membrane receptors called transmitter-gated channels. Binding of neurotransmitter induces a conformational change in these channel proteins that causes its pore to open. The response that is ultimately generated depends on the identity of the ion that enters the cell. For instance, influx of Na causes local depolarization in the postsynaptic membrane, which under favorable conditions (sufficient amount and duration of neurotransmitter release) prompts the opening of voltage-gated Na channels, thereby generating a nerve impulse.


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Histology_Ross. Some amino acid and amine neurotransmitters may bind to G-protein–coupled receptors to produce longer-lasting and more diverse postsynaptic responses. The neurotransmitter binds to a transmembrane receptor protein on the postsynaptic membrane. Receptor binding activates G-proteins, which move along the intracellular surface of the postsynaptic membrane and eventually activate effector proteins. These effector proteins may include transmembrane G-protein–gated ion channels or enzymes that synthesize second-messenger molecules (page 335). Several neurotransmitters (i.e., acetylcholine) can generate different postsynaptic actions, depending on which receptor system they act (see below). Porocytosis describes the secretion of neurotransmitter that does not involve the fusion of synaptic vesicles with the presynaptic membrane.


Histology_Ross

Histology_Ross. Porocytosis describes the secretion of neurotransmitter that does not involve the fusion of synaptic vesicles with the presynaptic membrane. Based on evaluation of physiologic data and the structural organization of nerve synapses, an alternate model of neurotransmitter secretion called porocytosis has recently been proposed to explain the regulated release of neurotransmitters. In this model, secretion from the vesicles occurs without fusion of the vesicle membrane with the presynaptic membrane. Instead, the synaptic vesicle is anchored to the presynaptic membrane next to Ca2-selective channels by SNARE and synaptotagmin proteins. In the presence of Ca2, the vesicle and presynaptic membranes are reorganized to create a 1-nm transient pore connecting the lumen of the vesicle with the synaptic cleft. Neurotransmitters can then be released in a controlled fashion through these transient membrane pores (see Fig. 12.7).


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Histology_Ross. The chemical nature of the neurotransmitter determines the type of response at that synapse in the generation of neuronal impulses. The release of neurotransmitter by the presynaptic component can cause either excitation or inhibition at the postsynaptic membrane.  In excitatory synapses, release of neurotransmitters such as acetylcholine, glutamine, or serotonin opens channels), prompting an influx of Na that causes local reversal of voltage of the postsynaptic membrane to a threshold level (depolarization). This leads to initiation of an action potential and generation of a nerve impulse.  In inhibitory synapses, release of neurotransmitters such as -aminobutyric acid (GABA) or glycine opens transmitter-gated Cl channels (or other anion channels), causing Cl– to enter the cell and hyperpolarize the postsynaptic membrane, making it even more negative. In these synapses, the generation of an action potential then becomes more difficult.


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Histology_Ross. The ultimate generation of a nerve impulse in a postsynaptic neuron (firing) depends on the summation of excitatory and inhibitory impulses reaching that neuron. This allows precise regulation of the reaction of a postsynaptic neuron (or muscle fiber or gland cell). The function of synapses is not simply to transmit impulses in an unchanged manner from one neuron to another. Rather, synapses allow for the processing of neuronal input. Typically, the impulse passing from the presynaptic to the postsynaptic neuron is modified at the synapse by other neurons that, although not in the direct pathway, nevertheless have access to the synapse (see Fig. 12.5). These other neurons may influence the membrane of the presynaptic neuron or the postsynaptic neuron and facilitate or inhibit the transmission of impulses. The firing of impulses in the postsynaptic neuron is caused by the summation of the actions of hundreds of synapses.


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Histology_Ross. A number of molecules that serve as neurotransmitters have been identified in various parts of the nervous system. The most common neurotransmitters are the following.


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Histology_Ross.  Acetylcholine (ACh). ACh is the neurotransmitter between axons and striated muscle at the neuromuscular junction (see page 322) and serves as a neurotransmitter in the ANS. ACh is released by the presynaptic sympathetic and parasympathetic neurons and their effectors. ACh is also secreted by postsynaptic parasympathetic neurons, as well as by a specific type of postsynaptic sympathetic neuron that innervates sweat glands. Neurons that use ACh as their neurotransmitter are called cholinergic neurons. The receptors for ACh in the postsynaptic membrane are known as cholinergic receptors and are divided into two classes on the basis of their interactions with muscarine, a substance isolated from poisonous mushrooms (muscarinic ACh receptor), and nicotine, isolated from tobacco plants (nicotinic ACh receptor). The muscarinic ACh receptor in the heart is an example of a G-protein–coupled receptor that is linked to K channels. ACh release stimulated by parasympathetic stimulation of the


Histology_Ross

Histology_Ross. ACh receptor). The muscarinic ACh receptor in the heart is an example of a G-protein–coupled receptor that is linked to K channels. ACh release stimulated by parasympathetic stimulation of the heart opens K channels, causing hyperpolarization of cardiac muscle fibers. This hyperpolarization slows rhythmic contraction of the heart. In contrast, the nicotinic ACh receptor in skeletal muscles is a transmitter-gated Na channel. Opening of this channel causes rapid depolarization of skeletal muscle fibers and initiation of contraction. Various drugs affect the release of ACh into the synaptic cleft as well as its binding to its receptors. For instance, curare, the South American arrow-tip poison—binds to Na channels and blocks the action of nicotinic ACh receptors, causing muscle paralysis. Atropin, an alkaloid extracted from the belladonna plant, blocks the action of muscarinic ACh receptors. The botulinum toxin produced by Clostridium botulinum that grows in improperly canned meat and


Histology_Ross

Histology_Ross. Atropin, an alkaloid extracted from the belladonna plant, blocks the action of muscarinic ACh receptors. The botulinum toxin produced by Clostridium botulinum that grows in improperly canned meat and vegetable products inhibits ACh release. Inhibition of ACh release decreases receptor stimulation and leads to paralysis of skeletal muscles, including respiratory muscles.


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Histology_Ross.  Catecholamines such as norepinephrine (NE), epinephrine (EPI, adrenaline), and dopamine (DA). These neurotransmitters are synthesized in a series of enzymatic reactions from the amino acid tyrosine. Neurons that use catecholamines as their neurotransmitter are called catecholaminergic neurons. Catecholamines are secreted by cells in the CNS that are involved in the regulation of movement, mood, and attention. Neurons that utilize epinephrine (adrenaline) as their neurotransmitter are called adrenergic neurons. They all contain an enzyme that converts NE to adrenaline (EPI), which serves as a transmitter between postsynaptic sympathetic axons and effectors in the ANS. EPI is also released into the bloodstream by the endocrine cells (chromaffin cells) of the adrenal medulla during the fight-or-ﬂight response.


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Histology_Ross.  Serotonin or 5-hydroxytryptamine (5-HT). Serotonin is formed by the hydroxylation and decarboxylation of tryptophan. It functions as a neurotransmitter in neurons of the CNS and enteric nervous system. Neurons that use serotonin as their neurotransmitter are called serotonergic. After the release of serotonin, a portion is recycled by reuptake into presynaptic serotonergic neurons.  Amino acids such as -aminobutyrate (GABA), glutamate (GLU), aspartate (ASP), and glycine (GLY) also act as neurotransmitters, mainly in the CNS.


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Histology_Ross.  Amino acids such as -aminobutyrate (GABA), glutamate (GLU), aspartate (ASP), and glycine (GLY) also act as neurotransmitters, mainly in the CNS.  Nitric oxide (NO), a simple gas with free radical properties, also has been identified as a neurotransmitter. At low concentrations, NO carries nerve impulses from one neuron to another. Unlike other neurotransmitters, which are synthesized in the nerve cell body and stored in synaptic vesicles, NO is synthesized within the synapse and used immediately. It is postulated that excitatory neurotransmitter GLU induces a chain reaction in which NO synthase is activated to produce NO, which in turn diffuses from the presynaptic knob via the synaptic cleft and post-synaptic membrane to the adjacent cell, resulting ultimately in generation of an action potential.


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Histology_Ross.  Small peptides have also been shown to act as synaptic transmitters. Among these are substance P (so named because it was originally found in a powder of acetone extracts of brain and intestinal tissue), hypothalamic releasing hormones, enkephalins, vasoactive intestinal peptide (VIP), cholecystokinin (CCK), and neurotensin. Many of these same substances are synthesized and released by enteroendocrine cells of the intestinal tract. They may act immediately on neighboring cells (paracrine secretion) or be carried in the bloodstream as hormones to act on distant target cells (endocrine secretion). They are also synthesized and released by endocrine organs and by the neurosecretory neurons of the hypothalamus. Neurotransmitters released into the synaptic cleft may be degraded or recaptured.


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Histology_Ross. The degradation or recapture of neurotransmitters is necessary to limit the duration of stimulation or inhibition of the post-synaptic membrane. The most common process of neurotransmitter removal after its release into the synaptic cleft is called high-affnity reuptake. About 80% of released neurotransmitters are removed by this mechanism, in which they are bound into specifc neurotransmitter transport proteins located in the presynaptic membrane. Neurotransmitters that were transported into the cytoplasm of the presynaptic bouton are either enzymatically destroyed or reloaded into empty synaptic vesicles. For example, the action of catecholamines on postsynaptic receptors is terminated by the reuptake of neurotransmitters into the presynaptic bouton utilizing Nadependent transporters. The efficiency of this uptake can be regulated by several pharmacologic agents such as amphetamine and cocaine, which block catecholamine reuptake and prolong the actions of neurotransmitters on the


Histology_Ross

Histology_Ross. The efficiency of this uptake can be regulated by several pharmacologic agents such as amphetamine and cocaine, which block catecholamine reuptake and prolong the actions of neurotransmitters on the postsynaptic neurons. Once inside the presynaptic bouton, catecholamines are reloaded into synaptic vesicles for future use. The excess of catecholamines is inactivated by the enzyme catechol O-methyltransferase (COMT) or is destroyed by another enzyme found on the outer mitochondrial membrane, monoamine oxidase (MAO). Therapeutic substances that inhibit the action of MAO are frequently used in the treatment of clinical depression; selective COMT inhibitors have been also developed.


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Histology_Ross. Enzymes associated with the postsynaptic membrane degrade the remaining 20% of neurotransmitters. For example, acetylcholinesterase (AChE), which is secreted by the muscle cell into the synaptic cleft, rapidly degrades ACh into acetic acid and choline. Choline is then taken up by the cholinergic presynaptic bouton and reused for ACh synthesis. The AChE action at the neuromuscular junction can be inhibited by various pharmacological compounds, nerve agents, and pesticides resulting in prolonged muscle contraction. Clinically, AChE inhibitors have been used clinically in the treatment of myasthenia gravis (see Folder 11.4 in Chapter 11), a degenerative neuromuscular disorder, glaucoma, and more recently Alzheimer’s disease. Substances needed in the axon and dendrites are synthesized in the cell body and require transport to those sites.


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Histology_Ross. Substances needed in the axon and dendrites are synthesized in the cell body and require transport to those sites. Most neurons possess elaborate axonal and dendritic processes. Because the synthetic activity of the neuron is concentrated in the nerve cell body, axonal transport is required to convey newly synthesized material to the processes. Axonal transport is a bidirectional mechanism. It serves as a mode of intracellular communication, carrying molecules and information along the microtubules and intermediate filaments from the axon terminal to the nerve cell body and from the nerve cell body to the axon terminal. Axonal transport is described as the following:  Anterograde transport carries material from the nerve cell body to the periphery. Kinesin, a microtubule-associated motor protein that uses ATP, is involved in anterograde transport (see page 59).


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Histology_Ross.  Retrograde transport carries material from the axon terminal and the dendrites to the nerve cell body. This transport is mediated by another microtubule-associated motor protein, dynein (see page 59). The transport systems may also be distinguished by the rate at which substances are transported:  A slow transport system conveys substances from the cell body to the terminal bouton at the speed of 0.2 to 4 mm/day. It is only an anterograde transport system. Structural elements such as tubulin molecules (microtubule precursors), actin molecules, and the proteins that form neurofilaments are carried from the nerve cell body by the slow transport system. So, too, are cytoplasmic matrix proteins such as actin, calmodulin, and various metabolic enzymes.


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Histology_Ross.  A fast transport system conveys substances in both directions at a rate of 20 to 400 mm/day. Thus, it is both an anterograde and a retrograde system. The fast anterograde transport system carries to the axon terminal different membrane-limited organelles, such as sER components, synaptic vesicles, and mitochondria, and low-molecular-weight materials such as sugars, amino acids, nucleotides, some neurotransmitters, and calcium. The fast retrograde transport system carries to the nerve cell body many of the same materials as well as proteins and other molecules endocytosed at the axon terminal. Fast transport in either direction requires ATP, which is used by microtubuleassociated motor proteins, and depends on the microtubule arrangement that extends from the nerve cell body to the termination of the axon. Retrograde transport is the pathway followed by toxins and viruses that enter the CNS at nerve endings. Retrograde transport of exogenous enzymes, such as horseradish peroxidase,


Histology_Ross

Histology_Ross. of the axon. Retrograde transport is the pathway followed by toxins and viruses that enter the CNS at nerve endings. Retrograde transport of exogenous enzymes, such as horseradish peroxidase, and of radiolabeled or immunolabeled tracer materials is now used to trace neuronal pathways and to identify the nerve cell bodies related to specific nerve endings.


Histology_Ross

Histology_Ross. Dendritic transport appears to have the same characteris tics and to serve the same functions for the dendrite as axonal transport does for the axon. SUPPORTING CELLS OF THE NERVOUS SYSTEM: THE NEUROGLIA In the PNS, supporting cells are called peripheral neuroglia; in the CNS, they are called central neuroglia. Peripheral neuroglia include Schwann cells, satellite cells, and a variety of other cells associated with specific organs or tissues. Examples of the latter include terminal neuroglia (teloglia), which are associated with the motor end plate; enteric neuroglia associated with the ganglia located in the wall of the alimentary canal; and Mler’s cells in the retina. Schwann Cells and the Myelin Sheath In the PNS, Schwann cells produce the myelin sheath.


Histology_Ross

Histology_Ross. Schwann Cells and the Myelin Sheath In the PNS, Schwann cells produce the myelin sheath. The main function of Schwann cells is to support myelinated and unmyelinated nerve cell fibers. Schwann cells develop from neural crest cells and differentiate by expressing transcription factor Sox-10. In the PNS, Schwann cells produce a lipid-rich layer called the myelin sheath that surrounds the axons (Fig. 12.9). The myelin sheath isolates the axon from the surrounding extracellular compartment of endoneurium. Its presence ensures the rapid conduction of nerve impulses. The axon hillock and the terminal arborizations where the axon synapses with its target cells are not covered by myelin. Unmyelinated fibers are also enveloped and nurtured by Schwann cell cytoplasm. In addition, Schwann cells aid in cleaning up PNS debris and guide the regrowth of PNS axons. Myelination begins when a Schwann cell surrounds the axon and its cell membrane becomes polarized.


Histology_Ross

Histology_Ross. Myelination begins when a Schwann cell surrounds the axon and its cell membrane becomes polarized. During formation of the myelin sheath (also called myelination), the axon initially lies in a groove on the surface of the Schwann cell (Fig. 12.10a). A 0.08to 0.1-mm segment of the axon then becomes enclosed within each Schwann cell that lies along the axon. The Schwann cell surface becomes polarized into two functionally distinct membrane domains. The part of the Schwann cell membrane that is exposed to the external environment or endoneurium, the abaxonal plasma membrane, represents one domain. The other domain is represented by the adaxonal or periaxonal plasma membrane, which is in direct contact with the axon. When the axon is completely enclosed by the Schwann cell membrane, a third domain, the mesaxon, is created (Fig. 12.10b). This third domain is a double membrane that connects the abaxonal and adaxonal membranes and encloses the narrow extracellular space.


Histology_Ross

Histology_Ross. The myelin sheath develops from compacted layers of Schwann cell mesaxon wrapped concentrically around the axon. Myelin sheath formation is initiated when the Schwann cell mesaxon surrounds the axon. A sheetlike extension of the mesaxon then wraps around the axon in a spiraling motion. The first few layers or lamellae of the spiral are not compactly


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Histology_Ross. FIGURE 12.9 • Photomicrographs of a peripheral nerve in cross and longitudinal sections. a. Photomicrograph of an osmium-fixed, toluidine blue–stained peripheral nerve cut in cross-section. The axons (A) appear clear. The myelin is represented by the dark ring surrounding the axons. Note the variation in diameter of the individual axons. In some of the nerves, the myelin appears to consist of two separate rings (asterisks). This is caused by the section passing through a Schmidt-Lanterman cleft. Epi, epineurium. 640. b. Photomicrograph showing longitudinally sectioned myelinated nerve axons (A) in the same preparation as above. A node of Ranvier (NR) is seen near the center of the micrograph. In the same axon, a Schmidt-Lanterman cleft (SL) is seen on each side of the node. In addition, a number of Schmidt-Lanterman clefts can be seen in the adjacent axons. The perinodal cytoplasm of the Schwann cell at the node of Ranvier and the Schwann cell cytoplasm at the Schmidt-Lanterman cleft


Histology_Ross

Histology_Ross. number of Schmidt-Lanterman clefts can be seen in the adjacent axons. The perinodal cytoplasm of the Schwann cell at the node of Ranvier and the Schwann cell cytoplasm at the Schmidt-Lanterman cleft appear virtually unstained. 640.


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Histology_Ross. FIGURE 12.10 • Diagram showing successive stages in the formation of myelin by a Schwann cell. a. The axon initially lies in a groove on the surface of the Schwann cell. b. The axon is surrounded by a Schwann cell. Note the two domains of the Schwann cell, the adaxonal plasma-membrane domain and abaxonal plasma-membrane domain. The mesaxon plasma membrane links these domains. The mesaxon membrane initiates myelination by surrounding the embedded axon. c. A sheetlike extension of the mesaxon membrane then wraps around the axon, forming multiple membrane layers. d. During the wrapping process, the cytoplasm is extruded from between the two apposing plasma membranes of the Schwann cell, which then become compacted to form myelin. The outer mesaxon represents invaginated plasma membrane extending from the abaxonal surface of the Schwann cell to the myelin. The inner mesaxon extends from the adaxonal surface of the Schwann cell (the part facing the axon) to the myelin. The inset shows the


Histology_Ross

Histology_Ross. from the abaxonal surface of the Schwann cell to the myelin. The inner mesaxon extends from the adaxonal surface of the Schwann cell (the part facing the axon) to the myelin. The inset shows the major proteins responsible for compaction of the myelin sheath. MBP, myelin basic protein; Nrq1, neurorequlin; P0, protein 0; PMP22, peripheral myelin protein of 22 kilodaltons.


Histology_Ross

Histology_Ross. arranged—that is, some cytoplasm is left in the first few concentric layers (Fig. 12.10c). The TEM reveals the presence of a 12to 14-nm gap between the outer (extracellular) leaflets and the Schwann cell cytoplasm that separates the inner (cytoplasmic) leaflets. As the wrapping progresses, cytoplasm is squeezed out from between the membrane of the concentric layers of the Schwann cell.


Histology_Ross

Histology_Ross. External to, and contiguous with, the developing myelin sheath is a thin outer collar of perinuclear cytoplasm called the sheath of Schwann. This part of the cell is enclosed by an abaxonal plasma membrane and contains the nucleus and most of the organelles of the Schwann cell. Surrounding the Schwann cell is a basal or external lamina. The apposition of the mesaxon of the last layer to itself as it closes the ring of the spiral produces the outer mesaxon, the narrow intercellular space adjacent to the external lamina. Internal to the concentric layers of the developing myelin sheath is a narrow inner collar of Schwann cell cytoplasm surrounded by the adaxonal plasma membrane. The narrow intercellular space between mesaxon membranes communicates with the adaxonal plasma membrane to produce the inner mesaxon (Fig. 12.10d).


Histology_Ross

Histology_Ross. Once the mesaxon spirals on itself, the 12to 14-nm gaps disappear and the membranes form the compact myelin sheath. Compaction of the sheath corresponds with the expression of transmembrane myelin-specifc proteins such as protein 0 (P0), a peripheral myelin protein of 22 kilodaltons (PMP22),and myelin basic protein (MBP). The inner (cytoplasmic) leaflets of the plasma membrane come close together as a result of the positively charged cytoplasmic domains of P0 and MBP. With the TEM, these closely aligned inner leaflets are electron opaque, appearing as the major dense lines in the TEM image of myelin (Fig. 12.10d). The concentric dense lamellae alternate with the slightly less dense intraperiod lines that are formed by closely apposed, but not fused, outer (extracellular) membrane leaflets. The narrow 2.5-nm gap corresponds to the remaining extracellular space containing the extracellular domains of P0 protein (Fig. 12.10d). P0 is a 30-kilodalton cell adhesion molecule expressed within


Histology_Ross

Histology_Ross. The narrow 2.5-nm gap corresponds to the remaining extracellular space containing the extracellular domains of P0 protein (Fig. 12.10d). P0 is a 30-kilodalton cell adhesion molecule expressed within the mesoaxial plasma membrane during myelination. This transmembrane glycoprotein mediates strong adhesions between the two opposite membrane layers and represents a key structural component of peripheral nerve myelin. Structural and genetic studies indicate that mutations in human genes encoding P0 produce unstable myelin and may contribute to the development of demyelinating diseases (see Folder 12.2).


Histology_Ross

Histology_Ross. In general, demyelinating diseases are characterized by preferential damage to the myelin sheath. Clinical symp-toms of these diseases are related to decreased or lost ability to transmit electrical impulses along nerve fibers. Several immune-mediated diseases affect the myelin sheath. Guillain-Barré syndrome, known also as acute in-fammatory demyelinating polyradiculoneuropathy, is one of the most common life-threatening diseases of the PNS. Microscopic examination of nerve fibers obtained from patients affected by this disease shows a large accu-mulation of lymphocytes, macrophages, and plasma cells around nerve fibers within nerve fascicles. Large segments of the myelin sheath are damaged, leaving the axons ex-posed to the extracellular matrix. These findings are consis-tent with a T cell–mediated immune response directed against myelin, which causes its destruction and slows or blocks nerve conduction. Patients exhibit symptoms of as-cending muscle paralysis, loss of muscle


Histology_Ross

Histology_Ross. a T cell–mediated immune response directed against myelin, which causes its destruction and slows or blocks nerve conduction. Patients exhibit symptoms of as-cending muscle paralysis, loss of muscle coordination, and loss of cutaneous sensation. Multiple sclerosis (MS) is a disease that attacks myelin in the CNS. MS is also characterized by preferential damage to myelin, which becomes detached from the axon and is eventually destroyed. In addition, destruction of oligodendroglia, which are responsible for the synthesis and maintenance of myelin, occurs. The myelin basic protein appears to be the major autoimmune target in this disease. Chemical changes in the lipid and protein con-stituents of myelin produce irregular, multiple plaques throughout the white matter of the brain. Symptoms of MS depend on the area in the CNS in which myelin is dam-aged. MS is usually characterized by distinct episodes of neurologic deficits such as unilateral vision impairment, loss of cutaneous


Histology_Ross

Histology_Ross. of MS depend on the area in the CNS in which myelin is dam-aged. MS is usually characterized by distinct episodes of neurologic deficits such as unilateral vision impairment, loss of cutaneous sensation, lack of muscle coordination and movement, and loss of bladder and bowel control. Treatment of both diseases is related to diminishing the causative immune response by immunomodulatory therapy with interferon as well as by administrating adrenal steroids. For more severe, progressive forms, immunosup-pressive drugs may be used.


Histology_Ross

Histology_Ross.  FOLDER 12.2 Clinical Correlation: Demyelinating Diseases The thickness of the myelin sheath at myelination is determined by axon diameter and not by the Schwann cell. Myelination is an example of cell-to-cell communication in which the axon interacts with the Schwann cell. Experimental studies show that the number of layers of myelin is determined by the axon and not by the Schwann cell. Myelin sheath thickness is regulated by a growth factor called neuregulin (Ngr1) that acts on Schwann cells. Ngr1 is a transmembrane protein expressed on the axolemma (cell membrane) of the axon. The node of Ranvier represents the junction between two adjacent Schwann cells.


Histology_Ross

Histology_Ross. The node of Ranvier represents the junction between two adjacent Schwann cells. The myelin sheath is segmented because it is formed by numerous Schwann cells arrayed sequentially along the axon. The junction where two adjacent Schwann cells meet is devoid of myelin. This site is called the node of Ranvier. Therefore, the myelin between two sequential nodes of Ranvier is called an internodal segment (Plate 28, page 392).


Histology_Ross

Histology_Ross. Myelin is composed of about 80% lipids because, as the Schwann cell membrane winds around the axon, the cytoplasm of the Schwann cell, as noted, is extruded from between the opposing layers of the plasma membranes. Electron micrographs, however, typically show small amounts of cytoplasm in several locations (Figs. 12.11 and 12.12): The inner collar of Schwann cell cytoplasm, between the axon and the myelin; the Schmidt-Lanterman clefts, small islands within successive lamellae of the myelin; perinodal cytoplasm, at the node of Ranvier; and the outer collar of perinuclear cytoplasm, around the myelin (Fig. 12.13). These areas of cytoplasm are what light microscopists identified as the Schwann sheath. If one conceptually unrolls the Schwann cell process, as shown in Figure 12.14, its full extent can be appreciated, and the inner collar of Schwann cell cytoplasm can be seen to be continuous with the body of the Schwann cell through the Schmidt-Lanterman clefts and through the perinodal


Histology_Ross

Histology_Ross. extent can be appreciated, and the inner collar of Schwann cell cytoplasm can be seen to be continuous with the body of the Schwann cell through the Schmidt-Lanterman clefts and through the perinodal cytoplasm. Cytoplasm of the clefts contains lysosomes and occasional mitochondria and microtubules, as well as cytoplasmic inclusions, or dense bodies. The number of Schmidt-Lanterman clefts correlates with the diameter of the axon; larger axons have more clefts.


Histology_Ross

Histology_Ross. Unmyelinated axons in the peripheral nervous system are enveloped by Schwann cells and their external lamina. The nerves in the PNS that are described as unmyelinated are nevertheless enveloped by Schwann cell cytoplasm as shown in Figure 12.15. The Schwann cells are elongated in parallel to the long axis of the axons, and the axons fit into grooves in the surface of the cell. The lips of the groove may be open, exposing a portion of the axolemma of the axon to the adjacent external lamina of the Schwann cell, or the lips may be closed, forming a mesaxon. A single axon or a group of axons may be enclosed in a single invagination of the Schwann cell surface. Large Schwann cells in the PNS may have 20 or more grooves, each containing one or more axons. In the ANS, it is common for bundles of unmyelinated axons to occupy a single groove.


Histology_Ross

Histology_Ross. The neuronal cell bodies of ganglia are surrounded by a layer of small cuboidal cells called satellite cells. Although they form a complete layer around the cell body, only their nuclei are typically visible in routine H&E preparations (Fig. 12.16, a and b). In paravertebral and peripheral ganglia, neural cell


Histology_Ross

Histology_Ross. FIGURE 12.11 • Electron micrograph of an axon in the process of myelination. At this stage of development, the myelin (M) consists of about six membrane layers. The inner mesaxon (IM) and outer mesaxon (OM) of the Schwann cell (SC) represent parts of the mesaxon membrane. Another axon (see upper left A) is present that has not yet been embedded within a Schwann cell mesaxon. Other notable features include the Schwann cell basal (external) lamina (BL) and the considerable amount of Schwann cell cytoplasm associated with the myelination process. 50,000. (Courtesy of Dr. Stephen G. Waxman.) processes must penetrate between the satellite cells to establish a synapse (there are no synapses in sensory ganglia). They help to establish and maintain a controlled microenvironment around the neuronal body in the ganglion, providing electrical insulation as well as a pathway for metabolic exchanges. Thus, the functional role of the satellite cell is analogous to that of the Schwann cell except


Histology_Ross

Histology_Ross. body in the ganglion, providing electrical insulation as well as a pathway for metabolic exchanges. Thus, the functional role of the satellite cell is analogous to that of the Schwann cell except that it does not make myelin.


Histology_Ross

Histology_Ross. Neurons and their processes located within ganglia of the enteric division of the ANS are associated with enteric neuroglial cells. These cells are morphologically and functionally similar to astrocytes in the CNS (see below). Enteric neuroglial cells share common functions with astrocytes, such as structural, metabolic, and protective support of neurons. However, recent studies indicate that enteric glial cells may also participate in enteric neurotransmission and help coordinate activities of the nervous and immune systems of the gut.


Histology_Ross

Histology_Ross. There are four types of central neuroglia:  Astrocytes are morphologically heterogeneous cells that provide physical and metabolic support for neurons of the CNS.  Oligodendrocytes are small cells that are active in the formation and maintenance of myelin in the CNS.  Microglia are inconspicuous cells with small, dark, elongated nuclei that possess phagocytotic properties.  Ependymal cells are columnar cells that line the ventricles of the brain and the central canal of the spinal cord. Only the nuclei of glial cells are seen in routine histologic preparations of the CNS. Heavy-metal staining or immunocytochemical methods are necessary to demonstrate the shape of the entire glial cell.


Histology_Ross

Histology_Ross. Although glial cells have long been described as supporting cells of nerve tissue in the purely physical sense, current concepts emphasize the functional interdependence of neuroglial cells and neurons. The most obvious example of physical support occurs during development. The brain and spinal cord develop from the embryonic neural tube. In the head region, the neural tube undergoes remarkable thickening and folding, leading ultimately to the final structure, the brain. During the early stages of the process, embryonic glial cells extend through the entire thickness of the neural tube in a radial manner. These radial glial cells serve as the physical scaffolding that directs the migration of neurons to their appropriate position in the brain. Astrocytes are closely associated with neurons to support and modulate their activities.


Histology_Ross

Histology_Ross. Astrocytes are closely associated with neurons to support and modulate their activities. Astrocytes are the largest of the neuroglial cells. They form a network of cells within the CNS and communicate with neurons to support and modulate many of their activities. Some astrocytes span the entire thickness of the brain, providing a scaffold for migrating neurons during brain development. Other astrocytes stretch their processes from blood vessels to neurons. The ends of the processes expand, forming end feet that cover large areas of the outer surface of the vessel or axolemma. Astrocytes do not form myelin. Two kinds of astrocytes are identified:  Protoplasmic astrocytes are more prevalent in the outermost covering of brain called gray matter. These astrocytes have numerous, short, branching cytoplasmic processes (Fig. 12.17).


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Histology_Ross.  Fibrous astrocytes are more common in the inner core of the brain called white matter. These astrocytes have fewer processes, and they are relatively straight (Fig. 12.18). Both types of astrocytes contain prominent bundles of intermediate filaments composed of glial fbrillary acidic protein (GFAP). The filaments are much more numerous in


Histology_Ross

Histology_Ross. FIGURE 12.12 • Electron micrograph of a mature myelinated axon. The myelin sheath (M) shown here consists of 19 paired layers of Schwann cell membrane. The pairing of membranes in each layer is caused by the extrusion of the Schwann cell cytoplasm. The axon displays an abundance of neurofilaments, most of which have been cross-sectioned, giving the axon a stippled appearance. Also evident in the axon are microtubules (MT ) and several mitochondria (Mit). The outer collar of Schwann cell cytoplasm (OCS) is relatively abundant compared with the inner collar of Schwann cell cytoplasm (ICS). The collagen fibrils (C) constitute the fibrillar component of the endoneurium. BL, basal (external) lamina. 70,000. Inset. Higher magnification of the myelin. The arrow points to cytoplasm within the myelin that would contribute to the appearance of the Schmidt-Lanterman cleft as seen in the light microscope. It appears as an isolated region here because of the thinness of the section. The


Histology_Ross

Histology_Ross. the myelin that would contribute to the appearance of the Schmidt-Lanterman cleft as seen in the light microscope. It appears as an isolated region here because of the thinness of the section. The intercellular space between axon and Schwann cell is indicated by the arrowhead. A coated vesicle (CV) in an early stage of formation appears in the outer collar of the Schwann cell cytoplasm. 130,000. (Courtesy of Dr. George D. Pappas.) inner collar of Schwann cell cytoplasm


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Histology_Ross. FIGURE 12.14 • Three-dimensional diagrams conceptualizing the relationship of myelin and cytoplasm of a Schwann cell. This diagram shows a hypothetically uncoiled Schwann cell. Note how the inner collar of the Schwann cell cytoplasm is continuous with the outer collar of Schwann cell cytoplasm via Schmidt-Lanterman clefts. the fibrous astrocytes, however, hence the name. Antibodies to GFAP are used as specific stains to identify astrocytes in sections and tissue cultures (see Fig. 12.18b). Tumors arising from fbrous astrocytes, fibrous astrocytomas, account for about 80% of adult primary brain tumors. They can be identified microscopically and by their GFAP specificity.


Histology_Ross

Histology_Ross. Astrocytes play important roles in the movement of metabolites and wastes to and from neurons. They help maintain the tight junctions of the capillaries that form the blood–brain barrier (see page 385). In addition, astrocytes provide a covering for the “bare areas” of myelinated axons— for example, at the nodes of Ranvier and at synapses. They may confine neurotransmitters to the synaptic cleft and remove excess neurotransmitters by pinocytosis. Protoplasmic astrocytes on the brain and spinal cord surfaces extend their processes (subpial feet) to the basal lamina of the pia mater to form the glia limitans, a relatively impermeable barrier surrounding the CNS (Fig. 12.19). Astrocytes modulate neuronal activities by buffering the K concentration in the extracellular space of the brain.


Histology_Ross

Histology_Ross. Astrocytes modulate neuronal activities by buffering the K concentration in the extracellular space of the brain. It is now generally accepted that astrocytes regulate K concentrations in the brain’s extracellular compartment, thus maintaining the microenvironment and modulating activities of the neurons. The astrocyte plasma membrane contains an abundance of K pumps and K channels that mediate the transfer K ions from areas of high to low concentration. Accumulation of large amounts of intracellular K in astrocytes decreases local extracellular K gradients. The astrocyte membrane becomes depolarized, and the charge is dissipated over a large area by the extensive network of astrocyte processes. The maintenance of the K concentration in the brain’s extracellular space by astrocytes is called potassium spatial buffering. Oligodendrocytes produce and maintain the myelin sheath in the CNS.


Histology_Ross

Histology_Ross. Oligodendrocytes produce and maintain the myelin sheath in the CNS. The oligodendrocyte is the cell responsible for producing CNS myelin. The myelin sheath in the CNS is formed by concentric layers of oligodendrocyte plasma membrane. The formation of the sheath in the CNS is more complex, however, than the simple wrapping of Schwann cell mesaxon membranes that occurs in the PNS (page 364).