Histology Nervous System PDF

C H A P T E R 9 DEVELOPMENT OF NERVE TISSUE Nerve Tissue & the Nervous System 161 CENTRAL NERVOUS SYSTEM...

C H A P T E R 9 DEVELOPMENT OF NERVE TISSUE Nerve Tissue & the Nervous System 161 CENTRAL NERVOUS SYSTEM 175 NEURONS 163 Meninges 179 Cell Body (Perikaryon) 163 Blood-Brain Barrier 180 Dendrites 165 Choroid Plexus 181 Axons 165 PERIPHERAL NERVOUS SYSTEM 182 Nerve Impulses 166 Nerve Fibers 182 Synaptic Communication 167 Nerve Organization 184 GLIAL CELLS & NEURONAL ACTIVITY 168 Ganglia 185 Oligodendrocytes 168 NEURAL PLASTICITY & REGENERATION 187 Astrocytes 168 SUMMARY OF KEY POINTS 190 Ependymal Cells 173 ASSESS YOUR KNOWLEDGE 191 Microglia 173 Schwann Cells 174 Satellite Cells of Ganglia 174 T he human nervous system, by far the most complex sys- tem in the body, is formed by a network of many billion nerve cells (neurons), all assisted by many more sup- porting cells called glial cells. Each neuron has hundreds of interconnections with other neurons, forming a very complex electrical potential, but cells that can rapidly change this poten- tial in response to stimuli (eg, neurons, muscle cells, some gland cells) are said to be excitable or irritable. Neurons react promptly to stimuli with a reversal of the ionic gradient (mem- brane depolarization) that generally spreads from the place system for processing information and generating responses. that received the stimulus and is propagated across the neuron’s Nerve tissue is distributed throughout the body as an entire plasma membrane. This propagation, called the action integrated communications network. Anatomically, the gen- potential, the depolarization wave, or the nerve impulse, eral organization of the nervous system (Figure 9–1) has two is capable of traveling long distances along neuronal processes, major divisions: transmitting such signals to other neurons, muscles, and glands. By collecting, analyzing, and integrating information in ⌀ Central nervous system (CNS), consisting of the brain such signals, the nervous system continuously stabilizes the and spinal cord intrinsic conditions of the body (eg, blood pressure, O2 and CO2 ⌀ Peripheral nervous system (PNS), composed of content, pH, blood glucose levels, and hormone levels) within the cranial, spinal, and peripheral nerves conducting normal ranges and maintains behavioral patterns (eg, feeding, impulses to and from the CNS (sensory and motor reproduction, defense, interaction with other living creatures). nerves, respectively) and ganglia that are small aggre- gates of nerve cells outside the CNS. Cells in both central and peripheral nerve tissue are of two kinds: neurons, which typically have numerous long ›â ºDEVELOPMENT OF NERVE TISSUE processes, and various glial cells (Gr. glia, glue), which have The nervous system develops from the outermost of the three short processes, support and protect neurons, and participate early embryonic layers, the ectoderm, beginning in the third in many neural activities, neural nutrition, and defense of cells week of development (Figure 9–2). With signals from the in the CNS. underlying axial structure, the notochord, ectoderm on the Neurons respond to environmental changes (stimuli) mid-dorsal side of the embryo thickens to form the epithelial by altering the ionic gradient that exists across their plasma neural plate. The sides of this plate fold upward and grow membranes. All cells maintain such a gradient, also called an toward each other medially, and within a few days fuse to form 161  FIGURE 9–1â ‡ The general organization of the nervous system. Anatomically the nervous system is divided into the CNS and PNS, Cerebrum which have the major components shown in the diagram. Central Cerebellum nervous Functionally the nervous system consists of: Spinal system (CNS) cord 1. Sensory division (afferent) A.â ‡Somatic – sensory input perceived consciously (eg, from eyes ears, skin, musculoskeletal structures) Cranial B.â ‡Visceral – sensory input not perceived consciously (eg, from nerves Peripheral internal organs and cardiovascular Neural groove structures) Spinal nervous 2. Motor division (efferent) nerves system (PNS) A.â ‡Somatic – motor output controlled consciously or volun- Ganglia Neural tarily (eg, by skeletal muscle effectors) crest Neural folds B.â ‡Autonomic – motor output not controlled consciously (eg, Notochord by heart or gland effectors) The autonomic motor nerves, comprising what is often called the autonomic nervous system (ANS), all have pathways involving Neural folds and neural groove form two neurons: a1preganglionic neuron with the cell body in the CNS from the neural plate. and a postganglionic neuron with the cell body in a ganglion. The ANS has two divisions: (1) The parasympathetic division, with its ganglia within or near the effector Neuralorgans, groove maintains normal body homeostasis. (2) The sympathetic division has its ganglia close to the CNS and controls the body’s responses during emergencies and excitement. ANS components located in the wall of the digestive tract are sometimes referred to as the enteric nervous system. 2 Neural folds elevate and approach one FIGURE 9–2â ‡ Neurulation in the early embryo. another. Neural groove Neural groove Neural Ectoderm crest cells Neural crest Neural folds Notochord 3 As neural folds prepare to fuse and form the neural tube and dorsal epidermis, 1 Neural folds and neural groove form neural crest cells loosen and become from the neural plate. mesenchymal. Neural groove Neural tube Neural crest cells Developing epidermis 2 Neural folds elevate and approach one another. 4 The mass of neural crest cells initially lies atop the newly formed neural tube. Neural groove Stages in the process of neurulation, by which cells of the CNS and PNS are produced, are shown in diagrammatic cross sections of a 3- and 4-week human embryo with the extraembryonic membranes Neuralremoved. Under an inductive influence from the medial notochord, the over- lying layer of ectodermal cells thickens as a bending neural Ectoderm crestplate, with a medial neural groove and lateral neural folds (1). All other ecto- cells derm will become epidermis. The plate bends further, making the neural folds and groove more prominent (2). The neural folds rise and fuse at the midline (3), converting the groove into the neural tube (4), which is large at the cranial end of the embryo and much narrower caudally. The neural tube will give rise to the entire CNS. As the neural tube detaches from the now overlying ectoderm, many cells separate from it and produce a mass of mesenchymal cells called the neural crest. Located initially above the neural tube, neural crest cells immediately begin migrating laterally. Cell derived from the neural crest 3 Aswill formfolds neural all components of the prepare to fuse andPNS and also contribute to certain non-neural tissues. form the neural tube and dorsal epidermis, neural crest cells loosen and become mesenchymal.  Neurons 163 the neural tube. Cells of this tube give rise to the entire CNS, stimuli from receptors throughout the body. Motor neu- including neurons and most glial cells. rons are efferent, sending impulses to effector organs such C H A P T E R As the folds fuse and the neural tube separates from the as muscle fibers and glands. Somatic motor nerves are under now overlying surface ectoderm that will form epidermis, a voluntary control and typically innervate skeletal muscle; large population of developmentally important cells, the neu- autonomic motor nerves control the involuntary or uncon- ral crest, separates from the neuroepithelium and becomes scious activities of glands, cardiac muscle, and most smooth mesenchymal. Neural crest cells migrate extensively and dif- muscle. ferentiate as all the cells of the PNS, as well as a number of Interneurons establish relationships among other neu- 9 other non-neuronal cell types. rons, forming complex functional networks or circuits in Nerve Tissue & the Nervous Systemâ ‡ â ‡Neurons the CNS. Interneurons are either multipolar or anaxonic and comprise 99% of all neurons in adults. ›â ºNEURONS In the CNS most neuronal perikarya occur in the gray matter, with their axons concentrated in the white matter. The functional unit in both the CNS and PNS is the neuron. These terms refer to the general appearance of unstained CNS Some neuronal components have special names, such as “neu- tissue caused in part by the different densities of nerve cell rolemma” for the cell membrane. Most neurons have three bodies. In the PNS cell bodies are found in ganglia and in main parts (Figure 9–3): some sensory regions, such as the olfactory mucosa, and axons ⌀ The cell body (also called the perikaryon or soma) are bundled in nerves. which contains the nucleus and most of the cell’s organ- elles and serves as the synthetic or trophic center for the entire neuron. › ⠺⠺ MEDICAL APPLICATION ⌀ The dendrites, which are the numerous elongated pro- Parkinson disease is a slowly progressing disorder affecting cesses extending from the perikaryon and specialized to muscular activity characterized by tremors, reduced activity receive stimuli from other neurons at unique sites called of the facial muscles, loss of balance, and postural stiffness. synapses. It is caused by gradual loss by apoptosis of dopamine- ⌀ The axon (Gr. axon, axis), which is a single long process producing neurons whose cell bodies lie within the nuclei ending at synapses specialized to generate and conduct of the CNS substantia nigra. Parkinson disease is treated nerve impulses to other cells (nerve, muscle, and gland with l-dopa (L-3,4-dihydroxyphenylalanine), a precursor of cells). Axons may also receive information from other dopamine which augments the declining production of this neurons, information that mainly modifies the transmis- neurotransmitter. sion of action potentials to those neurons. Neurons and their processes are extremely variable in size and shape. Cell bodies can be very large, measuring up to 150 μm in diameter. Other neurons, such as the cerebellar Cell Body (Perikaryon or Soma) granule cells, are among the body’s smallest cells. The neuronal cell body contains the nucleus and surround- Neurons can be classified according to the number of pro- ing cytoplasm, exclusive of the cell processes (Figure 9–3). cesses extending from the cell body (Figure 9–4): It acts as a trophic center, producing most cytoplasm for the processes. Most cell bodies are in contact with a great number ⌀ Multipolar neurons, each with one axon and two or of nerve endings conveying excitatory or inhibitory stimuli more dendrites, are the most common. generated in other neurons. A typical neuron has an unusu- ⌀ Bipolar neurons, with one dendrite and one axon, ally large, euchromatic nucleus with a prominent nucleolus, comprise the sensory neurons of the retina, the olfactory indicating intense synthetic activity. epithelium, and the inner ear. Cytoplasm of perikarya often contains numerous free ⌀ Unipolar or pseudounipolar neurons, which include polyribosomes and highly developed RER, indicating active all other sensory neurons, each have a single process that production of both cytoskeletal proteins and proteins for bifurcates close to the perikaryon, with the longer branch transport and secretion. Histologically these regions with con- extending to a peripheral ending and the other toward centrated RER and other polysomes are basophilic and are the CNS. distinguished as chromatophilic substance (or Nissl sub- ⌀ Anaxonic neurons, with many dendrites but no true stance, Nissl bodies) (Figure 9–3). The amount of this mate- axon, do not produce action potentials, but regulate elec- rial varies with the type and functional state of the neuron and trical changes of adjacent CNS neurons. is particularly abundant in large nerve cells such as motor neu- Because the fine processes emerging from cell bodies are rons (Figure 9–3b). The Golgi apparatus is located only in the seldom seen in sections of nervous tissue, it is difficult to clas- cell body, but mitochondria can be found throughout the cell sify neurons structurally by microscopic inspection. and are usually abundant in the axon terminals. Nervous components can also be subdivided function- In both perikarya and processes microtubules, actin ally (Figure 9–1). Sensory neurons are afferent, receiving filaments, and intermediate filaments are abundant, with the FIGURE 9–3â ‡ Structures of a typical neuron. G D Dendrites Nucleolus NS Nucleus Cell body N Chromatophilic (Nissl) substance Axon hillock Axoplasm Axolemma AH Neurofibrils Axon (beneath Axon collateral myelin sheath) Neurolemmocyte Neurofibril node A Myelin sheath b Telodendria Synaptic knobs Synaptic vesicles containing neurotransmitter Synaptic cleft Postsynaptic neuron (or effector) Synapse a (a) A “typical” neuron has three major parts: (1) The cell body (also called the perikaryon or soma) is often large, with a large, euchromatic nucleus and well-developed nucleolus. The cyto- plasmic contains basophilic Nissl substance or Nissl bodies, which are large masses of free polysomes and RER indicating the cell’s high rate of protein synthesis. (2) Numerous short den- drites extend from the perikaryon, receiving input from other neurons. (3) A long axon carries impulses from the cell body and is covered by a myelin sheath composed of other cells. The ends of axons usually have many small branches (telodendria), each of which ends in a knob-like structure that forms part of a func- tional connection (synapse) with another neuron or other cell. (b) Micrograph of a large motor neuron showing the large cell body and nucleus (N), a long axon (A) emerging from an axon hillock (AH), and several dendrites (D). Nissl substance (NS) can be seen throughout the cell body and cytoskeletal elements can be detected in the processes. Nuclei of scattered glial cells (G) are seen among the surrounding tissue. (X100; H&E)  Neurons 165 FIGURE 9–4â ‡ Structural classes of neurons. C H A P T E R Dendrites Cell body Dendrite Cell body Axon 9 b Bipolar neuron Nerve Tissue & the Nervous Systemâ ‡ â ‡Neurons Axon Dendrites a Multipolar neuron Axon Peripheral process Central process Cell body Dendrites Dendrites Cell body Single short process c Unipolar neuron d Anaxonic neuron Shown are the four main types of neurons, with short descriptions. neurons are unipolar or pseudounipolar. (d) Anaxonic neurons (a) Most neurons, including all motor neurons and CNS interneu- of the CNS lack true axons and do not produce action potentials, rons, are multipolar. (b) Bipolar neurons include sensory neurons but regulate local electrical changes of adjacent neurons. of the retina, olfactory mucosa, and inner ear. (c) All other sensory latter formed by unique protein subunits and called neurofila- and studied by confocal or electron microscopy. Dendritic ments in this cell type. Cross-linked with certain fixatives and spines serve as the initial processing sites for synaptic signals impregnated with silver stains, neurofilaments are also referred and occur in vast numbers, estimated to be on the order of 1014 to as neurofibrils by light microscopists. Some nerve cell bodies for cells of the human cerebral cortex. Dendritic spine mor- also contain inclusions of pigmented material, such as lipofus- phology depends on actin filaments and changes continuously cin, consisting of residual bodies left from lysosomal digestion. as synaptic connections on neurons are modified. Changes in dendritic spines are of key importance in the constant changes Dendrites of the neural plasticity that occurs during embryonic brain development and underlies adaptation, learning, and memory Dendrites (Gr. dendron, tree) are typically short, small pro- postnatally. cesses emerging and branching off the soma (Figure 9–3). Usually covered with many synapses, dendrites are the princi- pal signal reception and processing sites on neurons. The large Axons number and extensive arborization of dendrites allow a single Most neurons have only one axon, typically longer than its neuron to receive and integrate signals from many other nerve dendrites. Axonal processes vary in length and diameter cells. For example, up to 200,000 axonal endings can make according to the type of neuron. Axons of the motor neurons functional contact with the dendrites of a single large Purkinje that innervate the foot muscles have lengths of nearly a meter; cell of the cerebellum. large cell bodies are required to maintain these axons, which Unlike axons, which maintain a nearly constant diameter, contain most of such neurons’ cytoplasm. The plasma mem- dendrites become much thinner as they branch, with cyto- brane of the axon is often called the axolemma and its con- skeletal elements predominating in these distal regions. In the tents are known as axoplasm. CNS most synapses on dendrites occur on dendritic spines, Axons originate from a pyramid-shaped region of the which are dynamic membrane protrusions along the small perikaryon called the axon hillock (Figure 9–3), just beyond dendritic branches, visualized with silver staining (Figure 9–5) which the axolemma has concentrated ion channels which 166 CHAPTER 9â … â … Nerve Tissue & the Nervous System injected into regions with axon terminals, its later distribution FIGURE 9–5â ‡ Dendrites and dendritic spines. throughout the neurons serving such regions can be deter- mined histochemically. Anterograde and retrograde transports both occur fairly rapidly, at rates of 50-400 mm/d. A much slower anterograde stream, moving only a few millimeters per day, involves move- ment of the axonal cytoskeleton itself. This slow axonal trans- port corresponds roughly to the rate of axon growth. DS D D Nerve Impulses A nerve impulse, or action potential, travels along an axon like a spark moves along an explosive’s fuse. It is an electro- chemical process initiated at the axon hillock when other D impulses received at the cell body or dendrites meet a cer- tain threshold. The action potential is propagated along the CB axon as a wave of membrane depolarization produced by voltage-gated Na+ and K+ channels in the axolemma that allow diffusion of these ions into and out of the axoplasm. The extracellular compartment around all regions of the neuron is The large Purkinje neuron in this silver-impregnated section of cerebellum has many dendrites (D) emerging from its cell body a very thin zone immediately outside the cell that is formed (CB) and forming branches. The small dendritic branches each by enclosing glial cells which also regulate its ionic contents. have many tiny projecting dendritic spines (DS) spaced closely In unstimulated neurons ATP-dependent Na-K pumps along their length, each of which is a site of a synapse with and other membrane proteins maintain an axoplasmic Na+ con- another neuron. Dendritic spines are highly dynamic, the num- centration only one-tenth of that outside the cell and a K+ level ber of synapses changing constantly. (X650; Silver stain) many times greater than the extracellular concentration. This produces a potential electrical difference across the axolemma of about –65 mV, with the inside negative to the outside. This generate the action potential. At this initial segment of the difference is the axon’s resting potential. axon the various excitatory and inhibitory stimuli impinging on the neuron are algebraically summed, resulting in the deci- sion to propagate—or not to propagate—a nerve impulse. › ⠺⠺ MEDICAL APPLICATION Axons generally branch less profusely than dendrites, Most local anesthetics are low-molecular-weight molecules but do undergo terminal arborization (Figure 9–3). Axons that bind to the voltage-gated sodium channels of the axo- of interneurons and some motor neurons also have major lemma, interfering with sodium ion influx and, consequently, branches called collaterals that end at smaller branches with inhibiting the action potential responsible for the nerve impulse. synapses influencing the activity of many other neurons. Each small axonal branch ends with a dilation called a terminal bouton (Fr. bouton, button) that contacts another neuron or When the threshold for triggering an impulse is met, non-nerve cell at a synapse to initiate an impulse in that cell. channels at the axon’s initial segment open and allow a very Axoplasm contains mitochondria, microtubules, neuro- rapid influx of extracellular Na+ that makes the axoplasm filaments, and transport vesicles, but very few polyribosomes positive in relation to the extracellular environment and shifts or cisternae of RER, features which emphasize the dependence (depolarizes) the resting potential from negative to positive, of axoplasm on the perikaryon. If an axon is severed from its to +30 mV. Immediately after the membrane depolarization, cell body its distal part quickly degenerates and undergoes the voltage-gated Na+ channels close and those for K+ open, phagocytosis. which rapidly returns the membrane to its resting potential. Lively bidirectional transport of molecules large and This cycle of events occurs in less than 1 millisecond. small occurs within axons. Organelles and macromolecules Depolarization stimulates adjacent portions of the axo- synthesized in the cell body move by anterograde trans- lemma to depolarize and return immediately to the resting port along axonal microtubules via kinesin from the peri- potential, which causes a nerve impulse, or wave of depolariza- karyon to the synaptic terminals. Retrograde transport in tion, to move rapidly along the axon. After a refractory period the opposite direction along microtubules via dynein carries also measured in milliseconds, the neuron is ready to repeat certain other macromolecules, such as material taken up by this process and generate another action potential. Impulses endocytosis (including viruses and toxins), from the periph- arriving at the synaptic nerve endings promote the discharge ery to the cell body. Retrograde transport can be used to study of stored neurotransmitter that stimulates or inhibits action the pathways of neurons: if peroxidase or another marker is potentials in another neuron or a non-neural cell.  Neurons 167 Synaptic Communication ⌀ The postsynaptic cell membrane contains receptors for the neurotransmitter, and ion channels or other C H A P T E R Synapses (Gr. synapsis, union) are sites where nerve impulses mechanisms to initiate a new impulse. are transmitted from one neuron to another, or from neurons and other effector cells. The structure of a synapse (Figure 9–6) ⌀ A 20- to 30-nm-wide intercellular space called the synaptic cleft separates these presynaptic and postsyn- ensures that transmission is unidirectional. Synapses convert aptic membranes. an electrical signal (nerve impulse) from the presynaptic cell into a chemical signal that affects the postsynaptic cell. At the presynaptic region the nerve impulse briefly opens Most synapses act by releasing neurotransmitters, which calcium channels, promoting a Ca2+ influx that triggers neu- 9 are usually small molecules that bind specific receptor pro- rotransmitter release by exocytosis or similar mechanisms. Nerve Tissue & the Nervous Systemâ ‡ â ‡Neurons teins to either open or close ion channels or initiate second- Immediately the released neurotransmitter molecules diffuse messenger cascades. A synapse (Figure 9–6a) has the following across the synaptic cleft and bind receptors at the postsynap- components: tic region. This produces either an excitatory or an inhibitory effect at the postsynaptic membrane, as follows: ⌀ The presynaptic axon terminal (terminal bouton) contains mitochondria and numerous synaptic vesicles ⌀ Neurotransmitters from excitatory synapses cause from which neurotransmitter is released by exocytosis. postsynaptic Na+ channels to open, and the resulting Na+ FIGURE 9–6â ‡ Major components of a synapse. Nerve impulse Axon of presynaptic neuron Mitochondria Calcium Microtubules (Ca2+) ions of cytoskeleton T1 Voltage-regulated Synaptic vesicles calcium (Ca2+) containing channel acetylcholine (ACh) D Synaptic cleft Acetylcholine Acetylcholine binds T2 to receptor protein, Postsynaptic causing ion gates Sodium membrane to open (Na+) ions Receptor protein a Postsynaptic neuron b (a) Diagram showing a synapse releasing neurotransmitters (b) The TEM shows a large presynaptic terminal (T1) filled with by exocytosis from the terminal bouton. Presynaptic terminals synaptic vesicles and asymmetric electron-dense regions around always contain a large number of synaptic vesicles containing 20- to 30-nm-wide synaptic clefts (arrows). The postsynaptic mem- neurotransmitters, numerous mitochondria, and smooth ER as a brane contains the neurotransmitter receptors and mechanisms to source of new membrane. Some neurotransmitters are synthesized initiate an impulse at the postsynaptic neuron. The postsynaptic in the cell body and then transported in vesicles to the presynaptic membrane on the right is part of a dendrite (D), associated with terminal. Upon arrival of a nerve impulse, voltage-regulated Ca2+ fewer vesicles of any kind, showing this to be an axodendritic syn- channels permit Ca2+ entry, which triggers neurotransmitter release apse. On the left is another presynaptic terminal (T2), suggesting an into the synaptic cleft. Excess membrane accumulating at the axoaxonic synapse with a role in modulating activity of the other presynaptic region as a result of exocytosis is recycled by clathrin- terminal. (X35,000) mediated endocytosis, which is not depicted here. 168 CHAPTER 9â … â … Nerve Tissue & the Nervous System influx initiates a depolarization wave in the postsynaptic larger blood vessels, the CNS has only a very small amount of neuron or effector cell as just described. connective tissue and collagen. Glial cells substitute for cells ⌀ At inhibitory synapses neurotransmitters open Cl- or of connective tissue in some respects, supporting neurons and other anion channels, causing influx of anions and creating immediately around those cells microenvironments hyperpolarization of the postsynaptic cell, making its that are optimal for neuronal activity. The fibrous intercellular membrane potential more negative and more resistant to network of CNS tissue superficially resembles collagen by light depolarization. microscopy, but is actually the network of fine cellular pro- cesses emerging from neurons and glial cells. Such processes Interplay between excitatory and inhibitory effects on post- are collectively called the neuropil (Figure 9–8). synaptic cells allows synapses to process neuronal input and There are six major kinds of glial cells, as shown schemati- fine-tune the reaction of the effector cell. Impulses passing from cally in Figure 9–9, four in the CNS, two in the PNS. Their main presynaptic neurons to postsynaptic cells are usually modified functions, locations, and origins are summarized in Table 9–2. at the synapse by similar connections there with other neurons (Figure 9–6b). The response in postsynaptic neurons is deter- mined by the summation of activity at hundreds of synapses on Oligodendrocytes that cell. Three common morphological types of synapses occur Oligodendrocytes (Gr. oligos, small, few + dendron, tree + between neurons of the CNS and are shown in Figure 9–7. kytos, cell) extend many processes, each of which becomes The chemical transmitter used at neuromuscular junc- sheet-like and wraps repeatedly around a portion of a nearby tions and some synapses of the CNS is acetylcholine. Within CNS axon (Figure 9–9a). During this wrapping most cytoplasm the CNS other major categories of neurotransmitters include: gradually moves out of the growing extension, leaving multiple compacted layers of cell membrane collectively termed myelin. ⌀ Certain amino acids (often modified), such as gluta- An axon’s full length is covered by the action of many oligoden- mate and γ-aminobutyrate (GABA) drocytes. The resulting myelin sheath electrically insulates the ⌀ Monoamines, such as serotonin (5-hydroxytryptamine axon and facilitates rapid transmission of nerve impulses. Found or 5-HT) and catecholamines, such as dopamine, all of only in the CNS oligodendrocytes are the predominant glial cells which are synthesized from amino acids in white matter, which is white because of the lipid concentrated ⌀ Small polypeptides, such as endorphins and substance P. in the wrapped membrane sheaths. The processes and sheaths Important actions of these and other common neu- are not visible by routine light microscope staining, in which oli- rotransmitters are summarized in Table 9–1. Different recep- godendrocytes usually appear as small cells with rounded, con- tors and second messenger systems often occur for the same densed nuclei and unstained cytoplasm (Figure 9–8a). transmitter, greatly multiplying the possible effects of these molecules. After their release transmitters are removed quickly Astrocytes by enzymatic breakdown, by glial activity, or by endocytotic Also unique to the CNS astrocytes (Gr. astro-, star + kytos) recycling involving presynaptic membrane receptors. have a large number of long radiating, branching processes (Figures 9–9a and 9–10). Proximal regions of the astrocytic › ⠺⠺ MEDICAL APPLICATION processes are reinforced with bundles of intermediate filaments made of glial fibrillary acid protein (GFAP), which serves as Levels of neurotransmitters in the synaptic cleft and available a unique marker for this glial cell. Distally the processes lack for binding postsynaptic receptors are normally regulated GFAP, are not readily seen by microscopy, and form a vast net- by several local mechanisms. Selective serotonin reuptake work of delicate terminals contacting synapses and other struc- inhibitors (SSRIs), a widely used class of drugs for treat- tures. Terminal processes of a single astrocyte typically occupy ment of depression and anxiety disorders, were designed to a large volume and associate with over a million synaptic sites. augment levels of this neurotransmitter at the postsynaptic Astrocytes originate from progenitor cells in the embry- membrane of serotonergic CNS synapses by specifically onic neural tube and are by far the most numerous glial cells of inhibiting its reuptake at the presynaptic membrane. the brain, as well as the most diverse structurally and func- tionally. Fibrous astrocytes, with long delicate processes, are abundant in white matter; those with many shorter processes ›â ºGLIAL CELLS & NEURONAL ACTIVITY are called protoplasmic astrocytes and predominate in the gray matter. The highly variable and dynamic processes medi- Glial cells support neuronal survival and activities, and are ate most of these cells’ many functions. ten times more abundant than neurons in the mammalian brain. Like neurons most glial cells develop from progenitor › ⠺⠺ MEDICAL APPLICATION cells of the embryonic neural plate. In the CNS glial cells sur- Most brain tumors are astrocytomas derived from fibrous round both the neuronal cell bodies, which are often larger astrocytes. These are distinguished pathologically by their than the glial cells, and the processes of axons and dendrites expression of GFAP. occupying the spaces between neurons. Except around the  Glial Cells & Neuronal Activity 169 FIGURE 9–7â ‡ Types of synapses. C H A P T E R Axosomatic synapse Axodendritic synapse Axoaxonic synapse Axons Axon Axon Dendrite 9 Nerve Tissue & the Nervous Systemâ ‡ â ‡ Glial Cells & Neuronal Activity Dendritic spine Cell body Dendrites Axodendritic synapse Axosomatic synapse Cell body Axon hillock Axon Axoaxonic synapse Terminal arborizations The diagrams show three common morphologic types of synapses. All three morphologic types of synapses have the features of all Branched axon terminals usually associate with and transmit a true synapses: a presynaptic axon terminal that releases a transmit- nerve impulse to another neuron’s cell body (or soma) or a den- ter; a postsynaptic cell membrane with receptors for the transmit- dritic spine. These types of connections are termed an axosomatic ter; and an intervening synaptic cleft. synapse and an axodendritic synapse, respectively. Less fre- Synaptic structure usually cannot be resolved by light micros- quently, an axon terminal forms a synapse with an axon terminal of copy, although components such as dendritic spines may be another neuron; such an axoaxonic synapse functions to modu- shown with special techniques (Figure 9–5). late synaptic activity in the other two types. 170 CHAPTER 9â … â … Nerve Tissue & the Nervous System â ‡ TABLE 9–1 Common neurotransmitters and their actions. Neurotransmitter Description/Action ACETYLCHOLINE (ACh) CH3 O Chemical structure significantly different from that of other neurotransmitters; active in CNS and in both somatic and autonomic parts of PNS; binds to ACh receptors (cholinergic receptors) H3 C N+ CH2 CH2 O C CH3 in PNS to open ion channels in postsynaptic membrane and stimulate muscle contraction CH3 AMINO ACIDS O Molecules with both carboxyl (—COOH) and amine (—NH2) groups and various R groups; act as important transmitters in the CNS NH2 CH2 C OH R Glutamate Excites activity in neurons to promote cognitive function in the brain (learning and memory); most common neurotransmitter in the brain; opens Na+ channels Gamma-aminobutyric acid (GABA) Synthesized from glutamate; primary inhibitory neurotransmitter in the brain; also influences muscle tone; opens or closes various ion channels Glycine Inhibits activity between neurons in the CNS, including retina; opens Cl- channels MONOAMINES OH Aromatic ring Molecules synthesized from an amino acid by removing the carboxyl group and retaining the single amine group; also called biogenic amines NH2 CH2 CH OH OH Serotonin or 5-hydroxytryptamine (5-HT) Has various functions in the brain related to sleep, appetite, cognition (learning, memory), and mood; modulates actions of other neurotransmitters Catecholamines A distinct group of monoamines Dopamine Produces inhibitory activity in the brain; important roles in cognition (learning, memory), motivation, behavior, and mood; opens K+ channels, closes Ca2+ channels Norepinephrine (noradrenaline) Neurotransmitter of PNS (sympathetic division of autonomic nervous system) and specific CNS regions Epinephrine (adrenaline) Has various effects in the CNS, especially the spinal cord, thalamus, and hypothalamus NEUROPEPTIDES Tyr Gly Gly Phe Met Small polypeptides act as signals to assist in and modulate communication among neurons in the CNS Enkephalin Helps regulate response to noxious and potentially harmful stimuli Neuropeptide Y Involved in memory regulation and energy balance (increased food intake and decreased physical activity) Somatostatin Inhibits activities of neurons in specific brain areas Substance P Assists with pain information transmission into the brain Cholecystokinin (CCK) Stimulates neurons in the brain to help mediate satiation (fullness) and repress hunger Beta-endorphin Prevents release of pain signals from neurons and fosters a feeling of well-being Neurotensin Helps control and moderate the effects of dopamine OTHERS Adenosine Also part of a nucleotide, inhibits activities in certain CNS neurons Nitric oxide Involved in learning and memory; relaxes muscle in the digestive tract; important for relaxation of smooth muscle in blood vessels (vasodilation)  Glial Cells & Neuronal Activity 171 FIGURE 9–8â ‡ Neurons, neuropil, and the common glial cells of the CNS. C H A P T E R G N Np N 9 N Nerve Tissue & the Nervous Systemâ ‡ â ‡ Glial Cells & Neuronal Activity G Np N G G G a b (a) Most neuronal cell bodies (N) in the CNS are larger than the those properties seen here. The other glial cells seen here similar in much more numerous glial cells (G) that surround them. The vari- overall size, but with very little cytoplasm and more elongated or ous types of glial cells and their relationships with neurons are oval nuclei, are mostly astrocytes. Routine H&E staining does not difficult to distinguish by most routine light microscopic methods. allow neuropil to stand out well. (X200; H&E) However, oligodendrocytes have condensed, rounded nuclei and (b) With the use of gold staining for neurofibrils, neuropil (Np) is unstained cytoplasm due to very abundant Golgi complexes, more apparent. (X200; Gold chloride and hematoxylin) which stain poorly and are very likely represented by the cells with Functions attributed to astrocytes of various CNS regions ⌀ Extending fibrous processes with expanded perivas- include the following: cular feet that cover capillary endothelial cells and modulate blood flow and help move nutrients, wastes, ⌀ Extending processes that associate with or cover syn- and other metabolites between neurons and capillar- apses, affecting the formation, function, and plasticity of ies (Figure 9–9a) these structures ⌀ Regulating the extracellular ionic concentrations around ⌀ Forming a barrier layer of expanded protoplasmic pro- cesses, called the glial limiting membrane, which lines neurons, with particular importance in buffering extra- the meninges at the external CNS surface cellular K+ levels ⌀ Guiding and physically supporting movements and loca- ⌀ Filling tissue defects after CNS injury by proliferation to form an astrocytic scar. tions of differentiating neurons during CNS development â ‡ TABLE 9–2 Origin, location and principal functions of neuroglial cells. Glial Cell Type Origin Location Main Functions Oligodendrocyte Neural tube CNS Myelin production, electrical insulation Astrocyte Neural tube CNS Structural and metabolic support of neurons, especially at synapses; repair processes Ependymal cell Neural tube Line ventricles and central Aid production and movement of CSF canal of CNS Microglia Bone marrow (monocytes) CNS Defense and immune-related activities Schwann cell Neural crest Peripheral nerves Myelin production, electrical insulation Satellite cells (of ganglia) Neural crest Peripheral ganglia Structural and metabolic support for neuronal cell bodies 172 CHAPTER 9â … â … Nerve Tissue & the Nervous System FIGURE 9–9â ‡ Glial cells of the CNS and PNS. Functions of Astrocyte 1. Helps form the blood-brain barrier 2. Regulates interstitial fluid composition Astrocyte 3. Provides structural support and organization to the central Neuron nervous system (CNS) Perivascular feet 4. Assists with neuronal development 5. Replicates to occupy space of dying neurons Capillary Myelinated axon Functions of Ependymal Cell Ependymal cell 1. Lines ventricles of brain and central Myelin sheath (cut) canal of spinal cord 2. Assists in production and circulation Ventricle of Oligodendrocyte brain of cerebrospinal fluid (CSF) Functions of Microglial Cell 1. Phagocytic cells that move through Functions of Oligodendrocyte the CNS Microglial 2. Protects the CNS by engulfing 1. Myelinates and insulates CNS axons cell infectious agents and other 2. Allows faster action potential propagation along axons in the CNS potential harmful substances (a) Posterior root ganglion Functions of Satellite Cell Satellite cell 1. Electrically insulates PNS cell bodies. 2. Regulates nutrient and waste exchange for cell bodies in ganglia Functions of Neurolemmocyte Schwann cell Axon 1. Surround and insulate PNS axons and myelinate those having large diameters 2. Allows for faster action potential propagation along an axon in the PNS (b) (a) There are four major kinds of glial cells in the CNS: oligoden- (b) Two glial cells occur in the PNS: Schwann cells (sometimes called drocytes, astrocytes, ependymal cells, and microglial cells. The neurolemmocytes), which surround peripheral nerve fibers, and sat- interrelationships and major functions of these cells are shown ellite cells, which surround the nerve cell bodies and are thus found diagrammatically here. only in ganglia. Major functions of these cells are indicated.  Glial Cells & Neuronal Activity 173 FIGURE 9–10â ‡ Astrocytes. C H A P T E R P PF S A C 9 Nerve Tissue & the Nervous Systemâ ‡ â ‡ Glial Cells & Neuronal Activity A C P A A S P PF a b c (a) Astrocytes are the most abundant glial cells of the CNS and are processes. The small pieces of other GFAP-positive processes in the characterized by numerous cytoplasmic processes (P) radiating neuropil around this cell give an idea of the density of this glial cell from the glial cell body or soma (S). Astrocytic processes are not and its processes in the CNS. Astrocytes form part of the blood- seen with routine light microscope staining but are easily seen brain barrier (BBB) and help regulate entry of molecules and ions after gold staining. Morphology of the processes allows astrocytes from blood into CNS tissue. Capillaries at the extreme upper right to be classified as fibrous (relatively few and straight processes) or and lower left corners are enclosed by GFAP-positive perivascular protoplasmic (numerous branching processes), but functional dif- feet (PF) at the ends of numerous astrocytic processes. (X500; Anti- ferences between these types are not clear. (X500; Gold chloride) GFAP immunoperoxidase and hematoxylin counterstain) (b) All astrocytic processes contain intermediate filaments of GFAP, (c) A length of capillary (C) is shown here completely covered by and antibodies against this protein provide a simple method to silver-stained terminal processes extending from astrocytes (A). stain these cells, as seen here in a fibrous astrocyte (A) and its (X400; Rio Hortega silver) Finally, astrocytes communicate directly with one another ends of ependymal cells are elongated and extend branching via gap junctions, forming a very large cellular network for the processes into the adjacent neuropil. coordinated regulation of their various activities in different brain regions. Microglia › ⠺⠺ MEDICAL APPLICATION Less numerous than oligodendrocytes or astrocytes but nearly as common as neurons in some CNS regions, microglia are Alzheimer disease, a common type of dementia in the small cells with actively mobile processes evenly distributed elderly, affects both neuronal perikarya and synapses within throughout gray and white matter (Figures 9–9a and 9–12). the cerebrum. Functional defects are due to neurofibrillary Unlike other glial cells microglia migrate, with their processes tangles, which are accumulations of tau protein associated scanning the neuropil and removing damaged or effete syn- with microtubules of the neuronal perikaryon and axon hill- apses or other fibrous components. Microglial cells also con- ock regions, and neuritic plaques, which are dense aggre- stitute the major mechanism of immune defense in the CNS, gates of β-amyloid protein that form around the outside of removing any microbial invaders and secreting a number of these neuronal regions. immunoregulatory cytokines. Microglia do not originate from neural progenitor cells like other glia, but from circulating blood monocytes, belonging to the same family as macro- Ependymal Cells phages and other antigen-presenting cells. Ependymal cells are columnar or cuboidal cells that line the Nuclei of microglial cells can often be recognized in routine fluid-filled ventricles of the brain and the central canal of the hematoxylin and eosin (H&E) preparations by their small, dense, spinal cord (Figures 9–9a and 9–11). In some CNS locations, slightly elongated structure, which contrasts with the larger, the apical ends of ependymal cells have cilia, which facilitate spherical, more lightly stained nuclei of other glial cells. Immu- the movement of cerebrospinal fluid (CSF), and long micro- nohistochemistry using antibodies against cell surface antigens of villi, which are likely involved in absorption. immune cells demonstrates microglial processes. When activated Ependymal cells are joined apically by apical junctional by damage or microorganisms microglia retract their processes, complexes similar to those of epithelial cells. However, unlike proliferate, and assume the morphologic characteristics and a true epithelium there is no basal lamina. Instead, the basal functions of antigen-presenting cells (see Chapter 14). 174 CHAPTER 9â … â … Nerve Tissue & the Nervous System FIGURE 9–11â ‡ Ependymal cells. FIGURE 9–12â ‡ Microglial cells. E V N E a Microglia are monocyte-derived, antigen-presenting cells of the E CNS, less numerous than astrocytes but nearly as common as neurons and evenly distributed in both gray and white matter. By immunohistochemistry, here using a monoclonal antibody against human leukocyte antigens (HLA) of immune-related cells, the short branching processes of microglia can be seen. Routine staining demonstrates only the small dark nuclei of the cells. Unlike other glia of the CNS, microglia are not intercon- C nected; they are motile cells, constantly used in immune surveil- lance of CNS tissues. When activated by products of cell damage or by invading microorganisms, the cells retract their processes, begin phagocytosing the damage- or danger-related material, and behave as antigen-presenting cells. (X500; Antibody against HLA-DR and peroxidase) E (Used with permission from Wolfgang Streit, Department of Neuroscience, University of Florida College of Medicine, b Gainesville.) Ependymal cells are epithelial-like cells that form a single layer lin- ing the fluid-filled ventricles and central canal of the CNS. (a) Lining the ventricles of the cerebrum, columnar ependymal cells (E) extend cilia and microvilli from the apical surfaces into Schwann Cells the ventricle (V). These modifications help circulate the CSF and Schwann cells (named for 19th century German histolo- monitor its contents. Ependymal cells have junctional complexes gist Theodor Schwann), sometimes called neurolemmo- at their apical ends like those of epithelial cells but lack a basal lamina. The cells’ basal ends are tapered, extending processes that cytes, are found only in the PNS and differentiate from branch and penetrate some distance into the adjacent neuropil precursors in the neural crest. Schwann cells are the coun- (N). Other areas of ependyma are responsible for production of terparts to oligodendrocytes of the CNS, having trophic CSF. (X100; H&E) interactions with axons and most importantly forming their (b) Ependymal cells (E) lining the central canal (C) of the spinal myelin sheathes. However unlike an oligodendrocyte, a cord help move CSF in that CNS region. (X200; H&E) Schwann cell forms myelin around a portion of only one axon. Figure 9–9b shows a series of Schwann cells sheath- ing the full length of an axon, a process described more › ⠺⠺ MEDICAL APPLICATION fully with peripheral nerves. In multiple sclerosis (MS) the myelin sheaths surround- ing axons are damaged by an autoimmune mechanism Satellite Cells of Ganglia that interferes with the activity of the affected neurons and produces various neurologic problems. T lymphocytes and Also derived from the embryonic neural crest, small satel- microglia, which phagocytose and degrade myelin debris, lite cells form a thin, intimate glial layer around each large play major roles in progression of this disease. In MS, destruc- neuronal cell body in the ganglia of the PNS (Figures 9–9b tive actions of these cells exceed the capacity of oligodendro- and 9–13). Satellite cells exert a trophic or supportive effect cytes to produce myelin and repair the myelin sheaths. on these neurons, insulating, nourishing, and regulating their microenvironments.  Central Nervous System 175 FIGURE 9–13â ‡ Satellite cells around neurons of ›â ºCENTRAL NERVOUS SYSTEM C H A P T E R ganglia in the PNS. The major structures comprising the CNS are the cerebrum, cerebellum, and spinal cord (Figure 9–1). The CNS is com- S pletely covered by connective tissue layers, the meninges, but CNS tissue contains very little collagen or similar material, making it relatively soft and easily damaged by injuries affect- ing the protective skull or vertebral bones. Most CNS neurons 9 and their functional organization are more appropriately cov- Nerve Tissue & the Nervous Systemâ ‡ â ‡ Central Nervous System ered in neuroscience rather than histology courses, but certain N important cells and basic topics will be introduced here. Many structural features of CNS tissues can be seen in S unstained, freshly dissected specimens. Many regions show organized areas of white matter and gray matter, differ- ences caused by the differential distribution of lipid-rich myelin. The main components of white matter are myelinated axons (Figure 9–14), often grouped together as tracts, and the myelin-producing oligodendrocytes. Astrocytes and microg- lia are also present, but very few neuronal cell bodies. Gray L matter contains abundant neuronal cell bodies, dendrites, S astrocytes, and microglial cells, and is where most synapses occur. Gray matter makes up the thick cortex or surface layer of both the cerebrum and the cerebellum; most white matter is found in deeper regions. Deep within the brain are localized, variously shaped darker areas called the cerebral nuclei, each N a containing large numbers of aggregated neuronal cell bodies. In the folded cerebral cortex neuroscientists recognize six layers of neurons with different sizes and shapes. The most conspicuous of these cells are the efferent pyramidal neu- rons (Figure 9–15). Neurons of the cerebral cortex function N N in the integration of sensory information and the initiation of voluntary motor responses. The sharply folded cerebellar cortex coordinates mus- cular activity throughout the body and is organized with three layers (Figure 9–16): b S S ⌀ A thick outer molecular layer has much neuropil and scattered neuronal cell bodies. ⌀ A thin middle layer consists only of very large neurons Satellite cells are very closely associated with neuronal cell bod- called Purkinje cells (named for the 19th century Czech ies in sensory and autonomic ganglia of the PNS and support histologist Jan Purkinje). These are conspicuous even these cells in various ways. in H&E-stained sections, and their dendrites extend (a) Nuclei of the many satellite cells (S) surrounding the peri- throughout the molecular layer as a branching basket of karya of neurons (N) in an autonomic ganglion can be seen by nerve fibers (Figures 9–16c and d). light microscopy, but their cytoplasmic extensions are too thin to see with H&E staining. These long-lived neurons commonly ⌀ A thick inner granular layer contains various very accumulate brown lipofuscin (L). (X560; H&E) small, densely packed neurons (including granule cells, (b) Immunofluorescent staining of satellite cells (S) reveals the with diameters of only 4-5 μm) and little neuropil. cytoplasmic sheets extending from these cells and surrounding In cross sections of the spinal cord the white matter is the neuronal cell bodies (N). The layer of satellite cells around peripheral and the gray matter forms a deeper, H-shaped mass each soma is continuous with the myelin sheath around the axon. Like the effect of Schwann cells on axons, satellite glial (Figure 9–17). The two anterior projections of this gray matter, cells insulate, nourish, and regulate the microenvironment of the the anterior horns, contain cell bodies of very large motor neuronal cell bodies. (X600; Rhodamine red-labeled antibody neurons whose axons make up the ventral roots of spinal against glutamine synthetase) nerves. The two posterior horns contain interneurons which (Used with permission from Menachem Hanani, Laboratory of receive sensory fibers from neurons in the spinal (dorsal root) Experimental Surgery, Hadassah University Hospital, Jerusalem, Israel.) ganglia. Near the middle of the cord the gray matter surrounds a small central canal, which develops from the lumen of the neural tube, is continuous with the ventricles of the brain, is lined by ependymal cells, and contains CSF. 176 CHAPTER 9â … â … Nerve Tissue & the Nervous System FIGURE 9–14â ‡ White versus gray matter. A cross section of H&E-stained spinal cord G shows the transition between white matter G (left region) and gray matter (right). The gray matter has many glial cells (G), neuronal cell A bodies (N), and neuropil; white matter also A N contains glia (G) but consists mainly of axons (A) whose myelin sheaths were lost during preparation, leaving the round empty spaces shown. Each such space surrounds a dark- A stained spot that is a small section of the G axon. (X400) FIGURE 9–15â ‡ Cerebral cortex. P P A P P P A P A a b (a) Important neurons of the cerebrum are the pyramidal neurons (b) From the apical ends of pyramidal neurons (P), long dendrites (P), which are arranged vertically and interspersed with numerous extend in the direction of the cortical surface, which can be best smaller glial cells, mostly astrocytes, in the eosinophilic neuropil. seen in thick silver-stained sections in which only a few other (X200; H&E) protoplasmic astrocytes (A) cells are seen. (X200; Silver)  Central Nervous System 177 FIGURE 9–16â ‡ Cerebellum. C H A P T E R ML ML 9 Nerve Tissue & the Nervous Systemâ ‡ â ‡ Central Nervous System P GL GL M M a b ML P P P GL c d (a) The cerebellar cortex is convoluted with many distinctive small (c) A single intervening layer contains the very large cell bodies folds, each supported at its center by tracts of white matter in the of unique Purkinje neurons (P), whose axons pass through the cerebellar medulla (M). Each fold has distinct molecular layers (ML) granular layer (GL) to join tracts in the medulla and whose multiple and granular layers (GL). (X6; Cresyl violet) branching dendrites ramify throughout the molecular layer (ML). (b) Higher magnification shows that the granular layer (GL) Dendrites are not seen well with H&E staining. (X40; H&E) immediately surrounding the medulla (M) is densely packed with (d) With appropriate silver staining dendrites from each large several different types of very small rounded neuronal cell bodies. Purkinje cell (P) are shown to have hundreds of small branches, The outer molecular layer (ML) consists of neuropil with fewer, each covered with hundreds of dendritic spines. Axons from much more scattered small neurons. At the interface of these two the small neurons of the granular layer are unmyelinated and regions a layer of large Purkinje neuron (P) perikarya can be seen. run together into the molecular layer where they form synapses (X20; H&E) with the dendritic spines of Purkinje cells. (X40; Silver) 178 CHAPTER 9â … â … Nerve Tissue & the Nervous System FIGURE 9–17â ‡ Spinal cord. P C A a b Lumbar N T N T c d The spinal cord varies slightly in diameter along its length but in running along the length of the cord. (Center X5, a, b X100; All cross section always shows bilateral symmetry around the small, silver-stained) CSF-filled central canal (C). Unlike the cerebrum and cerebellum, (c) With H&E staining the large motor neurons (N) of the ventral in the spinal cord the gray matter is internal, forming a roughly horns show large nuclei, prominent nucleoli, and cyto