Copy of Histology-Nervous System chp1.pdf

The Nervous System GK Nerve tissue is distributed throughout the body as an integrated communications network. Anatomically, the general organization of the nervous system has two major divisions: The nervous system is divided into two main components: Central nervous system (CNS): consists of the b...

The Nervous System GK Nerve tissue is distributed throughout the body as an integrated communications network. Anatomically, the general organization of the nervous system has two major divisions: The nervous system is divided into two main components: Central nervous system (CNS): consists of the brain and spinal cord Peripheral nervous system: consists of the nerves and ganglia outside the brain and spinal cord, including the cranial nerves, spinal nerves, and their roots, peripheral nerves, and neuromuscular junctions Cells in both central and peripheral nerve tissue are of two kinds: neurons, which typically have numerous long processes, glial cells (Gr. glia, glue), which have short processes, support and protect neurons, and participate in many neural activities, neural nutrition, and defense of cells in the CNS. DEVELOPMENT OF NERVE TISSUE The nervous system develops from the outermost of the three early embryonic layers, the ectoderm, beginning in the third week of development. With signals from the underlying axial structure, the notochord, ectoderm on the mid-dorsal side of the embryo thickens to form the epithelial neural plate. The sides of this plate fold upward and grow toward each other medially, and within a few days fuse to form the neural tube. Cells of this tube give rise to the entire CNS, including neurons and most glial cells. As the folds fuse and the neural tube separates from the now overlying surface ectoderm that will form epidermis, a large population of developmentally important cells, the neural crest, separates from the neuroepithelium and becomes mesenchymal. Neural crest cells migrate extensively and differentiate as all the cells of the PNS, as well as a number of other nonneuronal cell types. The human nervous system, by far the most complex system in the body. Nerve tissue consists of: Neurons, which are excitable cells that transmit information as electrical signals, Glial cells (e.g., oligodendrocytes, Schwann cells, astrocytes, microglial cells), which perform a variety of nonsignaling functions such as forming myelin to provide support and insulation between neurons, phagocytosing and removing cellular debris, removing excess neurotransmitters, and forming the blood-brain barrier. Neurons respond to environmental changes (stimuli) by altering the ionic gradient that exists across their plasma membranes. All cells maintain such a gradient, also called an electrical potential, but cells that can rapidly change this potential 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 (membrane depolarization) that generally spreads from the place that received the stimulus and is propagated across the neuron’s entire plasma membrane. This propagation, called the action potential, the depolarization wave, or the nerve impulse, is capable of traveling long distances along neuronal processes, transmitting such signals to other neurons, muscles, and glands. By collecting, analyzing, and integrating information in such signals, the nervous system continuously stabilizes the intrinsic conditions of the body (eg, blood pressure, O and CO content, pH, blood glucose levels, and hormone levels) within normal ranges and maintains behavioral patterns (eg, feeding, reproduction, defense, and interaction with other living creatures). 2 2 NEURONS The functional unit in both the CNS and PNS is the neuron. Some neuronal components have special names, such as “neurolemma” for the cell membrane. Most neurons have three main parts: 1. The cell body (also called the perikaryon or soma), which contains the nucleus and most of the cell’s organelles and serves as the synthetic or trophic center for the entire neuron. Cell bodies can be very large, measuring up to 150 µm in diameter. Other neurons, such as those in the cerebellar granular layer, are among the body’s smallest cells. 2. The dendrites, which are the numerous elongated processes extending from the perikaryon and specialized to receive stimuli from other neurons at unique sites called synapses. 3. The axon (Gr. axon, axis), which is a single long process ending at synapses specialized to generate and conduct nerve impulses to other cells (eg, nerve, muscle, and gland cells). In the CNS, most neuronal cell body occurs in the gray matter, with their axons concentrated in the white matter. These terms refer to the general appearance of unstained CNS tissue caused in part by the different densities of nerve cell bodies. In the PNS, cell bodies are found in ganglia and in some sensory regions, such as the olfactory mucosa, and axons are bundled in nerves. Parkinson disease is a slowly progressing disorder affecting muscular activity characterized by tremors, reduced activity of the facial muscles, loss of balance, and postural stiffness. It is caused by gradual loss by apoptosis of dopamine- producing neurons whose cell bodies lie within the nuclei of the CNS substantia nigra. Parkinson disease is treated with l-dopa (l-3,4-dihydroxyphenylalanine), a precursor of dopamine that augments the declining production of this neurotransmitter. Cell Body (Perikaryon or Soma) The neuronal cell body contains the nucleus and surrounding cytoplasm, exclusive of the cell processes. It acts as a trophic center, producing most cytoplasm for the processes. Most cell bodies are in contact with a great number of nerve endings conveying excitatory or inhibitory stimuli generated in other neurons. Soma: contains the cell organelles Has Nissl substance Pigments: melanin, lipofuscin Cytoskeleton: microfilaments A typical neuron has an unusually large, euchromatic nucleus with a prominent nucleolus, indicating intense synthetic activity. Cytoplasm of perikarya often contains numerous free polyribosomes and highly developed RER, indicating active production of both cytoskeletal proteins and proteins for transport and secretion. Histologically, these regions with concentrated RER and other polysomes are basophilic and are distinguished as chromatophilic substance (or Nissl substance, Nissl bodies). The amount of this material varies with the type and functional state of the neuron and is particularly abundant in large nerve cells such as motor neurons. The Golgi apparatus is located only in the cell body, but mitochondria can be found throughout the cell and are usually abundant in the axon terminals. In both perikarya and processes microtubules, actin filaments and intermediate filaments are abundant, with the latter formed by unique protein subunits and called neurofilaments in this cell type. Dendrites Branching, thin projections from the cell body of neurons that receive input from neighboring neurons and transmit it to the cell body Contain spines that increase the number of synapses to other neurons Have Nissl substance Cytoskeleton: microfilaments Dendrites The large number and extensive arborization of dendrites allow a single neuron to receive and integrate signals from many other nerve cells. For example, up to 200,000 axonal endings can make functional contact with the dendrites of a single large Purkinje cell of the cerebellum. Unlike axons, which maintain a nearly constant diameter, dendrites become much thinner as they branch, with cytoskeletal elements predominating in these distal regions. Dendritic spines serve as the initial processing sites for synaptic signals and occur in vast numbers, estimated to be on the order of 1014 for cells of the human cerebral cortex. Dendritic spine morphology depends on actin filaments and changes continuously as synaptic connections on neurons are modified. Changes in dendritic spines are of key importance in the constant changes of the neural plasticity that occurs during embryonic brain development and underlies adaptation, learning, and memory postnatally. Axon the projection from a neuron's cell body along which action potentials travel to send intercellular signals Connected to the cell body at the axon hillock, which is a trigger zone for initiation of action potentials , and ends in a synapse Lacks a regular rough endoplasmic reticulum and thus does not contain Nissl substance Cytoskeleton Microtubules with associated motor proteins for rapid axonal transport Kinesin: anterograde transport (– → +) Dynein: retrograde transport (+ → –) Neurofilaments Provide structural support Most abundant in axons and the proximal part of dendrites Neurofilament protein is used as a marker for neuronal cells. Axons Most neurons have only one axon, typically longer than its dendrites. Axonal processes vary in length and diameter according to the type of neuron. Axons of the motor neurons that innervate the foot muscles have lengths of nearly a meter; large cell bodies are required to maintain these axons, which contain most of such neurons’ cytoplasm. The plasma membrane of the axon is often called the axolemma and its contents are known as axoplasm. Axons generally branch less profusely than dendrites, but do undergo terminal arborization. Axons of interneurons and some motor neurons also have major branches called collaterals that end at smaller branches with 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 non-nerve cell at a synapse to initiate an impulse in that cell. Axoplasm contains mitochondria, microtubules, neurofilaments, and transport vesicles, but very few polyribosomes or cisternae of RER, features that emphasize the dependence of axoplasm on the perikaryon. If an axon is severed from its cell body, its distal part quickly degenerates and undergoes phagocytosis. Lively bidirectional transport of molecules large and small occurs within axons. Organelles and macromolecules synthesized in the cell body move by anterograde transport along axonal microtubules via kinesin from the perikaryon to the synaptic terminals. Retrograde transport in the opposite direction along microtubules via dynein carries certain other macromolecules, such as material taken up by endocytosis (including viruses and toxins), from the periphery to the cell body. 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 movement of the axonal cytoskeleton itself. This slow axonal transport corresponds roughly to the rate of axon growth. Neurons Description signal-transmitting cells that comprise the central and peripheral nervous system Classified into unipolar, pseudounipolar, bipolar, and multipolar depending on the number of protoplasmic processes (neurites) Do not undergo mitosis Composed of soma (cell body), axon and dendrites Nissl staining positive (An aniline dye that stains RNA blue. Has high affinity for polyribosomes in the cytoplasm and on the rough endoplasmic reticulum.) in the cell body and dendrites, which have Nissl substance (aggregates of rough endoplasmic reticulum with bound polysomes) Unipolar or pseudounipolar neurons, which include all other sensory neurons, each have a single process that bifurcates close to the perikaryon, with the longer branch extending to a peripheral ending and the other toward the CNS. Unipolar – embryological development, pseudounipolar - Bipolar neurons, with one dendrite and one axon, comprise the sensory neurons of the retina, the olfactory epithelium, and the inner ear. (cochlear, vestibule) Multipolar neurons, each with one axon and two or more dendrites, are the most common. Anaxonic neurons, with many dendrites but no true axon, do not produce action potentials, but regulate electrical changes of adjacent CNS neurons. Myelin Insulating layer of modified plasma membrane that wraps around axons of nerve in a spiral structure Increases the space constant and the conduction velocity of signals traveling down axons Decreases membrane capacitance and increases membrane resistance Node of Ranvier Unmyelinated regions between two adjacent myelinated segments of axons in the CNS and PNS Contain a large amount of Na+ channels: allows saltatory conduction → increases the velocity of action potentials Demyelination: a process in which myelin sheaths of nerves become damaged, which impairs electrical conduction Central demyelination occurs within the CNS (e.g., seen with multiple sclerosis, progressive multifocal leukoencephalopathy, leukodystrophies). Peripheral demyelination affects the PNS (e.g., seen with Guillain-Barré syndrome). Nerve Impulses Most local anesthetics are lowA nerve impulse, or an action potential, travels along an axon like a molecular-weight molecules that bind to the voltage-gated sodium channels spark moves along an explosive’s fuse. It is an electrochemical process initiated at the axon hillock when other impulses received at of the axolemma, interfering with sodium ion influx and, consequently, the cell body or dendrites meet a certain threshold. The action inhibiting the action potential potential is propagated along the axon as a wave of membrane responsible for the nerve impulse. 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 a very thin zone immediately outside the cell that is formed by enclosing glial cells that also regulate its ionic contents. In unstimulated neurons, ATP-dependent Na-K pumps and other membrane proteins maintain an axoplasmic Na+ concentration only one-tenth of that outside the cell and a K+ level 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 difference is the axon’s resting potential. When the threshold for triggering an impulse is met, channels at the axon’s initial segment open and allow a very rapid influx of extracellular Na+ that makes the axoplasm positive in relation to the extracellular environment and shifts (depolarizes) the resting potential from negative to positive, to +30 mV. Immediately after the membrane depolarization, the voltage-gated Na+ channels close and those for K+ open, which rapidly returns the membrane to its resting potential. This cycle of events occurs in less than 1 millisecond. Depolarization stimulates adjacent portions of the axolemma to depolarize and return immediately to the resting potential, which causes a nerve impulse, or wave of depolarization, to move rapidly along the axon. After a refractory period, also measured in milliseconds, the neuron is ready to repeat this process and generate another action potential. Impulses arriving at the synaptic nerve endings promote the discharge of stored neurotransmitter that stimulates or inhibits action potentials in another neuron or a non-neural cell. Synaptic Communication Synapses: the junction across which signals or action potentials are transmitted from a presynaptic to a postsynaptic structure (e.g., neurons, muscle). Synaptic transmission: the process of communication between two neurons, involving the release of a neurotransmitter by the presynaptic neuron and the neurotransmitter binding to receptors on the postsynaptic membrane Fast neurotransmission: direct activation of a ligand-gated ion channel by a neurotransmitter Neuromodulation: occurs when a neurotransmitter binds to a G-protein-bound receptor and activates a chemical signaling cascade General There are two types of synapses: chemical and electrical Synapses can further be classified according to the structures between which they signal: Axodendritic synapses: signal between axons and dendrites Axoaxonic synapses: signal between axons Axosomatic synapses: signal between axons and the cell body of neurons Dendrodendritic synapses: signal between dendrites Chemical synapses A type of synapse that transmits signals between neurons separated by a cleft via a chemical neurotransmitter Composed of a presynaptic membrane, a synaptic cleft (the space between a presynaptic and postsynaptic neuron), and postsynaptic membrane Most neurotransmitters (e.g., GABA, glutamate, glycine) undergo the following steps: synthesis, storage, release, reuptake, and degradation The chemical transmitter used at neuromuscular junctions and some synapses of the CNS is acetylcholine. Within the CNS, other major categories of neurotransmitters include the following: Certain amino acids (often modified), such as glutamate and γ-aminobutyrate (GABA) Monoamines, such as serotonin (5hydroxytryptamine or 5-HT) and catecholamines, such as dopamine, all of which are synthesized from amino acids Small polypeptides, such as endorphins and substance P Levels of neurotransmitters in the synaptic cleft and available for binding postsynaptic receptors are normally regulated by several local mechanisms. Selective serotonin reuptake inhibitors (SSRIs), a widely used class of drugs for treat- ment of depression and anxiety disorders, were designed to augment levels of this neurotransmitter at the postsynaptic membrane of serotonergic CNS synapses by specifically inhibiting its reuptake at the presynaptic membrane. 1. Neurotransmitter synthesis Occurs in the presynaptic neuron A precursor amino acid accumulates into the neuron. The precursor is metabolized sequentially and yields a mature transmitter. 2. Neurotransmitter storage Vesicles filled with neurotransmitters are stored in the presynaptic terminal and to be released in response to stimulation of the neuron Synaptophysin is a major synaptic vesicle protein that is thought to play a role in synaptic vesicle formation and maintenance 1. Expressed throughout the brain 2. Used as a marker for neuronal cells as well as neuroendocrine tumors 3. Neurotransmitter release Action potentials in the presynaptic cell trigger the opening of voltage-gated Ca2+ channels in the presynaptic membrane, permitting Ca2+ influx. Ca2+ binds to synaptotagmin (a protein anchored in the vesicle membrane), which initiates the vesicle docking to the presynaptic membrane and formation of SNARE complex. SNARE complex Stands for Soluble NSF Attachment protein REceptor complex Consists of several SNARE proteins, which are attached to either: The vesicle membrane (v-SNARE proteins; e.g., synaptobrevin) The presynaptic target membrane (t-SNARE proteins; e.g., syntaxin 1, SNAP 25 ) v-SNARE and t-SNARE proteins combine at the presynaptic membrane to form the SNARE complex. During SNARE complex formation, the vesicle membrane and the presynaptic membrane merge, causing neurotransmittersto be released into the synaptic cleft. 1.Neurotransmitter binding and recognition by target receptors Neurotransmitters act on receptors on the postsynaptic membrane, resulting in the influx of ions into the postsynaptic cell. An action potential is created on the postsynaptic cell, completing the passage of the neurotransmitter from the presynaptic to the postsynaptic cell. 2.Termination of the action of the released transmitter Neurotransmitter actions may be terminated by the following three interlinked processes. Neurotransmitter reuptake: an active termination process triggered by specific transporter proteins on the presynaptic neuron or on glial cells where the neurotransmitter is stored Neurotransmitter enzymatic degradation: a termination process triggered by enzymes in the synaptic cleft (e.g., acetylcholinesterase) yielding an inactive substance Neurotransmitter diffusion: a dispersal of the neurotransmitter out of the synaptic cleft The presynaptic axon terminal (terminal bouton) contains mitochondria and numerous synaptic vesicles from which neurotransmitter is released by exocytosis. The postsynaptic cell membrane contains receptors for the neurotransmitter, and ion channels or other mechanisms to initiate a new impulse. A 20- to 30-nm-wide intercellular space called the synaptic cleft separates these presynaptic and postsynaptic membranes. 1.Postsynaptic potentials (PSPs) The postsynaptic response depends on the type of channel coupled to the receptor, and on the concentration of permeant ions inside and outside the cell. Excitatory postsynaptic potential (EPSP) A depolarizing potential that develops in a postsynaptic membrane as the result of increased influx of cations into the postsynaptic cell The summation of multiple excitatory postsynaptic potentials can cause the postsynaptic neuron to reach the threshold for the generation of an action potential. Examples include: neuromuscular junction, nicotinic synapses (e.g., autonomic ganglia), NMDA synapses (e.g., glutamateand aspartate neurotransmitters) Inhibitory postsynaptic potential (IPSP) A temporary hyperpolarizing or depolarizing potential that develops in a postsynaptic membrane as the result of increased influx of anions into the postsynaptic cell. Inhibitory postsynaptic potentials cause the postsynaptic neuron to move away from the threshold, decreasing firing and propagation of action potentials. Examples include: GABAnergic synapses, glycine synapses (e.g., occur in the Renshaw cells of the spinal cord) Electrical synapses A type of synapse that transmits signals between neurons joined by a gap junction by the flow of electrical current (i.e., movement of ions). Unlike chemical synapses, which require the transmission of a neurotransmitter across a cleft, electrical synapses transmit the signal directly and without delay. Found in the heart and smooth muscle Allows bidirectional flow of information between cells GLIAL CELLS & NEURONAL ACTIVITY Glial cells support neuronal survival and activities, and are 10 times more abundant than neurons in the mammalian brain. In the CNS, glial cells surround both the neuronal cell bodies, which are often larger than the glial cells, and the processes of axons and dendrites between neurons. Glial cells substitute for cells of connective tissue in some respects, supporting neurons and creating immediately around those cells microenvironments that are optimal for neuronal activity. The fibrous intercellular network of CNS tissue superficially resembles collagen by light microscopy, but is actually the network of fine cellular processes emerging from neurons and glial cells. Such processes are collectively called the neuropil. The nervous system develops from the outermost of the three early embryonic layers, the ectoderm, beginning in the third week of development. With signals from the underlying axial structure, the notochord, ectoderm on the mid-dorsal side of the embryo thickens to form the epithelial neural plate. The sides of this plate fold upward and grow toward each other medially, and within a few days fuse to form the neural tube. Cells of this tube give rise to the entire CNS, including neurons and most glial cells. As the folds fuse and the neural tube separates from the now overlying surface ectoderm that will form epidermis, a large population of developmentally important cells, the neural crest, separates from the neuroepithelium and becomes mesenchymal. Neural crest cells migrate extensively and differentiate as all the cells of the PNS, as well as a number of other non-neuronal cell types. Astrocytes Unique to the CNS astrocytes (Gr. astro-, star + kytos) have a large number of long radiating, branching processes. Proximal regions of the astrocytic processes are reinforced with bundles of intermediate filaments made of glial fibrillary acid protein (GFAP), which serves as a unique marker for this glial cell. Distally the processes lack GFAP, are not readily seen by microscopy, and form a vast network of delicate terminals contacting synapses and other structures. Terminal processes of a single astrocyte typically occupy a large volume and associate with over a million synaptic sites. Astrocytes originate from progenitor cells in the embryonic neural tube and are by far the most numerous glial cells of the brain, as well as the most diverse, structurally and functionally. There are two main morphological types of astrocytes: protoplasmic and fibrous astrocytes. Protoplasmic astrocytes have a starlike appearance due to their many radiating processes and are primarily found in the grey matter. Fibrous astrocytes, on the other hand, have relatively few but longer cytoplasmic processes that align with the nerve axons and are mainly found in white matter. Functions attributed to astrocyte: Buffering extracellular K+ levels Regulating the extracellular ionic concentrations around neurons. Guiding and physically supporting movements and locations of differentiating neurons during CNS development Blood-Blood-Barrier - Extending fibrous processes with expanded perivascular feet that cover capillary endothelial cells and modulate blood flow and help move nutrients, wastes, and other metabolites between neurons and capillaries. Forming a barrier layer of expanded protoplasmic processes, called the glial limiting membrane, which lines the meninges at the external CNS surface Replacement of damaged nerve cells by the process of astrocytosis, which involves the proliferation of astrocytes to occupy space left behind by dead neurons. Forming an astrocytic scar Glycogen Reserve – break down glycogen whenever neuron requires ATP Remove excess neurotransmitter Finally, astrocytes communicate directly with one another via gap junctions, forming a very large cellular network for the coordinated regulation of their various activities in different brain regions. Astrocytes make up the Blood Brain Barrier Most brain tumors are astrocytomas derived from fibrous astrocytes. These are distinguished pathologically by their expression of GFAP. 1. 2. 3. Endothelial cells (gap junctions) Basal Lamina Foot processes of Astrocytes Oligodendrocytes Oligodendrocytes (Gr. oligos, small, few + dendron, tree + kytos, cell) extend many processes, each of which becomes sheetlike and wraps repeatedly around a portion of a nearby CNS axon. During this wrapping, most cytoplasm gradually moves out of the growing extension, leaving multiple compacted layers of cell membrane collectively termed myelin. An axon’s full length is covered by the action of many oligodendrocytes. The resulting myelin sheath electrically insulates the axon and facilitates rapid transmission of nerve impulses. Found only in the CNS oligodendrocytes are the predominant glial cells in white matter, which is white because of the lipid concentrated in the wrapped membrane sheaths. The processes and sheaths are not visible by routine light microscope staining in which oligodendrocytes usually appear as small cells with rounded, condensed nuclei and unstained cytoplasm Schwann Cells Schwann cells sometimes called neurolemmocytes, are found only in the PNS and differentiate from precursors in the neural crest. Schwann cells are the counterparts to oligodendrocytes of the CNS, having trophic interactions with axons and most importantly forming their myelin sheathes. However, unlike an oligodendrocyte, a Schwann cell forms myelin around a portion of only one axon. Ependymal Cells Ependymal cells are columnar or cuboidal cells that line the fluid-filled ventricles of the brain and the central canal of the spinal cord. In some CNS locations, the apical ends of ependymal cells have cilia, which facilitate the movement of cerebrospinal fluid (CSF), and long microvilli, which are likely involved in absorption. Ependymal cells are joined apically by apical junctional complexes like those of epithelial cells. However, unlike a true epithelium, there is no basal lamina. Instead, the basal ends of ependymal cells are elongated and extend branching processes into the Microglia Microglia, consisting of small cell bodies from which radiate many long, branched processes, are less numerous than oligodendrocytes or astrocytes but nearly as common as neurons in some CNS regions. Evenly distributed throughout specific regions of gray and white matter, the microglial cell bodies are relatively static while their processes continuously probe and interact with neuropil, synapses, and other cells in an area up to 10-fold that of the cell body. Such probes remove apoptotic bodies and debris from damaged or remodeled synapses by phagocytosis. Microglial cells also constitute the major mechanism of immune defense in the CNS, removing any microbial invaders and secreting several immunoregulatory cytokines. Immunohistochemistry using antibodies against cell surface antigens of immune cells demonstrates microglial processes. When activated by CNS damage or infection, microglia retract their processes, proliferate, and assume the morphologic characteristics and functions of antigen-presenting cells Unlike other glial cells, microglia do not originate from neural progenitor cells, but from circulating blood monocytes, belonging to the same family as macrophages and other antigenpresenting cells. Nuclei of microglial cells can often be recognized in routine hematoxylin and eosin (H&E) preparations by their small, dense, slightly elongated structure, which contrasts with the larger, spherical, more lightly stained nuclei of other glial cells. In multiple sclerosis (MS), the myelin sheaths surrounding axons are damaged by an autoimmune mechanism that interferes with the activity of the affected neurons and produces various neurologic problems. T lymphocytes and microglia, which phagocytose and degrade myelin debris, play major roles in progression of this disease. In MS, destructive actions of these cells exceed the capacity of oligodendrocytes to produce myelin and repair the myelin sheaths. Satellite Cells of Ganglia Also derived from the embryonic neural crest, small satellite cells form a thin, intimate glial layer around each large neuronal cell body in the ganglia of the PNS. Satellite cells exert a trophic or supportive effect on these neurons, insulating, nourishing, and regulating their microenvironments. Same functions as astrocytes in PNS. Sensory ganglion Photomicrograph of a sensory ganglion (H&E stain, 450x magnification) The large round cells visible in this image are neuronal cell bodies (green overlay). These neurons are likely to be pseudounipolar as no axonal processes are visible arising from the cell bodies. The neurons have a central nucleus (green hatched overlay) with prominent nucleoli. The cytoplasm contains fine basophilic granules, which are the rough endoplasmic reticulum (Nissl bodies). Yellow-brown lipofuscin (red overlay; black arrow) is visible in the cytoplasm of the bottom-right neuron (the number of neurons containing lipofuscin increases with age). Small satellite glial cells (black arrowheads) form a ring surrounding each neuronal cell. The intervening tissue is composed of axonal tracts and connective tissue. Pseudounipolar neurons with lipofuscin are present in sensory ganglia (dorsal root ganglia of the spinal cord). The smaller neurons (green overlay) transmit nociception and the larger neurons (black dashed-outline) transmit proprioception. CENTRAL NERVOUS SYSTEM The major structures comprising the CNS are the Cerebrum, Cerebellum, Spinal cord. Cereberral cortex and cerebellar medulla The CNS is completely 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 affecting the protective skull or vertebral bones. Many regions show organized areas of white matter and gray matter, differences caused by the differential distribution of lipid-rich myelin. WHITE MATTER - The main components of white matter are myelinated axons), often grouped together as tracts, and the myelin-producing oligodendrocytes. Astrocytes and microglia are also present, but very few neuronal cell bodies. Most white matter is found in deeper regions. GRAY MATTER - contains abundant neuronal cell bodies, dendrites, 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; Deep within the brain are localized, variously shaped darker areas called the cerebral nuclei, each 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 neurons. Neurons of the cerebral cortex function in the integration of sensory information and the initiation of voluntary motor responses. There are 6 classically recognized layers of the cortex: I.Outer plexiform (molecular) layer: sparse neurons and glia II.Outer granular layer: small pyramidal and stellate neurons III.Outer pyramidal layer: moderate sized pyramidal neurons IV.Inner granular layer: densely packed stellate neurons (usually the numerous processes aren’t visible, but there are lots of nuclei reflecting the cell density) V.Ganglionic or inner pyramidal layer: large pyramidal neurons VI.Multiform cell layer: mixture of small pyramidal and stellate neurons Pyramidal cells in layers III and V tend to be larger because their axons contribute to efferent projections that extend to other regions of the CNS –pyramidal neurons in layer V of motor cortices send projections all the way down to motor neurons in the spinal cord! Layers of Cortex 1 -Molecular layer: nerve fibers 2 -External granular layer Densely packed, small nonpyramidal cells (e.g., stellate cells) Small pyramidal cells that project axons to other cortical areas 3- External pyramidal layer: small to medium-sized pyramidal cells that project axons to other cortical areas Pyramidal cells in layers III and V tend to be larger because their axons contribute to efferent projections that extend to other regions of the CNS – pyramidal neurons in layer V of motor cortices send projections all the way down to motor neurons in the spinal cord! 4 - Internal granular layer Termination area of thalamocortical projections Filled with densely packed, medium-sized pyramidal and nonpyramidal cells 5- Internal pyramidal layer: large pyramidal cells give rise to the axons that form the corticospinal tracts and corticobulbar tracts (pyramidal tracts to the brainstem and spinal cord) 6- Multiform layer: composed of pyramidal and nonpyramidal cells of various size Cortical pyramidal neurons Photomicrograph of cerebral cortex (silver stain, 300x magnification) Multiple pyramidal neurons and neuronal processes are visible. Pyramidal cells consist of a pyramidal cell body, a dominant apical dendrite, several basal dendrites, and a thin axon that originates from the base of the cell body (indicated with a black arrow). Non pyramidal cells The stellate cells play the role of interneurons within the cerebral cortex; their axons do not leave the cortex. The axons of pyramidal cells leave the cortex and project to a variety of other structures within the central nervous system. layer III of cerebral cortex showing two types of neurons: pyramidal and stellate. Pyramidal neurons (P) have a prominent apical dendrite (D). The axons (A) of pyramidal neurons exit the cortex and travel through white matter to the spinal cord, to the opposite cortex and to various nuclei in the brainstem. In contrast, stellate neurons (S) are local circuit neurons with synaptic connections to neighboring neurons The cerebellum is composed of the outer gray matter (cerebellar cortex) and inner white matter (cerebellar medulla). Cerebellar cortex Receives afferent inputs from the cerebrum, spinal cord, and vestibular nuclei Sends neural impulses to the cerebellar nuclei Composed of 5 types of neuronal cells, densely packed and arranged in 3 layers The cortex is primarily an inhibitory structure; all cerebellar cells except granule cells are inhibitory. Circuitry of the cerebellum The cerebellar cortex is composed of three layers: - Molecular layer: contains basket cells, astrocytes (stellate cells), and parallel fibers (axons of granule cells). The astrocytes and basket cells receive excitatory input from parallel fibers and send inhibitory impulses to the Purkinje cells. - Ganglion cell layer: contains Purkinje cells, which receive excitatory input from climbing fibers and parallel fibers and send inhibitory impulses to the deep cerebellar nuclei - Granular cell layer: contains golgi cells and granule cells. The golgi cells receive excitatory impulses from the molecular layer and send inhibitory impulses to the granule cells. The granule cells receive excitatory input from mossy fibers and send excitatory efferents to all other cells of the cerebellar cortex. Granule cells are the only excitatory neurons in the cerebellar cortex and use the neurotransmitter glutamate (GABA is the neurotransmitter of the inhibitory cerebellar cells). Granule cells = parallel fibers - Dark blue zone the cerebellar medulla, composed mainly of axonal fibers. The right side of the image - 3 layers of the cerebellar cortex. From the center of the image to the top left: - Granular layer (with golgi cells and the densely packed, deeply eosinophilic granular cells) - Ganglionic layer (containing Purkinje cells with their prominently protruding axons) - Molecular layer (pinkish zone with basket cells, stellate cells, and parallel fibers). Granular Cell Purkinje ecell Axons of Purkinje Cells Purkinje Layer Molecular layer Granular layer Granular Layer Molecular layer Axons of Purkinje Fibers Purkinje cell layer Cerebellar medulla Composed of climbing fibers, mossy fibers, Purkinje cell axons, and the deep cerebellar nuclei Mossy fibers : afferent axons from the cerebral cortex, pons, spinal cord, and vestibular nuclei to the cerebellum. Terminate on granule cells → send excitatory stimuli to the Purkinje cells. Climbing fibers: afferent axons from the inferior olivary nuclei of the medulla → terminate on Purkinje cells Four deep cerebellar nuclei (from lateral to medial): dentate, emboliform, globose, and fastigial nucleus o In cross sections of the spinal cord, the white matter is peripheral and the gray matter forms a deeper, H-shaped mass The two anterior projections of this gray matter anterior horns - contain cell bodies of very large motor neurons whose axons make up the ventral roots of spinal nerves. o The two posterior horns contain interneurons, which receive sensory fibers from neurons in the spinal (dorsal root) ganglia. o 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. The spinal cord varies slightly in diameter along its length but in cross section always shows bilateral symmetry around the small, CSF-filled central canal (C). Unlike the cerebrum and cerebellum, in the spinal cord, the gray matter is internal, forming a roughly H-shaped structure that consists of two posterior (P) horns (sensory) and two anterior (A) (motor) horns, all joined by the gray commissure around the central canal. (a) The gray matter contains abundant astrocytes and large neuronal cell bodies, especially those of motor neurons in the ventral horns. (b) The white matter surrounds the gray matter and contains primarily oligodendrocytes and tracts of myelinated axon running along the length of the cord. (c) With H&E staining, the large motor neurons (N) of the ventral horns show large nuclei, prominent nucleoli, and cytoplasm rich in Nissl substance, all of which indicate extensive protein synthesis to maintain the axons of these cells that extend great distances. (d) In the white commissure ventral to the central canal, tracts (T) run lengthwise along the cord, seen here in cross section with empty myelin sheaths surrounding axons, as well as small tracts running from one side of the cord to the other. Meninges The skull and the vertebral column protect the CNS, but between the bone and nervous tissue are membranes of connective tissue called the meninges. Three meningeal layers are distinguished: the dura, arachnoid, and pia maters. Dura Mater The thick external dura mater (L. dura mater, tough mother) consists of dense irregular connective tissue organized as an outer periosteal layer continuous with the periosteum of the skull and an inner meningeal layer. These two layers are usually fused, but along the superior sagittal surface and other specific areas around the brain, they separate to form the blood-filled dural venous sinuses. Around the spinal cord, the dura mater is separated from the periosteum of the vertebrae by the epidural space, which contains a plexus of thin- walled veins and loose connective tissue. The dura mater may be separated from the arachnoid by formation of a thin subdural space. ) ) Arachnoid The arachnoid (Gr. arachnoeides, spider web-like) has two components: a sheet of connective tissue in contact with the dura mater a system of loosely arranged trabeculae composed of collagen and fibroblasts, continuous with the underlying pia mater layer. Surrounding these trabeculae is a large, sponge-like cavity, the subarachnoid space, filled with CSF. This fluid-filled space helps cushion and protect the CNS from minor trauma. The subarachnoid space communicates with the ventricles of the brain where the CSF is produced. The connective tissue of the arachnoid is said to be avascular because it lacks nutritive capillaries, but larger blood vessels run through it. Because the arachnoid has fewer trabeculae in the spinal cord, it can be more clearly distinguished from the pia mater in that area. The arachnoid and the pia mater are intimately associated and are often considered a single membrane called the piaarachnoid. In some areas, the arachnoid penetrates the dura mater and protrudes into blood-filled dural venous sinuses located there. These CSF-filled protrusions, which are covered by the vascular endothelial cells lining the sinuses, are called arachnoid villi and function as sites for absorption of CSF into the blood of the venous sinuses. Pia Mater The innermost pia mater (L. pia mater, tender mother) con- sists of flattened, mesenchymally derived cells closely applied to the entire surface of the CNS tissue. The pia does not directly contact nerve cells or fibers, being separated from the neural elements by the very thin superficial layer of astrocytic processes (the glial limiting membrane, or glia limitans), which adheres firmly to the pia mater. Together, the pia mater and the layer of astrocytic end feet form a physical barrier separating CNS tissue from CSF in the subarachnoid space Blood vessels penetrate CNS tissue through long peri- vascular spaces covered by pia mater, although the pia disappears when the blood vessels branch to form the small capillaries. However, these capillaries remain completely covered by the perivascular layer of astrocytic processes Section of an area near the anterior median fissure showing the tough dura mater (D). Surrounding the dura, the epidural space (not shown) contains cushioning adipose tissue and vascular plexuses. The subdural space (SD). The middle meningeal layer is the thicker weblike arachnoid mater (A) containing the large subarachnoid space (SA) and connective tissue trabeculae (T). The subarachnoid space is filled with CSF and the arachnoid acts as a shock-absorbing pad between the CNS and bone. Fairly large blood vessels (BV) course through the arachnoid. The innermost pia mater (P) is thin and is not clearly separate from the arachnoid; together, they are sometimes referred to as the pia-arachnoid or the leptomeninges. The space between the pia and the white matter (WM) of the spinal cord here is an artifact created during dissection; normally the pia is very closely applied to a layer of astrocytic processes at the surface of the CNS tissue. (X100; H&E) Blood-Brain Barrier The blood-brain barrier (BBB) is a functional barrier that allows much tighter control than that in most tissues over the passage of substances moving from blood into the CNS tissue. The main structural component of the BBB is the capillary endothelium, in which the cells are tightly sealed together with well-developed occluding junctions, with little or no transcytosis activity, and surrounded by the basement membrane. The limiting layer of perivascular astrocytic feet, which closely envelops the basement membrane of the continuous capillaries in most CNS region, also contributes to the BBB and further regulates passage of molecules and ions from blood to brain. The BBB protects neurons and glia from bacterial toxins, infectious agents, and other exogenous substances, and helps maintain the stable composition and constant balance of ions in the interstitial fluid required for normal neuronal function. The BBB is not present in regions of the hypothalamus where plasma components are monitored, in the posterior pituitary that releases hormones, or in the choroid plexus where CSF is produced. Blood-brain barrier Description: a barrier of CNS blood vessels separating the brain from circulating blood Function: protects the central nervous system from microorganisms, cells, proteins, and drugs that can cause damage to the brain and other structures Components Capillary endothelial cells → have tight junctions The basal lamina Astrocytes Pericytes Transport mechanisms across the blood-brain barrier Ion channels (e.g., sodium, potassium) Selective transport (slow): amino acids, glucose, vitamin K, vitamin D Diffusion (fast): nonpolar and lipid-soluble substances (e.g., oxygen and carbon dioxide) Structures with no blood-brain barrier Structures located around the brain ventricles (circumventricular location), including: Area postrema: vomiting center (contains the chemoreceptor trigger zone) Organum vasculosum lamina terminalis (OVLT): osmoreceptors Neurohypophysis: oxytocin and ADH release directly into the blood Allow certain molecules to affect brain function (e.g., blood-borne drugs and hormones) Damage mechanisms Brain infarction and tumors break endothelial cell tight junctions, thereby causing vasogenic edema. Hyperosmolar solutions (e.g., mannitol) cause vasodilatation and shrinkage of endothelial cells, thereby disrupting the blood-brain barrier and increasing its permeability to other drugs. Choroid Plexus The choroid plexus consists of highly vascular tissue, elaborately folded and projecting into the large ventricles of the brain. It is found in the roofs of the third and fourth ventricles and in parts of the two lateral ventricular walls, all regions in which the ependymal lining directly contacts the pia mater. A decrease in the absorption of CSF or a blockage of outflow from the ventricles during fetal or postnatal development results in the condition Each villus of the choroid plexus contains a thin layer of well-vascularized pia mater known as hydrocephalus covered by cuboidal ependymal cells. (Gr. hydro, water + kephale, head), which promotes a progressive The function of the choroid plexus is to remove water from blood and release it as enlargement of the head followed by the CSF. CSF is clear, contains Na+, K+, and Cl– ions but very little protein, and its mental impairment. only cells are normally very sparse lymphocytes. It is produced continuously and it completely fills the ventricles, the central canal of the spinal cord, the subarachnoid and perivascular spaces. It provides the ions required for CNS neuronal activity and in the arachnoid serves to help absorb mechanical shocks. Arachnoid villi provide the main path- way for absorption of CSF back into the venous circulation. There are very few lymphatic vessels in CNS tissue. PERIPHERAL NERVOUS SYSTEM The main components of the peripheral nervous system (PNS) are the nerves, ganglia, and nerve endings. Peripheral nerves are bundles of nerve fibers (axons) individually surrounded by Schwann cells and connective tissue. Nerve Fibers Nerves are analogous to tracts in the CNS, containing axons enclosed within sheaths of glial cells specialized to facilitate axonal function. In peripheral nerves, axons are sheathed by Schwann cells or neurolemmocytes. The sheath may or may not form myelin around the axons, depending on their diameter. Myelinated Fibers As axons of large diameter grow in the PNS, they are engulfed along their length by a series of differentiating neurolemmocytes and become myelinated nerve fibers. The plasma membrane of each covering Schwann cell fuses with itself at an area termed the mesaxon and a wide, flattened process of the cell continues to extend itself, moving circumferentially around the axon many times. The multiple layers of Schwann cell membrane unite as a thick myelin sheath. Composed mainly of lipid bilayers and membrane proteins, myelin is a large lipoprotein complex that, like cell membranes, is partly removed by standard histologic procedure. Unlike oligodendrocytes of the CNS, a Schwann cell forms myelin around only a portion of one axon. With high-magnification TEM, the myelin sheath appears as a thick electron-dense axonal covering in which the concentric membrane layers may be visible. The prominent electron-dense layers visible ultrastructurally in the sheath, the major dense lines, represent the fused, protein-rich cytoplasmic surfaces of the Schwann cell membrane. Along the myelin sheath, these surfaces periodically separate slightly to allow transient movement of cyto- plasm for membrane maintenance; at these myelin clefts (or Schmidt-Lanterman clefts), the major dense lines temporarily disappear. Faintly seen ultrastructurally in the light staining layers are the intraperiod lines that represent the apposed outer bilayers of the Schwann cell membrane. Membranes of Schwann cells have a higher proportion of lipids than do other cell membranes, and the myelin sheath serves to insulate axons and maintain a constant ionic micro- environment most suitable for action potentials. Between adjacent Schwann cells on an axon, the myelin sheath shows small nodes of Ranvier (or nodal gaps), where the axon is only partially covered by interdigitating Schwann cell processes. At these nodes, the axolemma is exposed to ions in the interstitial fluid and has a much higher concentration of voltage-gated Na+ channels, which renew the action potential and produce saltatory conduction (L. saltare, to jump) of nerve impulses, their rapid movement from node to node. The length of axon ensheathed by one Schwann cell, the internodal segment, varies directly with axonal diameter and ranges from 300 to 1500 µm. Unmyelinated Fibers Unlike the CNS where many short axons are not myelinated at all but course among other neuronal and astrocytic processes, the smallest diameter axons of peripheral nerves are still enveloped within simple folds of Schwann cells. These very small unmyelinated fibers do not however undergo multiple wrapping to form a myelin sheath. In unmyelinated nerves, each Schwann cell can enclose portions of many axons with small diameters. Without the thick myelin sheath, nodes of Ranvier are not seen along unmyelinated nerve fibers. Moreover, these small-diameter axons have evenly distributed voltage-gated ion channels; their impulse conduction is not saltatory and is much slower than that of myelinated axons. portion of myelin in which the major dense lines of individual membrane layers can be distinguished, as well as the neurofilaments (NF) and microtubules (MT) in the axoplasm (A). At the center of the photo is a Schwann cell showing its active nucleus (SN) and Golgi-rich cytoplasm (SC). At the right is an axon around which myelin is still forming Unmyelinated axons (UM) are much smaller in diameter, and many such fibers may be engulfed by a single Schwann cell (SC). The glial cell does not form myelin wrappings around such small axons but simply encloses them. Whether it forms myelin or not, each Schwann cell is surrounded, as shown, by an external lamina containing type IV collagen and laminin like the basal laminae which underlie epithelia. longitudinally oriented nerve shows one node of Ranvier (N) with the axon visible. Col- lagen of the sparse endoneurium (En), blue in this trichrome stain, surrounds the Schwann cells and a capillary (C). At least one Schwann cell nucleus (S) is also clearly seen. (X400; Mallory trichome) The axon is enveloped by the myelin sheath, which, in addition to membrane, contains some Schwann cell cytoplasm in spaces called Schmidt-Lanterman or myelin clefts between the major dense lines of membranes. The upper diagram shows one set of such clefts ultrastructurally. The clefts contain Schwann cell cytoplasm that was not displaced to the cell body during myelin formation. This cytoplasm moves slowly along the myelin sheath, opening temporary spaces (the clefts) that allow renewal of some membrane components as needed for maintenance of the sheath. The lower diagram depicts the ultrastructure of a single node of Ranvier or nodal gap. Interdigitating processes extending from the outer layers of the Schwann cells (SC) partly cover and contact the axolemma at the nodal gap. This contact acts as a partial barrier to the movement of materials in and out of the periaxonal space between the axolemma and the Schwann sheath. The basal or external lamina around Schwann cells is continuous over the nodal gap. The axolemma at nodal gaps has abundant voltage-gated Na+ channels important for impulse conductance in these axons. 1 4 2 3 1 2 3 4 Nerve Organization In the PNS, nerve fibers are grouped into bundles to form nerves. Except for very thin nerves containing only unmyelinated fibers, nerves have a whitish, glistening appearance because of their myelin and collagen content. Axons and Schwann cells are enclosed within layers of connective tissue. Immediately around the external lamina of the Schwann cells is a thin layer called the endoneurium, consisting of reticular fibers, scattered fibroblasts, and capillaries. Groups of axons with Schwann cells and endoneurium are bundled together as fascicles by a sleeve of perineurium, containing flat fibrocytes with their edges sealed together by tight junctions. From two to six layers of these unique connective tissue cells regulate diffusion into the fascicle and make up the blood-nerve barrier that helps maintain the fibers’ microenvironment. Externally, peripheral nerves have a dense, irregular fibrous coat called the epineurium, which extends deeply to fill the space between fascicles. Very small nerves consist of one fascicle. Small nerves can be found in sections of many organs and often show a winding disposition in connective tissue. Myelin maintenance and nodes of Ranvier. Peripheral nerves establish communication between centers in the CNS and the sense organs and effectors (muscles, glands, etc). They generally contain both afferent and efferent fibers. Afferent fibers carry information from internal body regions and the environment to the CNS. Efferent fibers carry impulses from the CNS to effector organs commanded by these centers. Nerves possessing only sensory fibers are called sensory nerves; those composed only of fibers carrying impulses to the effectors are called motor nerves. Most nerves have both sensory and motor fibers and are called mixed nerves, usually also with both myelinated and unmyelinated axons. Ganglia Ganglia are typically ovoid structures containing neuronal cell bodies and their surrounding glial satellite cells supported by delicate connective tissue and surrounded by a denser capsule. Because they serve as relay stations to transmit nerve impulses, at least one nerve enters and another exits from each ganglion. The direction of the nerve impulse determines whether the ganglion will be a sensory or an autonomic ganglion. Sensory Ganglia Sensory ganglia receive afferent impulses that go to the CNS. Sensory ganglia are associated with both cranial nerves (cranial ganglia) and the dorsal roots of the spinal nerves (spinal ganglia). The large neuronal cell bodies of ganglia are associated with thin, sheetlike extensions of small glial satellite cells. Sensory ganglia are supported by a distinct connective tissue capsule and an internal framework continuous with the connective tissue layers of the nerves. The neurons of these ganglia are pseudounipolar and relay information from the ganglion’s nerve endings to the gray matter of the spinal cord via synapses with local neurons. Autonomic Ganglia Autonomic nerves affect the activity of smooth muscle, the secretion of some glands, heart rate, and many other involuntary activities by which the body maintains a constant internal environment (homeostasis). Autonomic ganglia are small bulbous dilations in autonomic nerves, usually with multipolar neurons. Some are located within certain organs, especially in the walls of the digestive tract, where they constitute the intramural ganglia. The capsules of these ganglia may be poorly defined the local connective tissue. A layer of satellite cells also envelops the neurons of autonomic ganglia although these may also be inconspicuous in intramural ganglia. Autonomic nerves use two neuron circuits. The first neuron of the chain, with the preganglionic fiber, is located in the CNS. Its axon forms a synapse with postganglionic fibers of the second multipolar neuron in the chain located in a peripheral ganglion system. The chemical mediator present in the synaptic vesicles of all preganglionic axons is acetylcholine. Neuronal cell bodies of preganglionic sympathetic nerves are located in the thoracic and lumbar segments of the spinal cord and those of the parasympathetic division are in the medulla and midbrain and in the sacral portion of the spinal cord. Sympathetic second neurons are located in small ganglia along the vertebral column, while second neurons of the parasympathetic series are found in very small ganglia always located near or within the effector organs, for example in the walls of the stomach and intestines. Parasympathetic ganglia may lack distinct capsules altogether, perikarya and associated satellite cells simply forming a loosely organized plexus within the surrounding connective tissue. Neural Plasticity & Regeneration Certain regions of the CNS, such as near the ependyma, retain rare neural stem and progenitor cells that allow some replacement of neurons throughout life; neural plasticity involving formation and remodeling of synaptic connections is also prevalent throughout life. The complexity and distances of the neuronal and glial interconnections with the CNS make regeneration and restoration of function within this tissue after major injury very difficult. The more simply organized peripheral nerves have better capacity for axonal regeneration, a process involving reactivation of the peri- karyon, Schwann cells, and macrophages. NEURAL PLASTICITY & REGENERATION Despite its general stability, the nervous system exhibits neuronal differentiation and formation of new synapses even in adults. Embryonic development of the nervous system produces an excess of differentiating neurons, and the cells which do not establish correct synapses with other neurons are eliminated by apoptosis. In adult mammals after an injury, the neuronal circuits may be reorganized by the growth of neuronal processes, forming new synapses to replace ones lost by injury. Thus, new communications are established with some degree of functional recovery. This neural plasticity and reforma- tion of processes are controlled by several growth factors pro- duced by both neurons and glial cells in a family of proteins called neurotrophins. Neuronal stem cells are present in the adult CNS, located in part among the cells of the ependyma, which can supply new neurons, astrocytes, and oligodendrocytes. Fully differentiated, interconnected CNS neurons cannot temporarily disengage these connections and divide to replace cells lost by injury or disease; the potential of neural stem cells to allow tissue regen- eration and functional recovery within the CNS components is a subject of intense investigation. Astrocytes do proliferate at injured sites and these growing cells can interfere with success- ful axonal regeneration in structures such as spinal cord tracts. In the histologically much simpler peripheral nerves, injured axons have a much greater potential for regeneration and return of function. If the cell bodies are intact, damaged or severed PNS axons can regenerate as shown in the sequence of diagrams in Figure 9–30. Distal portions of axons, isolated from their source of new proteins and organelles, degenerate; the surrounding Schwann cells dedifferentiate, shed the myelin sheaths, and proliferate within the surrounding layers of con- nective tissue. Cellular debris including shed myelin is removed by blood-derived macrophages, which also secrete neurotroph- ins to promote anabolic events of axon regeneration. The onset of regeneration is signaled by changes in the perikaryon that characterize the process of chromatolysis: the cell body swells slightly, Nissl substance is initially dimin- ished, and the nucleus migrates to a peripheral position within the perikaryon. The proximal segment of the axon close to the wound degenerates for a short distance, but begins to grow again distally as new Nissl substance appears and debris is removed. The new Schwann cells align to serve as guides for