Histology-Nervous System chp1 2 PDF

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 P...

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 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. 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.