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Ahmad Aulia Jusuf,/Histology / 2008 LECTURE NOTE All images in this document is removed due to copyright restriction The Histological Aspect in Neuroscience AHMAD AULIA JUSUF, MD, Ph.D Department of Histology Faculty of Medicine University of Indonesia Jakarta 2008 Histological Aspect of Neuroscience 1 Ahmad Aulia Jusuf,/Histology / 2008 2 THE HISTOLOGICAL ASPECT IN NEUROSCIENCE Ahmad Aulia Jusuf, MD, PhD Department of Histology Faculty of Medicine University of Indonesia INTRODUCTION Nerve tissue is one of the four basic tissues consisted mostly of the cells, the neuronal cells (neurons) and supporting cells (Glial cells), so it is also called as a cellular tissue. Nerve tissue comprises the entire mass of tissue in the body. The nervous system is organized anatomically (Fig-1 and 2) into 2 main divisions : (1) the central nervous system (CNS) consists of brain which is covered by the skull (cranium) and spinal cord which is located in the vertebral column and (2) the peripheral nervous system (PNS) which lies outside of the CNS includes cranial nerves, emanating from the brain and spinal nerve, emanating from the spinal cord and their associated ganglia. The autonomic nervous system (ANS), a subdivision of the PNS, consist of the nerve fibers that run together with the cranial and spinal nerves and their associated ganglia. The central nervous system consists of brain and spinal cord. The brain contains the cerebrum, cerebellum, pons and the medulla of oblongata. The central nervous tissue is enclosed by the skull in where the brain is located and the vertebrae which cover the spinal cord or medulla spinalis. The peripheral nervous system lies outside the CNS and consists of nerves and their special endings and ganglia. Nerves are collections of processes (axons) whose nerve cell bodies are usually within the CNS. Nerves leave the CNS in pairs, one nerve for each side of the body. Emerging from the brain are the 12 pairs of cranial nerves. Those arising from the spinal cord are the 31 pairs of spinal nerves. The PNS contains clusters of neurons, the ganglia, which are surrounded by the connective tissue capsules. These are two types: (1) the spinal or sensory ganglion, a fusiform swelling on each dorsal (sensory) root of spinal nerves; and (2) the autonomic ganglia, contained either in two parallel chains of connective tissue, the sympathetic chain ganglia, extending along the anterior surface of the vertebrae or a small, poorly encapsulated parasympathetic ganglia near or within various organs. Functionally the PNS is divided into two types of fibers, sensory or afferent fibers ( to carry toward to the CNS) and motor or efferent fibers (to carry away from the CNS). The Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 3 afferent division consists of nerve fibers that convey information (impulses) from receptors e.g. in skin, organ, and special senses, to the CNS. Those sensory fibers distributed to the body wall and limbs, e.g. skin, muscles and bones, are called somatic (Gk. Soma, body) afferent. Those innervating the viscera, e.g. internal organs and glands are called visceral afferents. Fig-1 Central Nervous Tissue Fig-2 Peripheral Nervous Tissue (A) (B) Fig-3. The autonomic nervous system, Sympathetic (A) and parasympathetic division (B) The efferent parts of the PNS are motor in function, i.e. they cause muscle to contract and glands to secrete. Somatic (voluntary) efferent fibers arise in the spinal cord and ends on skeletal muscles. Visceral (involuntary) efferents comprise most of the autonomic nervous system (ANS). They convey impulses from the CNS to smooth and cardiac muscles, causing them to contract, and to glands, stimulating them to secrete. The ANS (Fig-3) is divided into 2 groups; (1) the sympathetic division, a thoracolumbar divison of ANS, which their cells origin in the thoracic and upper lumbar levels of the spinal cord; (2) the parasympathetic divison, a craniosacral divison of ANS, which their cells origin in Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 4 the cranial and sacral levels of the spinal cord. The autonomic nervous system is linked to the higher nerve center in the brain and it is beyond the control of our free will. FUNCTION OF THE NERVOUS SYSTEM The nervous system functions in communicating which receives the signal from the outside and inside of the body and send the messages from one cell to the other cell in the body. To establish the functions of nervous system the protoplasm (perikaryon) of the nerve cell has 2 fundamental attributes i.e. the irritability (the capacity to react in a graded manner to physical or chemical stimuli) and conductivity (the ability to transmit excitation rapidly from one place to another. HISTOLOGICAL STRUCTURE OF NERVOUS TISSUE The nerve tissues histologically are composed of the Neurons, the cells responsible for the reception and transmission of nerve impulses to and from the CNS and the neuroglial cells, the cells responsible for supporting and protecting neurons. Neuron is the cell responsible for the receptive, integrative and motor function of the nervous system. Generally the neuron (Fig-4, left side) consists of the body of the cell also called as perikaryon (Gk. Peri, around; karyon, nucleus) or soma and the processes which are projecting from its body. Most neurons are composed of three distinct parts: a cell body, multiple dendrites and a single axon. Generally the bodies of the neurons in the central nervous system are polygonal with concave surfaces between the many cell processes, for example motor neurons in the anterior horn of spinal cord (Fig-4 right side), pyramidal cells in the cerebral cortex, Purkinje’s cell in the cerebellum etc. The neurons in the peripheral nervous system have a round cell body with a small number of processes, for example ganglion cells in dorsal root ganglia. Cell bodies present different sizes and shapes that are characteristic for their type and location. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 5 Fig-4 The schematic figure of neuron (left side) motor neuron in anterior horn of spinal cord (right side) PERIKARYON The cell body (Soma, Perikaryon) (Fig-5) is the region of the neuron containing the large pale staining nucleus and perinuclear cytoplasm. The nucleus is usually spherical to ovoid and centrally located. It contains finely dispersed chromatin in which DNA (Deoxyribonucleid acid), the heredity materials are located and the nucleolus. The nucleus appears pale when stainned with the basic dyes and it is often describe as the vesiculate in the large neurons, for example in the motor neuron and ganglion cells. Because the appearance of the neuronal cell body is very characteristic with large nucleus and small nucleolus in the central area like the Owl eyes, so it is also called the “owl eyes”. Fig-5. The Perikaryon, motor neuron (Left side) and Ganglion cells (right side) The cytoplasm of perikaryon (Fig-6) is crowded by organelles and inclusion bodies. Organelle is the membrane-limited structure with the particular function required for the living of neuronal cell. The organelles consist of rough endoplasmic reticulum (RER or Nissl’s Bodies), smooth endoplasmic reticulum (SER), Golgi complex, mitochondria and cytoskeleton. The cytoplasm of the cell body has abundant rough endoplasmic reticulum (Fig-6) with many cysternae in parallel arrays. Polyribosome are also scattered through out the cytoplasm. When this cisternae and polyribosomes are stained with the basic dyes, they appear as clumps of basophilic material called as Nissl bodies, which is visible with the light microscope. Since the pattern of Nissl bodies in the cytoplasm of the perikaryon like the skin of tiger, so it also called as tigroid substance. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 6 The Nissl bodies can be found clearly in the motor neuron in the anterior horn of spinal cord and in the ganglion cell. The Nissl bodies present in the perikaryon and in the dendrites. Function of the Nissl bodies is as the place for protein synthesis. Smooth endoplasmic reticulum (Fig-6) is found in the perikaryon, axon and dendrite. The role of this structure is still unclear but there is a speculation that it may have a role in the transport of protein through out the cell. Golgi complex (Fig-6) is the stacks of membranous structures in eukaryotic cells that function in processing and sorting the protein and lipids destined for other cellular compartment or for secretion. This structure also called as Golgi apparatus. It present abundant in all neurons. In the neuronal cell the Golgi complex has some additional functions i.e. concentrates and slightly modified protein synthesized in the Nissl bodies and involved in production of component of the cell membrane and the formation of lysosomes. These functions are most apparent in neurosecretory cells as in the hypothalamus and more subtle in cells that synthesize neurotransmitters. It is though that the Golgi complex produces transmitter molecules or the enzymes necessary for their production in the axon terminal. Figure-6 The Schematc Picture of Neuronal cytoplasm Mitochondria (Fig-6) is a large organelle that is surrounded by two phospholipids bilayer membranes, contains DNA and carries out the oxidative phosphorylation to produce the energy required to maintain the metabolism in the cell. Because the neurons have low energy reserves and a great need for glucose and oxygen, a numerous mitochondria are scattered throughout the cytoplasm of the soma, dendrites and axons, but they are most abundant at the axon terminal. Cytoskeleton (Fig-6) is a network of fibrous elements, consisting of microtubules, actin microfilament and intermediate filament. The cytoskeleton provides structural support for the cell and permits directed movement of organelles. When prepared by silver impregnation for visualized by light microscopy, the neuronal cytoskeleton exhibits neurofibriles (up to 2 m in diameter) coursing through out the cytoplasm of the soma and extending into the processes. Electron microscopic studies reveal three different filamentous structures: microtubules (24nm in diameter), neurofilament (intermediate filaments, 10 nm in diameter) and microfilament (6 nm in diameter). The Cytoskeleton of the neuron is important in supporting the organelles and in changes in shape of the cell as a whole. The microtubules also have an essential role in transport of vesicles and organelles that move along their surface within the cell body and along the length of the axon. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 7 The inclusion bodies (Fig-7) that can be found in the neuronal cells are melanin granules, lipofuscin and lipid droplets. Melanin granules are dark brown to black in color and can be found in neurons in certain regions of CNS (i.e. substansia nigra, locus cereleus, spinal cord) and in symphatetic ganglia of the PNS. Lipofuscin, an irregularly shaped pigment granule is more prevalent in the neuronal cytoplasm of Fig-7 Pigmen in the Neuronal cell older persons and is thought to be the remnants of lysosomal enzymatic activity. These granules increase with advancing age. Iron-containing pigments also maybe observed in certain certain neurons of the CNS and may accumulate with age. Lipid droplets sometimes are observed in the neuronal cytoplasm and may be the result of faulty metabolism, or they may be energy reserves PROCESSES OF NEURONS The cell processes (Fig-8) of the neurons are perhaps their most remarkable features. Long or short thick or thin, smooth or spiny, simply or elaborately branched on them depends most of the capacity of nerve cells to transmit, receive and integrate messages. In almost all neurons there are two kinds of processes: the dendrites and axon. DENDRITE Neurons usually have multiple dendrites arising directly from the cell body and these branches provide most of the surface for receiving signals from other neurons. Where the dendrites emerge from the perikaryon, they are relatively thick but they taper gradually along their length. Dendrites of most neurons are fairly short and confined to the immediate vicinity of the soma. Dendrite bifurcates into primary, secondary and tertiary and higher orders of the braches that form patterns ranging from simple to highly complex. Dendrite may appear thorny owing to the presence of minute projections called as spines (or gemullae) from their surfaces (Fig-9). These spines are specialized sites of synaptic contact Fig-8 The Processus of neuronal cell Histological Aspect of Neuroscience Fig-9. The Gemullae in the Piramid cell Ahmad Aulia Jusuf,/Histology / 2008 8 that could provide some selectivity and control of input. Dendrite contains Nissl bodies, free ribosome, mitochondria, microtubules and neurofilament. Dendrite receives the impulses from other neurons via their synapse with axon terminals. The dendritic tree of the large Purkinje cell (in cerebellum) may number in hundreds or thousands. AXONS The axon arises from a conical extension of the cell body called the axon hillock (Fig-8). Occasionally the neuron like in the amacrine cells of the retina does not contain axon, but this is quite uncommon. Axon is usually thinner and much longer than the dendrites of the same cell. The part of the axon between the hillock and the beginning of the myelin sheath is called the initial segment. The axoplasm does not contain Nissl bodies, ribosom and Golgi complex, but contain smooth endoplasmic reticulum, mitochondria, microtubule and neurofilament. Most of the axon has the myelin sheath. Axons lacking myelin sheath are called unmyelinated axons. Nerve impulses are conducted much faster along myelinated axons than along unmyelinated axons. In the fresh state the myelin sheath imparts a white, glistening appearance to the axon. The presence of myelin permits the subdivision of the CNS into white and gray matter. A single axon may terminate on many synapses since it has an extensive arborization at its terminal called as telodendria which end in small swellings called terminal boutons. Axon functions in conduction of impulses and in signal transmission at its ending. Another important function of axon is axonal transport of material between the soma and the axon terminal. Axonal transport is crucial to trophic relationships between neuron and muscle or glands. CLASSIFICATION OF NEURONS Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 9 Morphologically neurons are classified into 4 major type (Fig-10) according to their shape and arrangement of their processes: the unipolar neuron, bipolar neuron, pseudounipolar neuron, and multipolar neuron. Unipolar neurons posses a single process and are rare in vertebrates except in early embryonic development. Bipolar neurons posses two processes emanating from the soma, a single dendrite and a single axon. Bipolar neurons are located in the vestibular and cochlear ganglia and in the olfactory epithelium of the nasal cavity. Pseudounipolar neurons posses only one process emanating from the cell body, but this process branches later into a peripheral and a central branch. Pseudounipolar neurons are present in the dorsal root ganglia and in some of the cranial nerve ganglia. Fig-10. The classification of neurons according to their polarity Multipolar neurons are the most common type of neurons. They possess various arrangements of multiple dendrites emanating from the soma and a single axon. They are present throught out the nervous system, and most of them are motor neurons, for example pyramidal cells, Purkinje cells etc. AXONAL TRANSPORT (Fig-11) Axonal or axoplasmic transport is necessary for the neurons because there is virtually no protein synthesis (polyribosome or Nissl’s bodies) in the axon. The functions of axonal transport are the replacement of catabolized proteins in the axon and its ending and for the transportation of synaptic vesicle, enzymes required for neurotransmitter synthesis at the ending of the axon. Certain proteins and glycoproteins, as well as mitochondria and membranous vesicles, are continuously transported from the cell body toward the distal region of the axon, called as anterograde axonal transport. In contrast some constituents may be transported from the axon to the cell body called as retrograde axonal transport. Movement of macromolecular precursors as cytoskeletal elements and feedback from the periphery contribute to the regulation of the synthetic activity of the cell body. The mechanism of movement involves membranous organelles and vesicles which are filled Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 10 by the macromolecules, becoming attached to the microtubules by thin, cross-linking structures called as microtubule associated protein that posses ATPase activity. The energy from the ATP is used to move the vesicle along microtubule tracks that serve to direct the flow. Fig-11 The schematic figure of the axonal transport in axon The microtubules (Fig-11,12,13) play an important role in the axonal transport, like the “railways”. A macrotubule is a polymer of globular tubulin subunits which are arranged in a cylindrical tube measuring 24 nm in diameter. Microtubule may be arranged in the form of protofilaments consisted of singlet, doublet and triplet microtubules. A singlet microtubule is made of 13 protofilament, each of them is the heterodimers of -tubulin and -tubulin monomers. Each tubulin monomer is a globular protein 4 nm in diameter; Fig-13 The arrangement of protofilament Fig-12 The microtubule Microtubule the heterodimer subunit is therefore 8 nm in long. Each heterodimer binds two molecules of GTP nucleotide. One GTP binding site, located in -tubulin, binds GTP irreversibly and does not hydrolyze it, whereas the second site is also called the exchangeable site because GDF can be displaced by GTP. A tubulin dimmer has a plus- and minus-end. Therefore, a microtubule also has a plus- and minus- end. Polymerization of tubulin dimers to form microtubules requires binding of GTP. In elongating microtubule, they preferentially add subunits at one end Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 11 (the+ end) and may simultaneously depolymerize at the other end (the –end), returning the subunits to the cytoplasmic pool. The microtubules have a fixed polarity with their “plus end” toward the axon ending and their “minus end” toward the cell body. Kinesin (Fig-14) is a motor protein with ATP ase activity, that uses the energy from ATP hydrolysis to move along a microtubule towards the +end. It has 3 domains, apiar of large globular head, the central stalk, and the globular tail. The head binds a microtubules and ATP and is responsible for the force-generating motor activity required for anterograde axonal transport, resulting in movement of the transport vesicle toward the plus end at about 3 micrometer /second. The tail of kinesin binds to membrane of vesicle. Fig-14 The Kinesin, a microtubule associated protein, a motor protein used for anterograde axonal transport Dynein (Fig-15) is a motor protein with ATPase activity, that uses the energy from ATP hydrolylisis to move along microtubule towards the –end . Dynein are divided into two classes, cytosolic and axonemal (flagelar). Cytosolic dynein has 3 domains, the head, stalk and tail. The head binds microtubule and ATP, and the tail binds to vesicle membrane. It is responsible for movement of vesicles along microtubules. The axonemal (flagelar) dyneins are in the form of dynein arms, that are attached to the A tubule of each doublet microtubule. Fig-15 The dynein, a microtubule associated protein, a motor protein used for retrograde axonal transport The anterograde axonal transport is important to deliver the proetein, macromolecule, enzymes, neurotransmitter and other materials required for the metabolism processes in the axon. Although neurotransmitter can also be transported along the axon, the quantity reaching the ending by this mechanism is probably small compared to the amount Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 12 synthesized at the endings. The anterograde axonal transport is divided into 2 types, the fast transport and slow transport. The fast flowing stream moves anterograde at a speed of about 20 to 400 mm perday. The bulk of materials transported at this rate are membrane bounded organelles such as short tubules of reticulum, mitochondria, small vesicle, actin, myosin and the clathrin. The mechanism of slow axonal transport is less clear. Slow stream of flow moves at rate of 0.2-0.4 mm perday and carries protein subunit of neurofilament, tubules of the microtubules and soluble enzymes. In retrograde transport, movement of material occurs from the synaptic endings to the perikaryon and is powered by cytoplasmic dynein which is also an ATPase. Dynein plays an important role in movement of vesicles back to the cell body to regenerate new synaptic vesicles. It appears that surplus membrane at the synaptic terminal is packaged into multivesicular bodies that are transported retrograde to the cell body, where they are degraded by lysosomes. This type has a velocity of one half to two-thirds that of fast anterograde transport. Protein and small molecules picked up by the axon terminal are conveyed upward in vesicles or multivesicular bodies that fuse with lysosomes when they reach the cell body. But unfortunely, retrograde transport can be a liability because it may carry the tetanus toxin and neurotrophic viruses, such as those of herpes simplex and rabies directly to cell bodies in the CNS. Fig-16 The diagram of an axon and an large terminal region with the relationship with their axonal transport. SYNAPS Synapses (Fig-17) are the sites where nerve impulses are transmitted from a presynaptic cell (a neuron) to a postsynaptic cell (another neuron, muscle or gland cell). There are two kinds of synapses, the electric and chemical synaps. The electrical synaps is the synaps in which the nerve impuls is transmitted via inos that move freely through the gap junction. Transmision of the nerve impulse are faster in electrical synaps than that of chemical synaps. The chemical synaps is a synaps in which the nerve impulses are transmitted via a neurotransmitter (chemical substance) released by presynaptic membrane that pass through the synaptic cleft and binds to its receptor in the postsynaptic membrane. The chemical type is the most common mode of communication between two nerve cells. Synaps between nerve cells and Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 13 skeletal muscle is chemical type. There three component involved in chemical synaps e.g. (1) the presynaptic membrane of the first cell which contains the neurotransmitter; (2) the synaptic cleft, a small (20 to 30 nm) gap containing the microfilament, located between the presynaptic membrane of the first cell and the postsynaptic membrane of the second cell and (3) the postsynaptic membrane of the second cell. Fig-17 The synaps During synaptic transmission (Fig-18), as the action potential arrives at the nerve terminal, there is an opening of voltage-gated calcium channels and an influx of calcium ions into the nerve terminal. At the same time, both choline and acetate also will be reuptake from the extra-cellular together with calcium ions. Choline and acetate are the substrates hydrolyzed from the acetylcholine by enzyme acetylcholine esterase in the synaptic cleft. The acetate coming from the reuptake processes and anterograde axonal transport then will be activated in the mitochondria to become acetyl-coenzyme A. Acetylcholine is a neurotransmitter that is synthesized in the presynaptic membranous cisternae from its precursors e.g. choline and acetylcoenzym A in the presence of choline acetyl transferase, a enzyme synthesized in the perikaryon. After exocytosis of synaptic vesicle and neurotransmitter discharge, the membrane is internalized by endocytosis Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 14 coated vesicle. The clathrin coats are lost and the vesicles then will be filled with the newly formed acetylcholine (Ach) and adenosin triphosphate (ATP). Fig-18. Diagram illustrate the synthesizing process of neurotransmitter and its regulation The neurotransmitter then will release into the synaptic cleft, a small (20 to 30 nm) gap, located between the presynaptic membrane of the first cell and the postsynaptic membrane of the second cell. The neurotransmitter diffuses across the synaptic cleft to gate ion channel receptor on the postsynaptic membrane. The neurotransmitter molecules that are released into the synaptic cleft interact with neurotransmitter receptors in the postsynaptic membrane.Binding of neurotransmitter to this receptor initiated the opening of ion channel that permits the passage of certain ion, altering the permeability of the postsynaptic membrane and reversing its membrane potential. The changing of membrane potential stimulates an action potential. The acetylcholinesterase (AChE) hydrolyzed the acetylcholine to become choline and acetate in the synaptic cleft area that can be reutilized in the nerve terminal to form new Ach. Thus AChE limits the duration of response. An axon terminal can form a synapse with any part of the surface of another neuron. Various types of synaptic contacts between neurons: the axodendritic synapse (between an axon and a dendrite), axosomatic synapse (between an axon and a soma), axoaxonic synapse (between two axons) and dendrodenritic synapse (between two dendrites). Fig-19 The types of synaps The synaptic region involves a presynaptic portion or terminal and a postsynaptic portion or terminal. The end of an axon terminal of a presynaptic neuron is typically enlarge slightly into an end bulb or end foot (bouton terminaux) and the axolemma in this region is called the presyanptic membrane. At a distance of only 20-30 nm is the axolemma of postsynaptic neuron, called the postsynaptic membrane. The intervening region is called a synaptic cleft (20-30 nm wide). The presynaptic portion of the synapse is characterized by the presence of many mitochondria and an abundance of synaptic vesicles that are about 40-50 nm in diameter. NEUROTRANSMITTER Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 15 Neurotransmitter is the chemical substance that functions as signaling molecule released by pre-synaptic cells and contacts to the specific receptor at postsynaptic cell. There are perhaps 100 known neurotransmitter represented by the following three groups: small molecule, transmitters, neuropeptides and gases. Small molecule transmitters are of three major types: (1) acetylcholine; (2) the amino acids glutamate, aspartate; glycine; and beta amino-butyrate (GABA) and (3) biogenic amines, serotonin, and the three catecholamines: dopamine, norepinephrine (nor adrenalis) and epinephrine (adrenalin). Neuropeptides, many of which are modulators form a large group. They include the opioid peptides, enkephalins and andorphins, the gastrointestinal peptides, produced by cells of the diffuse neuroendocrine system-substance P, neurotensin, and vasoactive intestinal peptide; the hypothalamic releasing hormone and somatostatin; and hormones stored in and released from neurohypophysis. Recently, certain gases have been shown to act as neuromodulators. These are NO (nitric oxide) and CO (Carbon monoxide). NEUROGLIA Neuroglia or glial cells are supportive cells, not neuron. The term of neuroglia comes from Rudolf Virchow. Neuroglia means nerve glue. The neuroglial cells origins from mesoderm connective tissue cell except microglia which is ectodermal in origin. 70-80% of all cells in the CNS are neuroglial cells. Neuroglia include astrocytes (protoplasmatic and fibrous), oligodendroglia, microglia, and ependymal cells. ASTROCYTE Astrocyte (Fig-20) is the large neuroglia and has the shape like star (Astro means star). The are 2 types of astrocyte the protoplasmatic or mossy and fibrous or spiderlikeastrocyte. Both of them have the function in scavenging ions and remnants of neuronal metabolism and energy metabolism within the cerebral cortex by releasing the glucose from their storage glycogen. Astrocyte is one component of blood-brain barrier and also involved in the forming of cellular scar tissue. Fibrous astrocyte (Fig-20 left side) posses an euchromatic cytoplasm containing only a few organelles, free ribosome and glycogen. Their processes are long and mostly Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 16 unbranched. The fibrous astrocyte has many unbranched-long processes. Fibrous astrocyte are found mainly in the white matter of the central nervous system. Protoplasmic astrocyte (Fig-20 right side) displays abundant cytoplasm, a large nucleus and many short branching processes. Many cytoplasmic processes terminate as expanded endings, called perivascular feet which attached to the basal lamina of capillaries. These expansions may cover most of the blood vessels, thereby contributing to the blood brain barrier of the CNS. Protoplasmic astrocytes are found chiefly in the gray matter of the CNS. In damage to the CNS astrocyte may increase in number and size to form a glial scar.This process is called gliosis. Fig-20. Fibrous astrocyte (left side) and Protoplasmic astrocyte (right side) OLIGODENDROGLIA Oligodendroglia (Fig-21, Left side) is the most common of the supporting elements of the CNS. The appearance of oligodendroglia is like astrocyte but they have the smaller cell body with only a few processes. Oligodendroglia has a smaller often eccentric, dark nucleus with abundant heterochromatin. Oligodendroglia can be found in both grey and white matter of CNS. Oligodendroglia functions as supporting cell and it plays an important role in myelination of axon in the central nervous system. Thus they are analogous to the Schwann cells of peripheral nervous system. In the myelinization process, a single oligodendroglia may provide myelin sheath for a number of the adjacent axons. In some neuronal injuries the oligodendroglia proliferate, which may result in a tumor, a glioma or more specifically oligodendroglioma. MICROGLIA Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 17 Microglia (Fig-21, right side) is the only glial cells derived from mesoderm and therefore also called as mesoglia. They are the smallest of glial cells about 5-7 um in diameter, irregular shape, dark staining cell that faintly resemble oligodendroglia. It has a scant cytoplasm, an oval to triangular nucleus and irregular short processes. Spines also adorn the cell body and processes. Microglia functions as phagocytic cells, a part of the macrophage system. Fig-21 Oligodendroglia (Left side) and microglia (Right side) EPENDYMAL Fig- 22 Ependymal cells Ependymal cells (Fig-22) are the low columnar to cuboidal epithelial cell lining the ventricles of the brain and central canal of spinal cord and involved in forming the choroids plexus. The functions of ependymal cell are to facilitate the movement of cerebrospinal fluid and involved in the formation of the choroids plexus, responsible for secreting cerebrospinal fluid. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 18 CENTRAL NERVOUS SYSTEM The central nervous system are constituted by the brain and spinal cord. In the fresh conditon, the spinal cord and especially the brain are very soft almost jelly like (semifirm gel). In the fresh condition both the brain and spinal cord are each divided into the grey and white matter. Histologically the white matter is composed mostly of myelinated nerve fibers whereas the grey matter consists of aggreagation of neuronal cell bodies, dendrites, and neuroglia cells. The function of central nervous system is to receive integrated and processing the nerve impulses and then give back the response. SPINAL CORD Spinal cord (Fig-23) also known as medulla spinalis.A typical cross section of spinal cord is demarcated into an outer thick zone of white matter and an inner butterfly or H-shape zone of grey matter. Near the central of crossbar of the H is the small central canal lined with ependymal cells, a type of glial cells. Grey matter has a butterfly like shape, located in the inner part of spinal cord and consists of neuron and unmylinated nerve fibers. There are three types of multipolar neurons in grey matter: (1) the large, stellate motor cells in ventral or anterior horns, (2) the small and medium-size sympathetic efferent neurons in the lateral horn and (3) the medium size sensory neurons in the dorsal or posterior horns. The anterior horn contains mostly of multipolar neuron with large polygonal nucleus and large perikaryon and dendrites containing Nissl bodies. White matter of spinal cord located in the outer part of spinal cord and consists of bundles of axons having specific functions either motor or sensory for example pain, touch, proprioception. There are three of these large fiber column or funiculi named from their Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 19 Fig-23 Spinal Cord position i.e.,dorsal, lateral, and ventral.Each funiculus is subdivided into smaller nerve bundles the fasciculi or tract from the name of the tract, one can tell the locationof the cells of origin and the termination of the fibers. For example, in the corticospinalis tract, the cell bodies are in the cerebral cortex and their axons end synaptically on neurons in the spinal cord. BRAIN The brain can be divided into the large cerebrum and much smaller cerebellum and the inferiorly situated, funnel shaped brain stem which is consisted of pons and medulla of oblongata. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 20 CEREBRUM The cerebrum (Fig-24) is divided into two equal hemispheres by a deep, longitudinal fissure that contains the falx cerebri, vertical extension of dura mater. Histologically it consists of white matter or substansia alba and grey matter or substansia grisea. White matter contains the myelinated axon and located in the inner part. Grey matter located in the outer part of the brain, consists of perikaryon or body of neuronal cells. The cortex is highly convoluted i.e. thrown into deep folds which greatly increase the surface area. These convolutions are called gyri and the intervening depressions are sulci. Histologically the cerebral cortex shows six layers that vary in their cytoarchitecture from area to area of pyramidal. All pyramidal cells have an apical dendrite that projects towards the outer surface of the cortex. Its axon, emerging from the base of the pyramid, penetrates the deeper layers of the cortex to eventually form the efferent pathways of the brain in the white matter of the cortex. The layers of cerebral cortex are (1) The Molecular layer or Plexiform layer This is the outermost layer of the cortex. It is called molecular because in cross section the delicate fine fibers stain as tiny dots, giving it a molecular or punctate appearance. It is also plexiform in appearance because many dendrites and axon sectioned longitudinally and appear as network or plexus. Only a few neurons are present which are mostly of the horizontal cells (of Cajal). (2) The Outer Granule Layer Such a term is a misnomer since most of the cells are small, pyramidal cells. The remaining cells are small, stellate cells which when stained, appear as granules. Dendrites of both type of cells terminate in this layer or ascend into layer I. Their axons may descend into lower layers or continue deeper into the white matter. (3) The Outer Pyramidal Layer Most of the cells are medium-sized, pyramidal cells whose apical dendrites extend into the molecular layer. The axons descend into the deeper layers or enter the white matter. (4) The Inner Granular Layer The principal cells are closely packed small, stellate cells that resemble granules. Most of their axons are short and remain within the layer where they pass into layer V and VI Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 21 Fig- 24 Cerebrum (5) The Inner Pyramidal Layer or Ganglionic Layer The predominant cells are the medium and large pyramidal cells. In the motor cortex the giant pyramidal cells (of Betz) are landmarks. The apical dendrite of large pyramidal cells may penetrate into layer I, dendrites of smaller cells terminate in layer VI. Axon of all cells enter the white matter (6) The Multiform or Fusiform Layer The main cell type here is the fusiform or spindle cell whose long axis ies perpendicular to the surface of the cortex. Apical dendrites of the smaller cells end within the layer; those of larger cells extend into layer IV and V. All axon enter the white matter. Since there are also other cells of various shpes in this layer, it is also called the polymorphic layer . The neuroglia cells are present in the all layers of the cerebral cortex. They give protection and supporting the neuronal cells. The functions of cerebrum are for learning, memory, information analysis, initiation of motor response and integration of sensory signals. CEREBELLUM Like the cerebrum, the cerebellum is divided into right and left hemispheres which are separated by a wormlike, segmented band of gray matter called the vermis. The surface of the hemisphere is thrown into many thin, parallel folds or leaflets called Folia. Cerebellum is also consists of white matter in inner part and grey matter in outer part. Cerebellum consists of three layers (Fig-25): (1) Molecular layer This is the outermost layer of cerebellum that consists of a few, small, basket and stellate type cells and unmyelinated axons from the granular layer. (2) Purkinje Cell Layer This intermediate layer consists of a single layer of very large Purkinje cells whose cell bodies rest on the innermost granular layer. The Purkinje cell has a large, Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 22 prominent, flask-shape cell body with a clear vesicular nucleus. It has many tree-like dendritic arbor which project into the molecular layer. (3) Granular Layer Granular layer is the innermost layer of cerebellum consists of small granule cells whose nuclei essentilly fill the cells. The functions of cerebellum are to maintain the balance and equilibrium, muscle tone and coordination of skeletal muscle. Fig-25. Cerebellum MENINGES AND BLOOD BRAIN BARRIER The skull and the vertebral collumn protect the central nervous system. It is also encased in membrane of connective tissue called meninges (Fig-26, 27 and 28). Starting with the outermost layer, the menings are the duramater, arachnoid mater and pia mater. These three layers enveloping the brain and spinal cord are composed of connective tissue. The outermost, dura mater or pachymenings is dense connective tissue, whereas the innermost, the pia mater and the intermediate layer, the arachnoid mater are of looser connective tissue. The arachnoid and pia mater together constitute the leptomenings Figure-26. The three layers of Meninges DURA MATER Dura mater (Fig-26, 27 and 28) (dura = hard), is a dense, collagenous connective tissue composed of two layers that are closely apposed in the adult. The external layer, periosteal dura is composed of osteoprogenitor cells, fibroblast, and organized bundles of collagen fiber that are loosely attached and continuous with the periostium of the skull except at the sutures and base of the skull, where the attachment is firm. The inner layer, meningeal dura is composed of fibroblast and sheet like layers of fine collagen fiber and a few elastic fiber. Its fibroblast have a Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 23 slightly darker cytoplasm elongated processes and ovoid nuclei with more condensed chromatin than those of the outer layer. Both of these dura mater layers in the adult are closely joined. There is no distinct border between them. The small blood vessels are present in both layer of the dura. The dura mater that envelops the spinal cord is separated from the periosteum of the vertebrae by the epidural space, which contains thin-walled veins, loose connective tissue and adipose tissue. The internal surface of all dura mater as well as its external surface is covered by simple squamous epithelium of mesenchymal origin. In the skull the epidural space is a potential space which only appears in the abnormal condition like in the trauma. Normally there is no space between the dura mater and arachnoid. In the abnormal condition like in the trauma, there is a possibility of extravasation of the blood or other fluids to be accumulated together beneath the dura mater and disrupts cell junctions or tears off cell processes and so creates a larger space where normally does not exist. Therefore, the subdural hematoma that commonly follows head injuries is not beneath the dura as the name implies but is accumulation of blood within the dural border cell layer and thus intradural ARACHNOID MATER Arachnoid (Gr. Arachoiedes, cobweblike) mater (Fig-26, 27 and 28) is a thin, avascular layer in contact with the dura mater and a system of trabeculae connecting the layer with the pia mater. Histologically this layer consists of fibroblast, collagen and some elastic fiber. The fibroblast form gap junctions and desmosome with each other. The arachnoid is composed of two regions, a flat, sheet like membrane in contact with the dura and a deeper, grossamer-like region composed of loosely arranged arachnoid trabecular cells (modified fibroblast) along with a few collagen fibers that form trabeculae that contact the underlying pia mater. These arachnoid trabeculae span the subarachnoid space, a space between the sheet like portion of the arachnoid and the pia. The arachnoid trabeculae cells have long processes that attached to each other via desmosome and communicate with one another by gap junction. The subarachnoid space is filled with cerebrospinal fluid and it communicates with the ventricle of the brain. The blood vessel from the dura pierce the arachnoid on their way to the vascular pia mater. However they are isolated both from the arachnoid and subarachnoid space by a close investment of arachnoid derivated modified fibroblast. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 24 Figure-27. The meninges and subarachnoid space In some areas, the arachnoid perforates the dura mater, forming protrusions that terminate in venous sinuses in the dura mater. These protusions which are covered by endothelial cells of the veins are called arachnoid villi (Fig-28). Their function is to transport the cerebrospinal fluid from the subarachnoid space into the venous sinuses. So this structure will reabsorb the cerebrospinal fluid into the blood of the venous sinus. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 25 Figure-28. Arachnoid villi PIA MATER Pia mater (Fig-26, 27 and 28) is the innermost layer of the meninges and is intemately associated with the brain tissue, following closely all of its contours. It is composed of a thin layer of flattened modified fibroblast that resemble arachnoid trabeculae cells. Blood vessels abundant in this layer are surrounded by pial cells interspersed with macrophages, mast cells and lymphocytes. Fine collagenous and elastic fibers lie between the pia and neural tissue. Between the pia mater and the neural elements is a thin layer of neuroglial processes adhering firmly to the Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 26 pia mater and forming a physical barrier at the periphery of the central nervous system. This barrier separates the central nervous system from the cerebrospinal fluid. The pia mater follows all the irregularities of the surface of the central nervous system and penetrates it to some extent along with the blood vessels. Squamous cells of mesechymal origin cover pia mater. Blood vessel penetrate the central nervous system through tunnels covered by pia mater, called as the perivascular spaces (Fig-28). The pia mater disappears before the blood vessels are transformed into capillaries. In the central nervous system the blood capillaries are completely covered by expansions of the neuroglial cell processes. CHOROID PLEXUS, CEREBROSPINAL FLUID AND ARACHNOID VILLI Figure-29 Choroid Plexus The entire CNS is bathed in the cerebrospinal fluid secreted by the choroid plexuses. Choroid plexus (Fig-29) is the folds of pia mater housing an abundance of fenestrated capillaries and invested by the simple cuboidal (ependymal) lining extend into the third, fourth and lateral ventricles of the brain. These cuboidal cells poss a single spherical nucleus, numerous rod shaped mitochondria, and a moderately extensive endoplasmic reticulum. The free surface has an atypical brush border consisting of irregularly oriented microvilli that often have bulbous expansions at their tips. Between the ependymal cells there are a tight junction that prevent the blood in the blood vessel to mix with the cerebrospinal fluid (Fig-30). Figure-30. The Choroid plexus The choroid plexus produces cerebro-spinal fluid at a mean rate of 14-36 ml/h, replacing the total volume of about 150 ml four or five times per day. The cerebrospinal fluid fills the ventricles of the brain and central canal of the spinal cord. At the basal and basolateral surfaces of the cells, H+ ions are changed for Na+ ion in the plasma and these are pumped out at the cell apex. Cl- and HCO- ions move from the cytoplasm across the apical membrane to neutralize the excess Na+ ions. The osmotic gradient so produced results in diffusion of water into the ventricle. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 27 CSF is low in protein but rich in sodium, potassium and chloride ions. CSF contains 90% water and ions; however it may contain a few desquamated cells and occasionally lymphocytes. Movement of substances across the choroid epithelium takes place in both directions. Molecule such as glucose and amino acid required by the brain in large amounts move by facilitated diffusion down a concentration gradient, whereas substances required in small amount such as vitamin C, vitamin B, and foliates move by active transport. Protein are generally excluded from the cerebrospinal fluid, but very small amount present are believed to be secreted by the choroid plexus, which also excrete metabolic by product and certain drugs into the blood for degradation in the liver or elimination in the kidney. After secreted by choroid plexus, the CSF drainages from lateral ventricle to the third ventricle via the foramen of Monroi (Fig-31). The CSF then moves from the third ventricle and it enters into the fourth ventricle through aquaductus of Sylvii. The CSF then circulates through the central canal of spinal cord. At the roof of ventricle 4th there is the foramen, called as foramen of Luscha and Magendii through which the CSF drainages from ventricle 4th into the subarachnoid space. The CSF circulates among the subarachnoid space. The CSF is reabsorbed through the thin cells of the arachnoid villi in some area and is excreted into several sinus venous, such as superior sagittal venous sinus where the CSF is return to the bloodstream. Figure-31. The drainage of cerebrospinal fluid in the brain and spinal cord CSF is important to the metabolic activity of the central nervous system because brain metabolites diffuse into the CSF as it passes through the subarachnoid space. It also serves as a liquid cushion for protection of the CNS. So, the functions of CSF are (1) maintaining the optimal condition of liqur surrounding the neuronal tissue and (2) protecting the brain and spinal cord from the trauma or injury. BLOOD BRAIN BARRIER A highly selective barrier, known as the blood brain barrier, exist between specific blood borne substances and the neural tissue of the CNS. This barrier is established by the endothelial cells lining the continuous capillaries, the lamina basal and the endfeet of astrocytes, one type of neuroglial cells (Fig-32). Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 28 Figure-32. The component of blood brain barrier The endothelial cells form fasciae occludentes with one another, retarding the flow of materials between cells. Additionally, these endothelial cells have relatively few pinocytotic vesicles, and vesicular traffic is almost completely restricted to receptor– mediated transport. The substances such as O2, CO2, H2O and other small lipid soluble materials including some drugs can easily penetrate the blood brain Figure-33. The blood brain barrier components barrier. The g;lucose, amino acid, certain vitamins and nucleosides are transferred across the blood brain barrier by specific carrier proteins, many via facilitated diffusion. Ions are also transported across the blood brain through ion channels via active transport. The energy required for this process is satisfied by the presence of large numbers of mitochondria within the endothelial cell cytoplasm. The capillaries of the CNS are invested by well-defined basal laminae, which in turn are almost completely surrounded by the endfeet of numerous astrocytes, collectively called the perivascular glia limitans (Fig-33). It is believe that these astrocyte help convey metabolites from blood vessel to neurons. Additionally astrocytes remove excess K ions and neurotransmitters from the neuron’s enviroment, thus maintaining the neurochemical balance of the CNS’s extracellular milieu. Because the blood brain barrier is so selective, antibiotics, some therapeutic drugs, and certain neurotransmitter (e.g dopamine) cannot pass the barrier. Perfussion of a hypertonic solution of mannitol transiently opens the tight junctions of the capillaries endothelial cells for administration of therapeutic drugs. Therapeutic drugs can also be bound to antibiotic developed against transferrin receptors in the endothelial cells of the capillaries, which permits their transport across the blood brain barrier and into the CNS. In some diseases of the CNS (e.g. stroke, infection, tumor) the integrity of the blood brain barrier is compromised, resulting in the accumulation of toxins and extraneous metabolites in the extracellular enviroment. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 29 PERIPHERAL NERVOUS TISSUE Peripheral nerves are bundles of nerve fiber (axons) surrounded by several investments of connective tissue sheaths (Figure-34). Functionally the nerve fibers are divided into sensory (afferent) fiber and motor (efferent) fiber. Sensory nerve fiber carries sensory input from the cutaneous areas of the body and from the viscera back to the central nervous system for processing. Motor nerve fibers originate in the central nervous tissue and carry motor impulses to the effector organs. The sensory roots and motor roots of the spinal cord unite to form a mixed peripheral nerve called as spinal nerve (Figure-35) that carries both sensory and motor fibers. Figure-34. The nerve fiber (left side, schematic figure; right side, the histological appearance) The motor component is divided functionally into the somatic nervous system and the autonomic nervous system. The somatic nervous system provides motor impulse to the skeletal muscles, whereas the autonomic nervous system provide impulses to the smooth muscles of the viscera, cardiac muscle of the heart and secretory cells of the exocrine and endocrine glands. Figure-35 The spinal nerve SOMATIC NERVOUS SYSTEM The somatic nervous system (Fig-36) is the voluntary motor fibers with their neuronal cell bodies origin in the central nervous system. The cell bodies of neurons of somatic nervous system originate in motor nuclei of the brain or in the ventral horn of the spinal cord. These neurons belong to multipolar neuronal cells and their axons leave the brain and spinal cord and travel to the skeletal muscle by the cranial nerves or spinal nerves (Figure-36). The cranial nerves containing somatic efferent components are III, IV, VI and XII. Most of the 31 pairs of spinal Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 30 nerves contain somatic efferent components to skeletal muscle. They synapse with the skeletal muscle at the motor endplate. Figure-36 The cranial and spinal nerves AUTONOMIC NERVOUS SYSTEM The autonomic (involuntary, visceral) nervous system (Figure-37) is generally defined as an involuntary motor system that control the viscera of body by supplying the general visceral efferent (visceral motor) component to smooth muscle, cardiac muscle and glands. In contrast with the somatic system, in which one neuron, originating in the central nervous system, act directly on the effector organ, the autonomic nervous system have two neurons between the central nervous system and the effector. The cell bodies of the first neurons in the autonomic chain are located in the central nervous system, and their axon usually myelinated, whereas the second neurons are located in the autonomic ganglia which lie outside the CNS and their axon usually unmyelinated, although they are always enveloped by Schwann cells. In these ganglia the axon of preganglionic fibers (first neurons) synapse with the multipolar postganglionic fibers (second neurons) whose axons subsequently exit the ganglia to reach the effector organs (smooth muscle, cardiac muscle, and glands). Acetylcholine is the neurotransmitter at all synaps netween preganglionic and postganglionic fibers and between parasympathetic postganglionic endings and effector organs. Whereas the norepinephrine is the neurotransmitter at synaps between postganglionic symphatetic fibers and effector organs. The autonomic nervous system is subdivided into two functionally different divisions, the sympathetic and parasympathetic systems. The sympathetic system generally prepare the body for action by increasing respiration, blood pressure, heart rate, and blood flow to the skeletal musle, dilating pupils of eye and generally slowing down visceral function. The parasympathetic system on the other hand has the antagonistic function to the sympathetic by decreasing respiration, blood pressure, heart rate and generally reducing blood flow to skeletal muscle, constricting the pupils and generally increasing the actions and functions of the visceral system. Thus the parasympathetic system brings about homeostasis, whereas the sympathetic system prepares the body for fight or flight. In healthy condition there is a balance between sympathetic and parasympathetic system. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 31 Figure-37. Parasympathetic system (left) and sympathetic system (right) SYMPATHETIC SYSTEM The sympathetic system originates (Figure-37, right side and Figure 38) in the spinal cord from segments of the thoracic spinal cord and upper lumbar spinal cord (T1 to L2), also called as thoracolumbar division of autonomic nervous system. Cell bodies of preganglionic neurons are small spindle shaped cells located in the lateral horn of the spinal cord. Their axons exit the cord via the ventral roots to join the spinal nerve. The fiber then leave the spinal nerve via white rami communicates to enter the paravertebral chain ganglia. Some of preganglionic axons make synapse on cell body in the sympathetic trunk, while the other axons of postganglionic neurons only pass this sympathetic trunk and make synapse with the collateral ganglia (celiac ganglia, superior mesenteric ganglia, and inferior mesenteric ganglia). Axons of postganglionic neurons housed in the chain ganglia (sympathetic trunk) exit the ganglia via gray rami communicantes to reenter the peripheral nerve for distribution to effector organs in the periphery (i.e. swat glands, blood vessel, dilator pupillae muscles, cardiac muscle, bronchial tree, salivary glands and arrector pilimuscle). Axons of post ganglionic neurons housed in the collateral ganglia exit the ganglia and accompany the myriad blood vessel to the viscera, where they synapse on the effector organs (i.e. and smooth muscles and glands of viscera). PARASYMPATHETIC SYSTEM The parasympathetic system (Figure-37, left side and Figure-38) originates in the brain and sacral segments of the spinal cord (S2 to S4) thus the parasympathetic system is called the craniosacral division of autonomic system. Cell bodies of preganglinic parasympathetic neurons originating in the brain lie in the visceromotor nuclei of the four cranial nerves that carry visceral motor component s (III, VII, IX, and X). Axons of the preganglionic parasympathetic fibers of cranial nerves III, VII, and IX seek parasympathetic (terminal) ganglia located outside the brain case, where they synapse on cell bodies of postganglionic parasympathetic fibers housed in the ganglia. Axons of these nerves usually delivered by cranial nerve III, VII and IX to the effector organs they serve, including salivary glands, ciliary muscle, sphincter pupillae muscles, and mucous glands. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 32 Axons of preganglionic parasympathetic fibers in the cranial nerve X travel to the thorax and abdomen before synapsing in the terminal ganglia within the respective viscera. Axons of postganglionic parasympathetic nerves synapse on the glands, smooth muscle and cardiac muscle. Cell bodies of preganglionic parasympathetic nerves originating in segment of sacral spinal cord, located in the lateral segment of ventral horn and leave via the ventral root with the sacral nerves. From here the axons project to terminal ganglia (Meissner’s and Aurbach”s plexuses) in the walls of the lower gastrointestinal tract, where they synapse on cell bodies of postganglionic parasympathetic neurons. Axons of postganglionic neurons synapse on the effector organs in the viscera of the lower abdominal wall and pelvis. Figure-38.The schematic figure of autonomic nervous system GANGLIA Ganglia are aggregations of cell bodies of neurons located outside the central nervous system. There are two types of ganglia sensory and autonomic ganglia. Sensory ganglia are associated with cranial nerves V, VII, IX, and X and with each of the spinal nerves originating from the spinal cord. Sensory ganglia of cranial nerve present as a swelling of the nerve either inside the cranial vault or its exit. The sensory ganglia of spinal nerves are called as dorsal root ganglia. These ganglia contain the pseudounipolar cell bodies enveloped by cuboidal capsule cells. These are then surrounded by a connective tissue capsule composed of satellite cells and collagen. Cranial ganglia are consisted by the pseudounipolar neuron surrounded by satellite cells. Cranial ganglia can be found in the trigeminal, vestibular and facial ganglia. Spinal ganglia (Fig-40) are also consisted by pseudounipolar neuron surrounded by a layer of flattened satellite cells which provide structural and metabolic support and have similar embryological origin to the Schwann cells. The whole ganglion is encapsulated by condensed connective tissue which is continuous with the perineural and epineural sheaths of associated peripheral nerve. These ganglia can be found in the posterior or dorsal horn of medulla spinalis. Figure-40 the spinal ganglion Autonomic ganglia are ganglia that function as motor, because they cause smooth muscle or cardiac muscle contraction or glandular secretion. In the sympathetic system preganglionic sympathetic fiber synapse on postganglionic sympathetic cell bodies in the sympathetic ganglia located in either the sympathetic chain ganglia, adjacent to the spinal cord or the collateral Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 33 ganglia along the abdominal aorta in the abdomen. Postganglionic sympathetic nerves originating in these ganglia are then distributed. These nerves fiber then terminate in the effector organs that they innervate. In the parasympathetic system, preganglionic parasympathetic fibers originate in one of two places: in certain cranial nerves or in certain segments of the sacral spinal cord. These fibers synapse on postganglionic cell bodies located in the terminal ganglia. Preganglionic parasympathetic fibers originating in the nuclei of cranial nerves conducting parasympathetic fiber synapse in one of the four terminal ganglia (ciliary ganglia, submandibular ganglia, otic ganglia, pterygopalatine ganglia) located in head (except those of cranial nerve X). Terminal ganglia associated with cranial nerve X and preganglionic fibers from the sacral spinal cord are located in the walls of the viscera. The autonomic ganglia has the property 1. the size is smaller than craniospinal ganglia 2. It has the capsule made by connective tissue 3. It is a multipolar cell 4. the number of satellite cell is smaller than that in the craniospinal ganglia 5. the sympathetic ganglia The sympathetic ganglia has the bodies of neuronal cells that are distributed through out the ganglia, meanwhile the parasympathetic ganglia has the bodies that form into the groups which are separated one from the other by conncetive tissue (Figure-41A-B). A B Figure-41. The sympathetic ganglia (A) and parasympathetic ganglia (B) MYELIN SHEATH Figure-42. Myelinization in the central nervous tissue (left) and in the peripheral nervous tissue (right) The nerve fiber are grouped into the myelinated nerve fiber in which the nerve fiber is encapsulated by the myelin sheath and the unmyelinated nerve fiber that does not have the myelin sheath. In the central nervous tissue the myelin sheath (Figure-42) is made by oligodendroglia, while in the peripheral nervous tissue is made by Schwann cell. One oligodendroglia wrap several Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 34 nerve fiber, while one Schwann cell wraps only one nerve fiber. The myelin is a concentric lamellae made by the rolling of plasma membrane of Schwann cell. It is consisted of lipid and neurokeratin. Figure- 43. The myelin sheath in the hematoxyllin-eosin staining (Left side) and in the silver impregnation staining (Right side). Arrow indicates the Schwann cell and arrowheads indicate the node of Ranvier In the peripheral nervous tissue electron microscopy revealed that myelin is the plasmalema of Schwann cell organized into into a sheath that is wrapped several times around axon. Under light microscopy the myelin sheath is appeared as an empty tube, because the lipid is dissolved by alcohol during tissue processing, while the axon is appeared as a thin red line (Figure-43). At regular intervals along the length of axon, interruptions occurred in the myelin sheath called as nodes of Ranvier (Figure-42 right side and Figure-43 left side). If the tissue is stained with silver impregnation, the cleft between node of silver, giving the appearance of bar, called as Bar of Ranvier (Figure-43 right side). The nodes of Ranvier indicate an interface between the myelin sheaths of two different Schwann cells located along the axon. The outer portion of Schwann cell is covered by a basal lamina that dips into the nodes of Ranvier, covering the overlapped areas of the myelin sheath lamellae of adjacent Schwann cell. The myelinization process of axon begins (Figure-44) when the plasma membrane of Schwann cell start to wrap durround the axon. As the membrane of Schwann cell wraps the axon, it produces a series of alternating wide, dense lines with narrower, less-dense lines. The wide line is known as the major dense line or period line. It represents the fused cytoplasmic surfaces of the Schwann cell plasma membrane. The narrow less-dense line is called as intraperiod line. It represents the apposing outer leaflet of the Schwann cell plasma membrane. In some area the cytoplasmic surfaces of the Schwann cell plasma membrane failed to fuse, resulting in the trapping of small cleft called as cleft (incisures) Schmidt-Lantermann. The region of the interperiod line that is in intimate contact with axon is known as the internal mesaxon, whereas its outermost aspect in contact with the body of the Schwann cell is called as external mesaxon. This process is known as Jelly roll theory. Figure-44 The Jelly roll theory of myelinization Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 35 The conduction velocity of nerve impuls in the myelinated nerve is more rapid than that of unmyelinated nerve. In this way the action potential jumps from node to node, a process called as saltatory conduction. SCHWANN SHEATH Except of myelin sheath all type of nerve fiber (myelinated or unmyelinated) in the peripheral nervous tissue is enveloped by the Schwann sheath (Figure-8 right side). The Schwann sheath itself is a sheath made by the cytoplasmic of Schwann cell. In the myelinated nerve fiber it is located outside of myelin sheath, while in the unmyelinated nerve fiber located directly outside of nerve fiber. Schwann cells are flattened cell whose cytoplasmm contains a flattened nucleus, a small Golgi apparatus, and a few mitochondria. In the myelinated nerve, one Schwann cell wraps one nerve fiber while in the unmyelinated nerve 0ne Schwann cell wraps several nerve fiber (Figure-45). Figure-45. The Schwann sheath in the unmyelinated nerve CONNECTIVE TISSUE INVESTMENTS Figure-46 The connective tissue sheaths The nerve fiber in the peripheral nervous tissue is cover outside of Schwann sheath by 3 layer of connective tissue (Figure-46): epineurium, perineurium and endoneurium. Epineurium is the outermost layer of the three connective tissue investments covering a nerve. It is composed of dense irregular fibrous conncetive tissue containing some thick elastic fibers that completely ensheathes the nerve. Collagen fibers within the sheath are aligned and oriented to prevent damage by overstretching of the nerve bundle. The perineurium is the middle layer of connective tissue investment, covered each bundle of nerve fibers within the nerve. It is composed of dense conncetive tissue but is thinner than epineurium. The endoneurium is the innermost layer of the three connective tissue investment of a nerve, surrounds each axon. It is a loose conncetive tissue composed of a thin layer of reticular fibers, scatter fibroblast, fixed macrophages, capillaries, and Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 36 perivascular mast cells in extra cellular fluid and it is contact with the basal lamina of the Schwann cells. THE NERVE ENDING Figure-47 Pacinian corpuscle According to its location the nerve ending can be grouped into 3 1. In the skeletal muscle : muscle spindle (sensory nerve ending) and motor endplate (motor nerve ending) 2. In the epithel : Free nerve ending 3. In the tissue: Ruffini corpuscle, Krause corpuscle, Vater Paccini corpuscle and Meissner corpuscle Pacinian corpuscle, another of encapsulated mechanoreceptors, are located in the dermis and hypodermis in the digits of the hands and in the breast, connective tissue of joints and deep fascia about the mesenteries. These mechanoreceptor are specialized to perceive pressure, touch and vibration. Pacinian corpuscle are large ovoid receptors measuring 1 to 2 mm in length by 0.1 to 0.7 mm in diameter. The core of corpuscle contains the nonmyelinated nerve terminal and its Schwann cells surrounded by approximately 60 layers of modified fibroblast, each layer separated from the next by a small fluid filled space. The arrangement of the cells in the lamellae makes the histological section of a pacinian corpuscle resemble a sliced of onion (Figure-47). Meissner corpuscle are encapsulated mechanoreceptors specilaized for tactile discrimination. This receptor located in the dermal papillae of glabrous (non hairy) portion of the fingers and palms of the hand, skin of the foot, eyelids, lips, tongue, nipples and forearm. Meissner corpuscle which measure 80 um x 30 um are located in the dermal papillae with their long axis orientated perpendicular to the skin. This corpuscle is formed by three or four nerve terminal and their associated Schwann cells, all of which are encapsulated by connective tissue. The structure makes the histological section of a pacinian corpuscle resemble an egg (Figure-48). Meissner corpuscle are especially sensitive to edges and oints and to movements of these objects. Figure-48 Meissner corpuscle Figure-49 Muscle spindle Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 37 Each skeletal muscle receives at least two types of nerve fibers, the motor and sensory. The motor nerve functions in eliciting contraction, whereas the sensory fibers pass to muscle spindles. Muscle spindle also called as neuromuscular spindle is an encapsulated mechanoreceptor located in the skeletal muscle and it is involved in propioception. These receptor are composed of from 3 to 12 small, intrafusal muscle fiber encapsulated by a collagen sheath. Both primary and secondary afferent fibers enter one end of the organ and become specialized into annulospiral endings and flower spray endings. This receptor react to the changes in uscle tension and muscle length (Figure-49). Each motor neuron and the muscle fibers it controls form a motor unit. Motor fiber are myelinated axons of alfa motor neurons which pass i the connective tissue of the muscle. The axon arborizes eventually losing its myelin sheath (but not its Schwann cells). The terminal of each arborized twig become dilated and overlies the motor endplate of individual muscle fibers. The structure of motor endplate gives the appearance in histological section like chicken feet (Figure-50). Each of these muscle-nerve junctions known as a myoneural junction, is composed of an axon terminal, synaptic cleft and the muscle cell membrane. Figure-50 Motor Endplate REGENERATION OF THE NERVOUS TISSUE The mammalian neurons usually do not divide and proliferate therefore their degeneration represents a permanent loss. However neuronal processes in the central nervous system are within very narrow limits, replaceable by growth through the synthetic activity of their perikaryons. Peripheral nerve fibers can also regenerate if their perikaryons are not destroyed. The degeneration and regeneration in the nervous tissue can be separated into 2 groups: the central and peripheral nervous tissue. In this lecture note explain more both the regeneration in the central nervous tissue and peripheral nervous tissue. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 38 REGENERATION IN THE PERIPHERAL NERVOUS TISSUE Since nerves are widely distributed throughout the body, they are often injured. When a nerve axon is transected or injured, degenerative changes take place followed by a reparative phase. The neuron attempts to repair the damage, regenerate the process and restore function by initiating a series of structural and metabolic events, called as axon reaction. The reaction to the trauma is characteristically localized in three regions of the neuron (Figure-51): at the site of damage, local changes; distal to the site of damage, anterograde changes; and proximal to the site of damage, retrograde changes. Some of the changes occur simultaneously, whereas others may occur weeks or months apart. LOCAL REACTION At the site of damage (Fig-51 dan 52), the severed ends of the axon retract away from each other and the cut membrane of each stump fuses to cover the open end and preventing loss of axoplasm. Each severed end begins to expand as material delivered by axoplasmic flow accumulates. Macrophage invades the damaged area and phagocytose the debris. Figure-51.The schematic diagram of nerve regeneration ANTEROGRADE REACTION Anterograde reaction occurs in the distal part of the damage site (Fig-51 dan52). In this nerve stub distal to the injury, both the axon (now separated from its trophic center) and the myelin sheath degenerate completely and their remnants, excluding their connective tissue and perineurial sheath are removed by macrophages. This process is known as Wallerian degeneration. While these regressive changes take place, Schwann cells proliferate within the remaining connective tissue sleeve, giving rise to solid cellular columns. These rows of Shwann cells serve as guide to the sprouting axons formed during the reparative phase. Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 39 RETROGRADE REACTION Axonal injury causes several changes in the perikaryon, called as chromatolysis (Figure-51 dan 52); ie dissolution of Nissl substances with a consequent decrease in cytoplasmic basophilic; an increase in the volume of perikaryon; and migration of the nucleus to a peripheral position in the perikaryon. The soma then is actively producing free ribosome, synthesizing proteins and various macromolecules. The chromatolysis process may last several months. The proximal axon stump and surrounding myelin sheath degenerate as far proximally as the nearest collateral axon. The proximal segment of the axon degenerates close to the wound for a short distance, but growth starts as soon as debris is removed by macrophages. Macrophages produce interleukin-1 which stimulates Shwann cells to secrete substances that promote nerve growth. Then several sprouts of axon emerge from the proximal axon stump enter the connective tissue sheath and are guided by the Schwann cells to their target cell. The sprout that reaches the target cell first forms a synapse, whereas the other sprouts degenerate. The process of regeneration proceeds at about 3 to 4 mm/day. When there is an extensive gap between the distal and proximal segments or when the distal segment disappearances altogether (as in the case of amputation of a limb), the newly grown nerve fibers may form swelling or neuroma (Figure-1 and 2), that can be the source of spontaneous pain. Figure-52.The schematic diagram of nerve regeneration Regeneration is functionally efficient only when the fibers and the columns of Schwann cells are directed to the correct place. The possibility is good, however since each regenerating fiber gives origin to several processes and each column of Schwann cells receives processes from several regenerating fibers. In an injured mixed nerve however if regenerating sensory fibers grow into columns connected to motor end-plates that were occupied by motor fibers, the function of the muscle will not be reestablished. The nerve cell has a trophic influence on the cell it contacts. If the neuron dies, not only does its target cell atrophy and degenerate but other cells targeting that particular Histological Aspect of Neuroscience Ahmad Aulia Jusuf,/Histology / 2008 40 neuron also atrophy and degenerate. This process called transneuronal degeneration may thus be anterograde or retrograde. Several factors influenced the regeneration of nerve fiber such as the distance between the proximal and distal stumps of axon, infection, scar tissue and nutrition. REGENERATION IN THE CENTRAL NERVOUS TISSUE Damage in the central nervous tissue is permanent, because regeneration in the central nervous tissue is much less likely than in the peripheral nervous tissue. Several factors inhibit the regeneration of central nervous tissue such as 1. The neuronal cells have no capacity to proliferate 2. The connective tissue is absent in the central nervous tissue 3. Glial scar is formed rapidly The injured cells within the central nervous tissue are phagocytosed by special macrophages, known as microglia, and the space liberated by the phagocytosis is occupied by proliferation of glial cells, which form a cell mass called glial scars. It is believed that these glial cell masses hinder to the process of repair. Thus generally neuronal damage within the central nervous tissue is irreparable. 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