HISTOLOGY د.عبد الجبار فالح الربيعي

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1 Nervous System The human Nervous system is the most complex system in the human body, is formed by a network of more than 100 million nerve cells (neurons) assisted by many more glial cells. Anatomically the nervous system is divided into the Central Nervous System consisting of the brain and the spinal cord AND the Peripheral Nervous System, composed of the nerve fibers and small aggregates of nerve cells called nerve ganglia. Structurally, nerve tissue consist of two cell types: nerve cells or neurons, which show numerous long processes and several types of glial cells, which have short processes, support and protect neurons and participate in neural activity, nutrition and the defense processing in the Central Nervous System. Neurons: Nerve cells or neurons, are responsible for the reception, transmission and processing of stimuli; the triggering of certain cell activities; and the release of neurotransmitters. Most neurons consist of three parts: the dendrites which are multiple elongated processes specialized in receiving stimuli from the environment, sensory epithelium, or other neurons, the cell body or the perikaryon which is the trophic center and is also receptive to stimulus and the axon which is a single process specialized in generating or conducting nerve impulse to other cells. The distal portion of the axon is usually branched and constitutes the terminal arborization, each branch is terminates on the next cell in a dilatation called end bulbs (boutons) which interact with other neurons or non nerve cells, forming structures called synapses, synapses transmit information to the next cell. Neurons and their processes are variable in size and shape, cell body can be spherical. Ovoid or angular, some are very small 4-5 µm in diameter others can be seen by naked eye.

2 Figure 1. Motor neuron. The myelin sheath is produced by oligodendrocytes in the central nervous system and by Schwann cells in the peripheral nervous system. The neuronal cell body has an unusually large, euchromatic nucleus with a well-developed nucleolus. The perikaryon contains Nissl bodies, which are also found in large dendrites. An axon from another neuron is shown at upper right. It has 3 end bulbs, one of which forms a synapse with the neuron. Note also the 3 motor end-plates, which transmit the nerve impulse to striated skeletal muscle fibers. Arrows show the direction of the nerve impulse. Based on the shape and the size of their processes, most of the neurons can be placed in one of the following categories: Multipolar neurons which have more than two processes one is the axon, the others are the dendrites, Bipolar neurons with one process is the axon, the other is the dendrite and Pseudounipolar which have a single process that divide into two processes one being the dendrite and the other is the axon. In pseudounipolar neurons, stimuli that are picked up by the dendrites travel directly to the axon terminal without passing through the perikaryon.

3 Figure 2. Simplified view of the 3 main types of neurons, according to their morphologic characteristics Neurons can also be classified according to their functional role into: Motor neurons which control the effector organs such as muscles and glands, Sensory neurons are involved in the reception of sensory stimulus and Interneurons which establish relationship among other neurons. In the Central Nervous System nerve cell bodies are present only in the gray matter, white matter contains neuronal processes but no nerve cell bodies. In the Peripheral Nervous System, cell bodies are found in ganglia and some sensory region (Olfactory mucosa). Cell body: Also called perikaryon, contains the nucleus and surrounding cytoplasm, exclussive of the cell processes. Most nerve cells have spherical unusually large, euchromatic nucleus with prominent nucleolus reflecting high synthetic activity, it also contain highly developed rough endoplasmic reticulum organized into aggregates of parallel cisternae. Between the cisternae are numerous polyribosomes, the R.E.R and ribosomes appear under the light microscope as basophilic granular areas called (Nissl bodies), the number of which varies according to neuronal type, they are abundant in motor neurons. Golgi complex located only in the cell body consists of multiple arrays of smooth cisternae around the nucleus. Mitochonderia are scattered in the cytoplasm and abundant especially in the axon terminals. Neurofilaments (Intermediate filament-10nm) are abundant in the

4 perikaryon and cell processes. Nerve cell also contains inclusions of pigments such as lipofuscin which is a residue of undigested materials by lysosome. Figure 3. Ultrastructure of a neuron. The neuronal surface is completely covered either by synaptic endings of other neurons or by processes of glial cells. At synapses, the neuronal membrane is thicker and is called the postsynaptic membrane. The neuronal process devoid of ribosomes (lower part of figure) is the axon hillock. The other processes of this cell are dendrites. Dendrites: Are usually short, divide like a tree, they receive many synapses most nerve cell have numerous dendrites which increase the surface area of the cell, these enable the nerve cell to integrate with high number of neurons. Unlike axons, which maintain a constant diameter from one end to other end, dendrites become thinner as they divide into branches, the cytoplasm of the dendritic base, close to the perikaryon is similar to that of perikaryon but devoid from Golgi complex.

5 Axons: Is cylindrical process that varies in length and diameter according to the type of neuron. All axons originate from short pyramid-shaped region, the axon hillock. The plasma membrane of the axon is called the axolemma. The part of the axon between the axon hillock and the point at which myelination begins is called the (initial segment). There are several types of ion channels are localized in this segment, these channels are important in generating the change in electrical potential. Occasionally, the axon shortly after its formation from the cell body gives rise to a branch that return to the area of the nerve cell body, all these branches are called collateral branches. Axoplasm possesses mitochonderia, microtubules, neurofilaments, some cisternae of smooth endoplasmic reticulum, so the absence of polyribosomes and R.E.R emphasize the dependence of the axon on the perikaryon for its maintenance. There is bidirectional transport of small and large molecules along the axon, macromolecules and organelles that are synthesized in the cell body are transported by anterograde flow along the axon to its terminal, this flow occurs at three distinct speed: Slow for protein and actin filaments, Intermediate speed transport mitochonderia and Fast stream transport substances contained in vesicles that are needed, Retrograde flow in the opposite direction transport substances taken up by endocytosis (viruses and toxins) to the cell body. Glial Cells: They are ten times more abundant than nerve cells, they surround the nerve cells and occupy the inter-neuronal spaces. They furnish a microenvironment suitable for neuronal activity. *Oligodendrocytes: Produce the myelin sheath that provides the electrical insulation of neurons in the central nervous system, these cells have processes that wrap around the axons producing a myelin sheath. In fact, a single oligodendrocyte can contribute to the myelination of up to 50 axons, conversely only one axon will require the services of numerous different oligodendrocytes since the myelin internodes along its length are synthesize by different cells. The mechanism of myelin sheath formation is very similar to that of schwann cells in the peripheral nervous system. Myelin sheath formation begins in the CNS of the human embryo at about 4 months gestational age with the formation of most sheaths by the age of 1 year. The final myelin sheath thickness is achieved by the time of physical maturity. There are three types of oligodendrocytes: light, medium, and dark.

6 Oligodendrocyte * Schwann Cells: Have the same function as oligodendrocytes but these cells located around axons of peripheral nervous system. One schwann cell form myelin sheath around one axon in contrast to the oligodendrocyes which form a myelin sheath for more than one neurons. The myelin sheath isolates the axon from the surrounding extracellular compartment of endoneurium. Its presence ensures the rapid conduction of nerve impulses. The axon hillock and the terminal arborizations where the axon synapses with its target cells are not covered by myelin. Unmyelinated fibers are also enveloped and nurtured by Schwann cell cytoplasm. In addition, Schwann cells aid in cleaning up PNS debris and guide the regrowth of PNS axons. *Astrocytes: Star shaped cell with multiple processes, have bundles of intermediate filaments that reinforce their structure, there are two types, Fibrous Astrocytes which have few long processes and located in the white matter and Protoplasmic Astroctes which have many short processes and found in the gray matter. The astrocytes bind the neurons to the capillary and the pia matter and control the ionic and biochemical environment of the neurons so they influence neuronal survival and activity. Some astrocytes develop processes with expanded (end feet) that are linked to endothelial cells, it is believed that this end feet facilitate the transport of ions and molecules from the blood to the neurons. In addition, astrocytes provide a covering for the bare areas of myelinated axons for example, at the nodes of Ranvier and at synapses. They may confine neurotransmitters to the synaptic cleft and remove excess neurotransmitters by pinocytosis. Expanded processes are also present at the external surface of the central nervous system, where they make a continuous layer separating the nervous tissue from the pia matter called glial limitans. Furthermore, when the

7 CNS is damaged, astrocytes proliferate to form cellular scar tissue. Astrocytes can interact with the oligodendrocytes to influence myelin turnover in both normal and abnormal conditions. Tumors arising from fibrous astrocytes, fibrous astrocytomas, account for about 80% of adult primary brain tumors. They can be identified microscopically and by their specific GFAP protein (Glial Fibrillary Acidic Protein) Protoplasmic astrocyte Fibrous astrocyte *Microglia: They account for about 5% of all glial cells. They are small elongated cells with short irregular processes characterized by their dense elongated nuclei in contrast to spherical nuclei of other glial cells, they are phagocytic cells represent the mononuclear phagocytic system, they are derived from bone marrow, they are involved in inflammation and repair of central nervous system, when activated the microglia assume the morphology of macrophage by retraction of their processes and may act as Ag-presenting cells. Recent evidence suggests that microglia play a critical role in defense against invading microorganisms and neoplastic cells. They remove bacteria, injured cells, and the debris of cells that undergo apoptosis. They also mediate neuroimmune reactions, such as those occurring in chronic pain conditions. In multiple sclerosis, the myelin sheath is destroyed, microglia phagocytose and degrade myelin debris by phagocytosis and lysosomal activity.

8 Microglia Ependymal cells: Ependymal cells form the epithelium-like lining of the fluid filled cavities of the CNS. They form a single layer of cuboidal to columnar cells that have the morphologic and physiologic characteristics of fluid-transporting cells. They are tightly bound by junctional complexes located at the apical surfaces. At the TEM level, the basal cell surface exhibits numerous infoldings that interdigitate with adjacent astrocyte processes. The apical surface of the cell possesses cilia and microvilli. The latter are involved in absorbing cerebrospinal fluid. Within the system of the brain ventricles, this epithelium-like lining is further modified to produce the cerebrospinal fluid by transport and secretion of materials derived from adjacent capillary loops. The modified ependymal cells and associated capillaries are called the choroid plexus.

9 Distribution of glial cells in the brain. This diagram shows the three types of glial cells astrocytes, oligodendrocytes, and microglial cells interacting with several structures and cells found in the brain tissue. Note that the astrocytes and their processes interact with the blood vessels as well as with axons and dendrites. Note that astrocytes also send their processes toward the brain surface, where they contact the basement membrane of the pia mater, forming the glia limitans. In addition, processes of astrocytes extend toward the fluidfilled spaces in the CNS, where they contact the ependymal lining cells. Oligodendrocytes are involved in myelination of the nerve fibers in the CNS. Microglia exhibit phagocytotic functions. Clinical Correlations: 1- Guillian Barre syndrome: Is one of the most common life-threatening diseases of the PNS. Microscopic examination of nerve fibers shows a large accumulation of lymphocytes, macrophages, and plasma cells around nerve fibers within nerve fascicles. Large segments of the myelin sheath are damaged, leaving the axons exposed to the extracellular matrix. These findings are consistent with a T cell mediated immune response directed against myelin, which causes its destruction and slows or blocks nerve conduction. Patients exhibit symptoms of ascending muscle paralysis, loss of muscle coordination, and loss of cutaneous sensation.

10 2- Multiple Sclerosis (MS): Is a disease that attacks myelin in the CNS. MS is also characterized by preferential damage to myelin, which becomes detached from the axon and is eventually destroyed. In addition, destruction of oligodendroglia, which are responsible for the synthesis and maintenance of myelin, occurs. The myelin basic protein appears to be the major autoimmune target in this disease. Chemical changes in the lipid and protein constituents of myelin produce irregular, multiple plaques throughout the white matter of the brain. Symptoms of MS depend on the area in the CNS in which myelin is damaged. MS is usually characterized by distinct episodes of neurologic deficits such as unilateral vision impairment, loss of cutaneous sensation, lack of muscle coordination and movement, and loss of bladder and bowel control.