nervous system

Histology of Nervous System

The nervous system is the most complex system in the body, is formed by a network of many billion nerve cells (neurons), all assisted by many more supporting cells called (glial cells). Each neuron has hundreds of interconnections with other neurons, forming a very complex system for processing information and generating responses. Nerve tissue is distributed throughout the body as an integrated communications network. Anatomically, the general organization of the nervous system has two major divisions:
■ Central nervous system (CNS) , consisting of the brain and spinal cord.
■ Peripheral nervous system (PNS) , composed of the cranial, spinal, and peripheral nerves conducting impulses to and from the CNS (sensory and motor nerves, respectively) and ganglia that are small groups of nerve cells outside the CNS.
NEURONS
The functional unit in both the CNS and PNS is the neuron or nerve cell. Some neuronal components have special names, such as “neurolemma” for the cell membrane. Most neurons consist of three main parts:
■The cell body, or perikaryon, which contains the nucleus and most of the cell’s organelles and serves as the synthetic or trophic center for the entire neuron. 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.
■The axon (Gr. axon, axis), which is a single long process ending at synapses specialized to generate and conduct nerve impulses to other cells (nerve, muscle, and gland cells). Axons may also receive information from other neurons, information that mainly modifies the transmission of action potentials to those neurons. Neurons and their processes are extremely variable in size and shape. Cell bodies can be very large, measuring up to 150 μm in diameter. Other neurons, such as the cerebellar granule cells, are among the body’s smallest cells.
Neurons can be classified according to the number of processes extending from the cell body:
■Multipolar neurons, which have one axon and two or more dendrites, Most neurons are multipolar
■Bipolar neurons, with one dendrite and one axon, Bipolar neurons are found in the retina, olfactory mucosa, and the (inner ear) cochlear and vestibular ganglia, where they serve the senses of sight, smell, and balance, respectively.
■Unipolar or pseudounipolar neurons, which 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, Pseudounipolar neurons are found in the spinal ganglia (the sensory ganglia found with the spinal nerves) and in most cranial ganglia.
■Anaxonic neurons, with many dendrites but no true axon, do not produce action potentials, but regulate electrical changes of adjacent neurons.

Functionally neurons subdivided into:

1)Sensory neurons are afferent and receive stimuli from the receptors throughout the body.
2)Motor neurons are efferent, sending impulses to effector organs such as muscle or gland.
3)Interneurons establish relationships among other neurons, forming complex functional networks or circuits (as in the CNS and retina). Interneurons are generally multipolar or anaxonic and are estimated to include 99% of the neurons in the human CNS.
In the CNS most neuronal perikarya occur in the gray matter, with 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.


Cell Body (Perikaryon)
The cell body is the neuronal region that contains the nucleus and surrounding cytoplasm, exclusive of the cell processes. It acts as a trophic center, producing cytoplasm for movement into the processes, although most cell bodies also receive a great number of nerve endings conveying excitatory or inhibitory stimuli generated in other nerve cells. Most nerve cells have a generally spherical, unusually large, euchromatic (pale-staining) nucleus with a prominent nucleolus. The chromatin is finely dispersed, reflecting the intense synthetic activity of these cells.
Cytoplasm of perikarya often contains a highly developed RER with many parallel cisternae and neighboring regions with numerous polyribosomes, indicating active production of both cytoskeletal proteins and proteins for transport and secretion. Histologically these regions with concentrated RER and other polysomes appear as clumps of basophilic material called chromatophilic substance (or Nissl substance, Nissl bodies). The amount of this basophilic material varies with the type and functional state of the neuron and is particularly abundant in large nerve cells such as motor neurons. The Golgi apparatus is located only in the cell body, but mitochondria can be found throughout the cell and are usually abundant in the axon terminals.
Intermediate filaments are abundant both in perikarya and processes and in this cell are often called neurofilaments.

Dendrites

Dendrites (Gr. dendron, tree) are usually short and divided like tree branches. They are usually covered with many synapses and are the principal signal reception and processing sites on neurons. Most nerve cells have many dendrites, which increase the receptive area of the cell considerably. The arborization of dendrites makes it possible for one neuron to receive and integrate a great number of axon terminals from other nerve cells.
Unlike axons, which maintain a nearly constant diameter, dendrites become much thinner as they subdivide. The cytoplasm of the dendrite base is similar to that of the perikaryon, with cytoskeletal elements predominating in the branched regions. Most synapses impinging on neurons occur on dendritic spines, which are short blunt structures projecting at points along dendrites, visible with silver staining methods. Dendritic spines occur in vast numbers and serve as the initial processing sites for synaptic signals.

Axons

Most neurons have only one axon, a fine cylindrical process that varies in length and diameter according to the type of neuron.
Axons are usually very long processes. For example, axons of the motor neurons of the spinal cord that innervate the foot muscles may have a length of nearly 100 cm and require large cell bodies for their maintenance. Axons originate from a pyramid- shaped region of the perikaryon called the axon hillock . The plasma membrane of the axon is often called the axolemma and its contents are known as axoplasm.
Just beyond the axon hillock, at an area called the initial segment, is the site where various excitatory and inhibitory stimuli impinging on the neuron are algebraically summed, resulting in the decision to propagate—or not to propagate—a nerve impulse. The axolemma of the initial segment contains various ion channels important in generating the action potential. In contrast to dendrites, the typical axon is much longer, has a constant diameter, and branches less profusely. however, the distal end of an axon forms a terminal arborization, and axons of interneurons and some motor neurons have branches called collaterals that end at synapses influencing the activity of many other neurons.
Each 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 some cisternae of smooth ER, but essentially no polyribosomes or RER, emphasizing its dependence on the perikaryon for maintenance. If an axon is severed, its peripheral part quickly degenerates. There is a lively bidirectional transport of small and large molecules along the axon. Organelles and macromolecules synthesized in the cell body move by anterograde transport along the axon from the perikaryon to the synaptic terminals. Retrograde transport in the opposite direction carries certain other macromolecules, such as material taken up by endocytosis (including viruses and toxins), from the periphery to the cell body.
Axonal transport in both directions uses motor proteins on microtubules. Kinesin, a microtubule- activated ATPase, mediates anterograde vesicular transport, and the similar ATPase called cytoplasmic dynein provides retrograde transport.

Synaptic Communication

Synapses (Gr. synapsis, union) are sites where nerve impulses are transmitted from one neuron to another or from neurons and other effector cells. The structure of a synapse ensures that transmission is unidirectional. Synapses convert an electrical signal (nerve impulse) from the presynaptic cell into a chemical signal that affects the postsynaptic cell. Most synapses act by releasing neurotransmitters, which are usually small molecules that bind specific receptor proteins to either open or close ion channels or initiate second-messenger cascades. A synapse has the following components:
■Presynaptic axon terminal (terminal bouton) from which neurotransmitter is released by exocytosis from synaptic vesicles.
■Postsynaptic cell membrane with receptors for the transmitter and ion channels or other mechanisms to initiate a new impulse.
■Synaptic cleft intercellular space separating the presynaptic and postsynaptic membranes.


Morphologically, various types of synapses are seen between neurons:
1) Axosomatic synapse; axon forms a synapse with a cell body.
2) Axodendritic; axon with a dendrite.
3) Axoaxonic. with another axon, Axoaxonic synapses modulate activity of the other two types.
Synaptic structure cannot be resolved by light microscopy, although components such as dendritic spines may be shown by methods such as silver precipitation. M
EDICAL APPLICATION
GLIAL CELLS & NEURONAL ACTIVITY
Glial cells support neuronal survival and activities, and are ten times more abundant in the mammalian brain than the neurons. Like neurons, most glial cells develop from progenitor cells of the embryonic neural plate. In the CNS glial cells surround both the neuronal cell bodies, which are often larger than glial cells, and the processes of axons and dendrites occupying the spaces between neurons. Except around the larger blood vessels, the CNS has only a very small amount of connective tissue and collagen. Glial cells substitute for cells of connective tissue in some respects, supporting neurons and creating a microenvironment immediately around those cells that is optimal for neuronal activity. The fibrous intercellular network surrounding cells of the CNS may superficially resemble collagen with light microscopy, but it is actually the network of cellular processes emerging from neurons and glial cells. Such processes are collectively called the neuropil.

There are six kinds of glial cells;

Oligodendrocytes
Oligodendrocytes (Gr. oligos, small, few + dendron, tree + kytos, cell) produce the myelin sheaths around axons that provide the electrical insulation for neurons in the CNS. Oligodendrocytes extend sheetlike processes that wrap around parts of several axons, producing myelin sheaths. These are the predominant glial cells in CNS white matter, which is white because of the lipid concentrated in the wrapped membrane sheaths.

Astrocytes

Astrocytes (Gr. astron, star + kytos) have a large number of radiating processes and are also unique to the CNS. Astrocytes are by far the most numerous glial cells of the CNS, as well as the most diverse structurally and functionally. Those with relatively few, long processes are called fibrous astrocytes and are typical in white matter; those with many shorter, branched processes are called protoplasmic astrocytes and predominate in the gray matter.
Terminal branching of astrocytic processes is very extensive, allowing a single astrocyte to associate with over a million synaptic sites. The larger processes of all astrocytes are reinforced with bundles of intermediate filaments made of glial fibrillary acid protein (GFAP), which serves as a unique marker for astrocytes, the most common source of brain tumors.
Functions associated with various astrocytes include the following:
■ Extending processes with expanded perivascular feet that cover capillary endothelial cells and contribute to the Blood Brain Barrier BBB.
■ Extending processes that associate with or cover synapses in the CNS, affecting the formation, function, and plasticity of these structures.
■ Forming a barrier layer of expanded processes, called the Glial limiting membrane, lining the meninges at the external CNS surface. 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.


Ependymal Cells
Are columnar or cuboidal cells that line the ventricles of the brain and 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 junctional complexes similar to 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 adjacent neuropil.

Microglia

Less numerous than oligodendrocytes or astrocytes but nearly as common as neurons, microglia, macrophage of CNS are small cells with short irregular processes evenly distributed throughout gray and white matter. Unlike other glial cells, microglia migrate through the neuropil, scanning the tissue for damaged cells and invading microorganisms. They secrete a number of immunoregulatory cytokines and constitute the major mechanism of immune defense in the CNS. Microglia do not originate from neural progenitor cells like other glia, but from circulating blood monocytes, belonging to the same family as macrophages and other antigen-presenting cells.

Schwann Cells

Schwann cells, sometimes called neurolemmocytes, are found only in the PNS and differentiate from precursors in the neural crest. Schwann cells have trophic interactions with axons and importantly allow for their myelination, like the oligodendrocytes of the CNS. As discussed with peripheral nerves, one Schwann cell forms myelin around a segment of one axon, in contrast to the ability of oligodendrocytes to branch and ensheath parts of more than one axon.

Satellite Cells of Ganglia

Also derived from the embryonic neural crest, small satellite cells form an intimate covering layer over the large neuronal cell bodies in the ganglia of the PNS. Satellite cells exert a trophic or supportive effect on these neurons, insulating, nourishing, and regulating their microenvironments.

CENTRAL NERVOUS SYSTEM

The major regions of the central nervous system (CNS) are the cerebrum, cerebellum, and spinal cord. The CNS is covered by three connective tissue layers, the meninges, but contains very little collagen or fibrous tissue throughout its substance, making it relatively soft and easily damaged by injuries affecting its protective cranium or vertebral bones. The entire CNS displays organized areas of white matter and gray matter, differences caused by the differential distribution of myelin. The main components of white matter are myelinated axons, often grouped together as tracts, and the myelin-producing oligodendrocytes. White matter contains very few neuronal cell bodies, but astrocytes and microglia are present. Gray matter contains abundant neuronal cell bodies, dendrites, the initial unmyelinated portions of axons, astrocytes, and microglial cells. Gray matter is where most synapses occur, and it occupies the thick surface or cortex of both the cerebrum and the cerebellum; most white matter is found in deeper regions. Deep regions of the CNS also have darker aggregates called nuclei consisting of large numbers of neuronal cell bodies and surrounded by white matter.
Neuroscientists recognize six layers of neurons with different sizes and shapes in the cerebral cortex. The most conspicuous of these cells are the efferent pyramidal neurons that come in many sizes. Neurons of the cerebral cortex function in the integration of sensory information and the initiation of voluntary motor responses.
The cerebellar cortex, which coordinates muscular activity throughout the body, also has a layered organization:
1) Outer molecular layer,
2)Central layer of very large neurons called Purkinje cells.
3)Inner granule layer.
The Purkinje cell bodies are conspicuous even in H&E-stained material, and their dendrites extend throughout the molecular layer as a branching basket of nerve fibers. The granule layer is formed by very small neurons, which are packed together densely, in contrast to the neuronal cell bodies in the molecular layer which are sparse.


In cross sections of the spinal cord
white matter is peripheral and gray matter is internal and has the general shape of the letter H. In the center is an opening, the central canal, which develops from the lumen of the embryonic neural tube. The canal is continuous with the ventricles of the brain, contains CSF, and is lined by ependymal cells. The gray matter forms the anterior horns, which contain motor neurons whose axons make up the ventral roots of spinal nerves, and the posterior horns, which receive sensory fibers from neurons in the spinal (dorsal root) ganglia. Spinal cord neurons are large and multipolar, especially the motor neurons in the anterior horns.

Meninges

The skull and the vertebral column protect the CNS, but between the bone and nervous tissue are membranes of connective tissue called the meninges. Three meningeal layers are distinguished: the dura, arachnoid, and pia maters.
Dura Mater
The thick external dura mater (L., dura mater, tough mother) consists of dense, fibroelastic connective tissue that is continuous with the periosteum of the skull.
Arachnoid
The arachnoid (Gr. arachnoeides, spiderweblike) has two components:
(1) a sheet of connective tissue in contact with the dura mater
(2) a system of loosely arranged trabeculae composed of collagen and fibroblasts, continuous with the underlying pia mater layer. Surrounding the trabeculae is a large, sponge-like cavity, the subarachnoid space, filled with CSF.
This fluid-filled space helps cushion and protect the CNS from minor trauma. The subarachnoid space communicates with the ventricles of the brain where the CSF is produced. The arachnoid and the pia mater are intimately associated and are often considered a single membrane called the pia-arachnoid.
Pia Mater
The innermost pia mater consists of flattened, mesenchymally derived cells closely applied to the entire surface of the CNS tissue. The pia does not directly contact nerve cells or fibers, being separated from the neural elements by the very thin superficial layer of astrocytic processes (the Glia limitans), which adheres firmly to the pia mater. Together, the pia mater and the layer of astrocytic end feet form a physical barrier separating CNS tissue from CSF in the subarachnoid space.
Blood vessels penetrate the CNS through long perivascular spaces covered by pia mater, although the pia disappears when the blood vessels branch to form the small capillaries.
However, these capillaries remain completely covered by the perivascular limiting layer of astrocytic processes.
Blood-Brain Barrier
The blood-brain barrier (BBB) is a functional barrier that allows much tighter control than that in most tissues over the passage of substances moving from blood into the CNS tissue. The main structural component of the BBB is
1-The capillary endothelium, in which the cells are tightly sealed together with well-developed occluding junctions and with little or no transcytosis activity.
2-The limiting layer of perivascular astrocytic feet.
3-The basal lamina of the capillaries that completely enveloped by astrocytic feet.
The BBB protects neurons and glia from:
bacterial toxins
infectious agents
exogenous substances
helps maintain the stable composition and constant balance of ions in the interstitial fluid that is required for normal neuronal function.
The components of the BBB are not found in the choroid plexus where CSF is produced, in the posterior pituitary which releases hormones, or in regions of the hypothalamus where plasma components are monitored.


Choroid Plexus
The choroid plexus consists of highly specialized tissue with folds and many villi projecting into the four large ventricles of the brain. It is found in the roofs of the third and fourth ventricles and in parts of the two lateral ventricular walls, all regions in which the ependymal lining directly contacts the pia mater.
Each villus of the choroid plexus contains a thin layer of well-vascularized pia mater covered by cuboidal ependymal cells . The function of the choroid plexus is production of CSF.
CSF is clear, colorless fluid, contains Na+, K+, and Cl– ions but very little protein, and its only cells are normally very sparse lymphocytes. It is produced continuously and it completely fills the ventricles, the central canal of the spinal cord, the subarachnoid and perivascular spaces. It provides the ions required for CNS neuronal activity and in the arachnoid serves to help absorb mechanical shocks. There are no lymphatic vessels in CNS tissue.

PERIPHERAL NERVOUS SYSTEM

The main components of the peripheral nervous system (PNS) are the nerves, ganglia, and nerve endings. Nerves are bundles of nerve fibers (axons) surrounded by Schwann cells and layers of connective tissue.

Nerve Fibers

Nerve fibers are analogous to tracts in the CNS, containing axons enclosed within sheaths of glial cells specialized to facilitate axonal function. In peripheral nerve fibers, axons are sheathed by Schwann cells, or neurolemmocytes. The sheath may or may not form myelin around the axons, depending on their diameter.

Myelinated Fibers

As axons of large diameter grow in the PNS, they are engulfed along their length by a series of differentiating neurolemmocytes and become myelinated nerve fibers. The plasma membrane of each covering Schwann cell fuses with itself around the axon, and the fused membrane (or mesaxon) becomes wrapped around the axon as the glial cell body moves circumferentially around the axon many times. The multiple layers of Schwann cell membrane unite as a thick myelin sheath. Composed mainly of lipid bilayers and membrane proteins, myelin is a large lipoprotein complex that, like cell membranes, is partly removed by standard histologic procedures. Unlike oligodendrocytes of the CNS, a Schwann cell forms myelin around only a
portion of one axon.
Membranes of Schwann cells have a higher proportion of lipids than do other cell membranes, and the myelin sheath serves to insulate axons and maintain a constant ionic microenvironment most suitable for action potentials. Between adjacent Schwann cells on an axon the myelin sheath shows small nodes of Ranvier (or nodal gaps), where the axon is only partially covered by interdigitating Schwann cell processes. At these nodes the axolemma is exposed to ions in the interstitial fluid and has a much higher concentration of voltage-gated Na+ channels, which renew the action potential and produce salutatory conduction (L. saltare, to jump) of nerve impulses, their rapid movement from node to node.

Unmyelinated Fibers

Unlike the CNS where many short axons are not myelinated at all but run free among the other neuronal and glial processes, the smallest-diameter axons of peripheral nerves are still enveloped within simple folds of Schwann cells. In these unmyelinated fibers the glial cell does not form the multiple wrapping of a myelin sheath. In unmyelinated fibers, each Schwann cell can enclose portions of many axons with small diameters. Without the thick myelin sheath, nodes of Ranvier are not seen along unmyelinated nerve fibers.
Moreover, these small-diameter axons have evenly distributed voltage-gated ion channels; their impulse conduction is not salutatory and is much slower than that of myelinated axons.

Nerve Organization

In the PNS nerve fibers are grouped into bundles to form nerves. Except for very thin nerves containing only unmyelinated fibers, nerves have a whitish, glistening appearance because of their myelin and collagen content.
Axons and Schwann cells are enclosed within layers of connective tissue. Immediately around the external laminae of the Schwann cells is a thin layer called the (Endoneurium), consisting of reticular fibers, scattered fibroblasts, and capillaries.
Groups of axons with Schwann cells and endoneurium are bundled together as fascicles by a sleeve of (Perineurium), containing flat fibrocytes with their edges sealed together by tight junctions. From two to six layers of these unique connective tissue cells regulate diffusion into the fascicle and make up the (blood-nerve barrier) that helps maintain the fibers’ microenvironment.
Externally, peripheral nerves have a dense, irregular fibrous coat called the (Epineurium), which extends deeply to fill the space between fascicles.