Degeneration_and_Regeneration_2nd_Semester

Degeneration : After complete transaction of the nerve, the peripheral parts of the axons undergo certain degenerative changes which are often called Wallerian degeneration. Degeneration takes place at three levels : • In the nerve cell • In the proximal part of the cut fibre and • In the distal part of the cut fibre Degeneration : Change occurring in the proximal part of the axons and also the cell bodies following section of an axon is known as retrograde degeneration. The changes in the cell bodies are : 1. Chromatolysis : Nissl granules disappear. It starts within 48 hours and becomes maximum by 15-20 days. 2. Golgi apparatus, mitochondria and neurofibrils break up and disappear. 3. The cell draws in more fluid, swells up and becomes rounded. 4. The nucleus is pushed to the periphery. In severe cases it may be totally extruded, in which case, the nerve cell completely dies and disappears. The degree of damage and chromatolysis depend on : a) The distance of lesions from the nerve cell- Lesser the distance greater will be the damage. b) Nature of Section : If it is a sharp cut, the effects will be less. But if forcibly torn, the damage is severe and often the cell dies. Degeneration in the Proximal part of the cut fibre Since this part remains connected with the mother cell, degeneration cannot be complete unless the nerve cell dies. Ordinarily, degeneration proceeds centrally as far as upto the first node of Ranvier and in most cases degenerative changes may extend up to a few internodes when regenerative changes are initiated from the end of the central stump. In more severe cases, it may proceed to a little higher. The nature of this degeneration and the subsequent regeneration is same as in the distal stump or part. Regeneration takes place if the neurone survives. Degeneration in the distal part of the cut fibre

Since this part is totally separated from the mother cell, it degenerates completely. Degeneration starts simultaneously in the whole length of the fibre up to its terminal arborizations within 24 hours and is completed by 3 weeks. Following degenerative changes are seen : Histological Changes : 1. The neurofibrils swell, become tortuous and ultimately disappear and the axis cylinder breaks up into short lengths. 2. The myelin sheath disintegrates into droplets of fat. Lecithin splits up into glycerol, phosphoric acid, fatty acid and choline. They are partly removed by macrophages and partly washed out in the blood stream. If the damage be inside the central nervous system, no further change takes place. But if it be in the peripheral nervous system the neurolemma shows the following changes : The nuclei of Schwann cell multiply mitotically and the Schwann cell cytoplasm increases in amount. It starts 4-9 days after section. The macrophages penetrate the neurolemmal tubes and remove the debris. The Schwann tissue gradually fill up the whole tube and the process is completed by three months. From the cut of the distal end, the proliferating Schwann tissue spreads upwards toward the central cut end and in this way may bridge up a considerable gap (even up to 3 cm) between the two cut ends. The rate of progress of this growth is 1-2 mm per day. The peripheral neurolemmal tube shrinks to half its original diameter in 7 weeks and may remain so for about 18 months. The above degenerative changes in the distal cut end of the fibres were first observed by Waller and according to him it is known as Wallerian degeneration. Degeneration of Nerve endings : The framework of both sensory and motor endings can resist degeneration for months. If the nerve fibre fail to regenerate, the endings also atrophy. Transneuronal degeneration : When neurone or its motor fibre degenerates, the neurone next in the chain is often found to degenerate also. This takes place in spite of the fact that there is no anatomical continuity through the synapses. It is probably an example of disuse atrophy. In many conditions, this type of degeneration occurs e.g., 1. After section of the optic nerve, the cells in the lateral geniculate body degenerate.

2. After section of the posterior spinal root, the posterior horn cells degenerate. 3. In lesions of the motor cortex or pyramidal tracts, the anterior horn cells may degenerate. This type of degeneration may be the underlying cause of the so-called System diseases viz., Amyotorphic lateral sclerosis, etc., where degeneration of anterior horn cells follows that of the pyramidal tracts. Regeneration : Regeneration takes place only outside the central nervous system where neurolemma is present. Presence of neurolemma is, therefore, essential for the process. Hence, in the central nervous system, neurolemma being absent, nerve fibre do not regenerate at all. The following steps are seen during regeneration :  The axis cylinder grows from the central cut end as a rounded sprout and proceeds towards the solid neurolemmal cord. The proliferated Schwann tissue in the peripheral cut end and its prolongation towards the central cut end provide an influence which guides the approaching axis cylinder. Each growing fibre splits up into numerous neurofibrils (even up to 100), the Schwann cells disappear and the fibrils enter the newly made neurolemmal tube (2-3weeks after the section, the inner wall of the tube may contain a number of fibrils). All the fibrils degenerate, excepting a single one, which gradually enlarges and occupies the central part of the whole length of the tube proceeding peripherally. The daily rate of growth is about 0.25 mm in the scar tissue between the two cut ends and 3-4 mm in the peripheral neurolemmal tubes.  Myelin sheath begins to appear in about 15 days and proceeds peripherally along the fibre at a slower rate than the growing axis cylinder.  Increase in the diameter of the fibre takes place slowly. The diameter of the fibre is limited by the size of the neurolemmal tube and that of the parent nerve cell. With a clean sharp wound and the cut ends being in apposition, some degree of recovery usually takes place in 6-24 months. For a motor nerve, recovery may be complete. But for a mixed nerve, it is rarely so. In the regenerated fibres the axis cylinder and myelin sheath are reduced in thickness, the intermodal distance is also diminished. But the rate of conduction of nerve impulses in the regenerated fibres remains the same. Complete functional regeneration occurs after histological regeneration- 3 weeks in case of motor nerve fibres and 5 weeks in case of sensory nerve fibres.

Neuromuscular Junction : The skeletal muscle fibres are innervated by large, myelinnated nerve fibres that originate from large motor neurons in the anterior horns of the spinal cord. Each nerve ending make a junction, called the neuromuscular junction, with the muscle fibre near its midpoint. The action potential initiated in the muscle fibre by the nerve signals travels in both directions toward the muscle fibre ends. Physiologic anatomy of the neuromuscular junction- The motor end plate The neuromuscular junction form a large, myelinated nerve fibre to a skeletal muscle fibre. The nerve fibre forms a complex of branching nerve terminals that invaginate into the surface of the muscle fibre but lie outside the muscle fibre plasma membrane. The entire structure is called the motor end plate. It is covered by one or more Schwann cells that insulate it from the surroundings fluids.  The invaginated membrane of the muscle fibre membrane is called the synaptic gutter or synaptic trough.

 The space between the terminal and the fibre membrane is called the synaptic space or synaptic cleft. This space is 20-30 nm wide.  At the bottom of the gutter are numerous smaller folds of the muscle membrane called subneural clefts, which greatly increase the surface area at which the synaptic transmitter can act.  In the axon terminal numerous mitochondria supply ATP for the synthesis of neurotransmitter acetylcholine.  The acetylcholine inturn excites the muscle fibre membrane. Acetylcholine is synthesized in the cytoplasm of axon terminals but are absorbed rapidly in to many small synaptic vesicles about 300,000 in the terminal of a single end plate.  In the synaptic space are large quantities of the enzyme acetylcholine esterase, which destroys acetylcholine in a few milliseconds after it has been released from the synaptic vesicles. Mechanism of transmission of nerve impulse across the neuromuscular junction  When a nerve impulse reaches the neuromuscular junction, about 125 vesicles of acetylcholine is released from the terminals into the synaptic space.  On the inside surface of the neural membrane are linear dense bars. To each side of each dense bar are protein particles that penetrate the neural membrane, these are voltage gated calcium channels.  When action potential spreads over the terminals, these channels open and allow calcium ions to diffuse from the synaptic space to the interior of the nerve terminal. The calcium ions, in turn, are believed to exert an attractive influence on the acetylcholine vesicles, drawing them to the neural membrane adjacent to the dense bars. The vesicles then fuse with the neural membrane and empty their acetylcholine into the synaptic space by the process of exocytosis.  At the neck of the subneural clefts there exists the acetylcholine receptors in the muscle fibre membrane.

 These are acetylcholine-gated ion channels, and they are located almost entirely near the mouths of the subneural clefts lying immediately below the dense bar areas, where acetylcholine is emptied into the synaptic space.  The receptor is a protein complex(MW-275,000), the complex is composed of five subunits proteins, two alpha proteins and one each of beta, delta, and gamma proteins. These protein molecules penetrate all the way through the membrane , lying side by side in a circle to form a tubular channel.  The channel remains constricted until two acetylcholine molecules attach respectively to the two alpha subunit proteins . This causes a conformational change that opens the channel.  The opened acetylcholine channel has a diameter of 0.65 nm, which is large enough to allow the important positive ions – Na+, K+ and Ca++ to move easily through the opening.

 Whereas the negative ions such as Cl- ions cannot pass through because of strong negative charges in the mouth of the channel that repel these negative ions.  In practice far more Na+ ions move through the acetylcholine channels than any other ions due to two reasons : 1. The extracellular concentration of Na+ ions is more , and 2. The inside is electronegative (-70 to -90mV) which easily allows the Na+ ions to enter and at the same time prevents the efflux of the K+ ions to outside.  This creates a local positive potential change inside the muscle fiber membrane, called the end-plate potential.  In turn, this end plate potential initiates an action potential that spreads along the muscle membrane and thus causes muscle contraction.  The acetylcholine, once released into the synaptic space , continues to activate the acetylcholine receptors as long as the acetylcholine persists in the space.

 Acetylcholine is removed by two means- 1. Most of the acetylcholine is destroyed by the acetylcholinesterase enzyme present in the synaptic space remains attached to the fine connective tissues. 2. A small amount of acetylcholine diffuses out of the synaptic space and is then no longer available to act on the muscle fibre membrane.