CSB332 Lecture 5 Notes

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Cell and Systems Biology
Francis Bambico

CSB332 Lecture 5 Slide 3 - Nerves are bundles of axons that are located outside of the CNS. - Tracts are bundles of axons that are located within the CNS (e.g., spinothalamic tract). - Ganglia are clusters of cell bodies that located outside of the CNS. - Do not memorize the cranial nerves. - Most nerve injuries that you experience are introduced in the spinal nerves. Slide 4 - The motor neuron axons and the sensory neuron axons fuse together to form the spinal nerves. The spinal nerve is a combination or aggregate of sensory neuron axons and motor neuron axons. - A cross-section of a spinal nerve contains a lot of bundles. This slide is depicting one bundle. This is a collection of the axons. The red areas are blood vessels. The yellow circles are either sensory neuron axons or motor neuron axons. The green areas around the axons are myelinating Schwann cells. All of the axon fibers are collectively called fascicle. Fascicle is a bundle of many axons. Fascicle is enveloped or protected by an epithelial connective tissue layer called the perineurium. The perineurium is a protective sheath around fascicles. The area that immediately surrounds each axon that contains Schwann cells is called endoneurium. Endoneurium is the protective connective tissue around each axon. The perineurium is the protective epithelial tissue that surrounds bundles of axons. Slide 5 - What happens to a severed axon? Will it grow back or will It regenerate? It depends on where the injury occurs. - If the injury occurs on a spinal nerve in the PNS, it will most likely regenerate, but it has to undergo certain cellular events before regenerating. The sequence of events that comes after axotomy is called Wallerian degeneration. Wallerian degeneration pertains to degeneration and regeneration that comes after degeneration. 1) Axotomy 2) Wallerian degeneration  Degenerative processes  Regenerative processes - Consequences of spinal nerve injury: o Pain o Paralysis  Most often, sensory impairments and motor impairments (e.g., paralysis) go hand in hand because the sensory axons and the motor axons are bundled together within a fascicle within the spinal nerve. When you injure the spinal nerve, then most often you are injuring sensory fibers and motor axons. o Fasciculation and fibrillation  Usually benign. However, if recurrent and associated with other major symptoms, then it could underlie severe damage to the nerves. - Muscle fibers tend to become overactive when motor axons are denervated. Slide 6 - The events that describe Wallerian degeneration: o The distal region of the axon fibers degenerates rapidly. o The proximal end of the axon that is closest to the cell body degenerates a little bit. o In response to the injury, the immune system is activated. Macrophages delivered by blood capillaries, including microglia, would approach conglomerate in the lesion site. Macrophages are scavenger cells that clear up the debris that is left by the degeneration of the axon, including some disconnected myelin sheaths. Macrophages invade the site of lesion and clear out the lesion site from debris left by the degenerating axon and by the degenerating myelin sheaths. o The cell body undergoes chromatolysis. Chromatolysis refers to injured neurons losing its ability to stain purple with a basophilic staining method. Basophilic stains are basic dyes that, when applied to a neural tissue, would stain mainly cell bodies. They react to acidic components of the cell, which are RNA, DNA, and nucleic acids that are mainly located in the cell bodies. Ribosomes and RER have a lot of acidic components.  In response to a basophilic stain, you would stain the cell body with a purple or blue colour. The substances that is used for the stain reacts with the RER and ribosomes in the cell body that are enriched with nucleic acids.  In an injured neuron cell body, the neuron loses its ability to be stained by the basophilic stain. This indicates that the integrity of the RER and mRNA in ribosomes is degenerated. - The distal segment of the axon will degenerate, along with myelin sheathes that wrap around it. - In response to the inflammation resulting from the lesion, macrophages (coming from the blood stream) and microglia (immune cells that are within the brain) will invade the site of the lesion. They will clear out the remnants left by the degenerating myelin and distal region of the axon. o Inflammation is an active, pro-growth process. o Acute inflammation is a protective process. Acute inflammation is able to activate the macrophages to clear out any debris that would get in the way of the regrowth of the axons. You have to clear out the debris so that once the denervated axon degenerates, it can smoothly go through the region and synapse with the original target. o Macrophages and microglia also functions to stimulate the dedifferentiation of Schwann cells, which happens later on during regeneration. Once invading macrophages reach the site of the lesion, it will release cytokines that will signal Schwann cells to dedifferentiate. The Schwann cells will go into the precursory mode and be able to multiple. They will proliferate in response to the cytokines released by macrophages. o Later on, the cytokines will also induce the Schwann cells to synthesis BDNF and NGF (which are growth factors that are able to stimulate the growth of axons and stimulate the development of a cell). LIF is released by the invading macrophages, stimulates the synthesis of BDNF by Schwann cells. BDNF and NGF are released by Schwann cells and bind receptors that are located on the cell membrane of the Schwann cells. BDNF and NGF are held on the plasma membrane of the Schwann cells (the same Schwann cells that synthesize and release BDNF and NGF). o Later on, during regeneration, Schwann cells will proliferate and have BDNF on the plasma membrane. Schwann cells that have BDNF on the plasma membrane are able to guide the regenerating proximal region of the growth cone. o Macrophages also stimulate the proximal region of the axon to release another signalling molecule called Reg2. Reg2 is able to guide the growth cone along, to sustain the health of the growth cone, to stimulate and contribute to the signaling that allows Schwann cells to synthesize BDNF. o Reg2 and LIF stimulate the synthesis of BDNF by Schwann cells. - Wallerian degeneration usually continues to proceed without any interference in the PNS (e.g., spinal nerves). - Muscle fibers and postsynaptic cells also synthesize BDNF and NGF. BDNF and NGF synthesized by the muscle fiber will not be able to reach the cell body because BDNF has to travel through the axon terminals. BDNF binds receptors on the plasma membrane of the axon terminal. BDNF is carried by axoplasmic transport back into the cell body. BDNF in the cell body will synthesize proteins that are responsible for the maintenance of the structure and the health of the neuron. If you denervate the axon, then the cell body is unable to pick up the BDNF released by the postsynpatic cell (myofiber). o The consequences of not being able to accept BDNF:  The cell body bloats, and then shrinks. Atrophy.  The nucleus will get displaced and translocated to an eccentric area of the cell body. Initially, the nucleus is located in the center of the cell body, but in response to axotomy, the nucleus will get displaced and will be found close to the edge of the cell. The translocation of the nucleus indicates that some regenerating process is happening within the cell body. The nucleus is located in the periphery of the cell body. The nucleus is located at the center of the cell body in a normal neuron.  The Nissl bodies in the cell body denote the aggregate of RER and ribosomes. Nissl bodies are rich in ribonucleic acids. Axotomy will result in some degree of degeneration of the Nissl bodies and dispersal of the remaining Nissl bodies. An indication that Nissl bodies are dissolve would be apparent if you observe the cell under a basophilic stain, which would stain the Nissl bodies purple/violet. A cell that has undergone axotomy would result in the loss of the purple/blue stain, indicating that Nissl bodies have dispersed and some have degenerated. This process is called chromatolysis (loss of color). - Macrophages do two things: (1) clears up the debris, and (2) releases cytokines (e.g., LIF). LIF stimulates the dedifferentiation and proliferation of the remaining Schwann cells in the endoneurial tube. LIFE stimulates the Schwann cells to synthesize BDNF. BDNF is important for the guidance of the growth cone within the intact endoneurial tube back to its original synaptic connectivity with the muscle fibre. o Wallerian degeneration will undergo completion rapidly if the endoneurial tube is intact (e.g., when the nerve is crushed). If you sever the fiber and the endoneurial tube, then the Schwann cells will spill out. It will not be effective to guide the growing growth cone back to its original target. If the ends are totally far apart from each other, then the axon would have to leave the endoneurial tube of the distal region. If the growth cone of the axon leaves the endoneurial tube, then you won’t find any Schwann cells in the vicinity. There will not be any Schwann cells or any molecules released by Schwann cells to guide the growth cone back to its original target.  Two scenarios:  The growth cone can travel a few millimeters and then stop.  There are postsynpatic cells (e.g., muscle fibres) within the vicinity, so the growth cone will synapse with the closest muscle fibre. It will not be able to synapse with its original muscle fibre target. - LIF stimulates the release of Reg2. Reg2 stimulates the Schwann cells to proliferate and to synthesize BDNF. - In response to the slowly degenerating cell body of the axotomized neuron, the presynaptic axon terminals undergoes synaptic trimming. Inputs of healthy neurons that synapse with the degenerated cell body slowly retracts and recedes from the area of innervation of the cell body. o Why do axons retract away from degenerating cell bodies?  If the cell body is undergoing degeneration, then there will be a decrease in the synthesis of growth factors, BDNF and NGF, which help to sustain the health of the presynaptic axons. Slide 7 - If Schwann cells become successful in their proliferation (stimulated by macrophages) and are able to synthesize BDNF, then BDNF is able to maintain the health of the growth cone and to guide the navigation of the growth cone within the endoneurial tube back to its original muscle fiber target. - The basal lamina or the endoneurial tube (connective tissue that ensheathes a single axon) must be intact for complete Wallerian degeneration to take place. The completion of Wallerian degeneration terminates in the actual re-growing back of the axon and the synapsing of the axon to its original muscle fiber target. Slide 8 - These are the events that happen in the postsynaptic cell (e.g., muscle fiber) in the spinal nerves. In response to a denervated axon, the muscle fiber undergoes supersensitivation. The muscle fiber becomes supersensitive to stimulation by ACh and supersensitive with the absence of ACh. The muscle fiber generates action potentials by itself, even without ACh to activate the receptors on the muscle fibers. This explains why muscle fibers undergo fibrillation and fasciculation. - (A) Fetal form of a single muscle fiber. o Fetal form contains cholinergic receptors. The cholinergic receptors and the mRNA of the cholinergic receptors are in an embryonic form. The embryonic form of cholinergic receptors is different from the subunit composition of the adult form of cholinergic receptors. The embryonic form of cholinergic receptors is composed of two alpha subunits, one beta subunit, one delta subunit, and one gamma subunit. During fetal development, the fetal form of cholinergic receptors are seen everywhere in the muscle fiber and start to concentrate on the motor endplate (postsynaptic region of the NMJ; opposite to the presynaptic axon). During embryonic development, muscle fibers express the fetal form of cholinergic receptors along the entire extent of the muscle fiber. - (B) Adult form of a muscle fiber with axons coming from motor neurons. o The adult form of cholinergic receptors on muscle fibers consists o
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