When axons are transected, the distal section dies, and the cell body begins synthesis of proteins necessary for axonal regeneration - regrowth; this is often succssful in the peripheral nervous system, but not in the central nervous system
When an axon is transected, the terminal portion of the axon degenerates (Wallerian Degeneration), and the central end of the cut axon begins to regrow. The growing end of this regenerating axon is known as the growth cone.
The metabolism of the neurone alters so that it synthesises structural proteins; the changes in the body of the neurone include marked changes to the Nissl substance, and are described as Chromatolysis.
The growing sprouts of the axons may reconnect with their target organ. In skeletal muscle damage to alpha motoneurones can result in the sprouting of adjacent motoneurones and reinnervation of the denervated muscle fibres. In this instance the size of the motor unit is increased.
In the CNS, such regeneration is rarely successful, and the loss of synaptic inputs can cause post-synaptic neurones to degenerate or atrophy or show functional changes.
Adult neurones are largely incapable of mitosis. However there are a few sites in the CNS where new neurones can be produced from stem cells: these include the sub-ventricular zone (SVZ) of the hypothalamus, the hippocampus and cerebellum in most mammalian species
Why is the structure of a nerve trunk important for good functional reinnervation?
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The diagram shows the structure of a peripheral nerve.
Neurones in the peripheral nervous system are able to regrow and reinnervate their taget organs after injury to their axons, whereas damage within the CNS is not normally associated with the ability to regenerate axons.
Arrangement of axons within a nerve trunk
A nerve trunk consists of many axons of all sizes, often arranged in bundles and surrounded by layers of connective tissue.
A connective sheath, the epineurium, surrounds each spinal nerve, and the nerve fibres are arranged in bundles called fasciculi.
Each fasciculus has a membrane around it (the perineurium) and each axon is supported by a tube of connective tissue - the endoneurium.
These structures are of some importance because they can provide guidance for regenerating axons.
If nerve trunks are totally transected, microsurgery is useful in joining the cut ends of fascicles
What are the different types of nerve injury?
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The diagram shows the different levels of damage that can occur in a nerve trunk.
Axonal regeneration following injury to a peripheral nerve
Injury to axons in peripheral nerves usually occurs as a result of pressure, blunt injury or transection, and the severity and duration of the symptoms depends on the degree of damage inflicted.
The milder degrees of nerve injury produce symptoms that are transient, and not associated with complete transection of the axon.
Symptoms arising from pressure on nerves include weakness of the muscles that are innervated, and sensory symptoms of tinglings, numbness or lack of sensation.
Neuropraxia is a condition where pressure on the nerve reduces bood flow and may cause some damage to myelin, resulting in a transient block of action potentials. The effects on nerve conduction are reversible and transient.
Axonotmesis is more severe that neurapraxia, and causes conduction block in the axon. If the axon degenerates, time is needed for the axons to grow back through their endoneurial sheaths to reinnervate the muscle and sensory endings they had done originally.
But regeneration of the axons occurrs along empty sheaths, so the axon eventually make contact with their original contacts.
Neurotmesis is the most severe injury, with axons and the nerve sheath being severed. Axons develop growth cones but do not necessaily grow along their original fasciculi, and may reinnervate targets other than the original ones.
Cellular changes following axonal injury
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Regeneration of Peripheral Nerve Axons.
Neurones in the peripheral nervous system are able to regrow and reinnervate their taget organs after injury to their axons, whereas damage within the CNS is not accompanied by the ability to regenerate axons.
The diagram shows the events following axonal transection. Some Schwann cells become phagocytic and engulf degenerating axon and myelin.
The central end of the axon sprouts and the sprouts grow into the endoneurial sheaths left behind by the degenerated terminal portion of the original axon. Schwann cells proliferate as the axon grows towards the muscle
The axon re-establishes contact with the muscle fibre. At this stage the axon is quite fine and not yet fully myelinated
The terminal axon increases in diameter due to the production of new neurofilaments that increase the axonal diameter; and the terminal axon becomes myelinated.
Skeletal muscle fibres that have lost their innervation show abnormal electrical activity (fibrillation potentials), and when regenerating axons make contact with these cells, new neuromuscular juntions form, and become functional.
It may be that the distal portion of the regenerated axon never reaches the diameter or degree of myelination of the original axon, as the conduction velocity does not necessarily return to its previous level
If regeneration of axons fails, then the muscle fibre atrophies, and the neuronal cell body degenerates and undergoes apoptosis.
If only some of the axons regenerater, motor unit size is increased following re-innervation of a muscle by these regenerating axons.
After the nerve transection, the neuronal cell body undergoes a process of chromatolysis, in which the nucleus of the cell moves to one side, away from the centre of the perikaryon; and the Nissl Substance (RNA) disaggregates and is much reduced.
At this point in time the protein synthesis in the cell changes so that the proteins required for the axonal growth are manufactured, packaged and transferred to the growing terming by means of anterograde axonal transport.
Tinel's test involves tapping over a generating nerve, whose sensitive endings indicate the extent to regrowth. Electrophysiological measurements of the reconnection of motor nerves and skeletal muscle provide more precise information about the progress of regeneration.
Clinical Methods for monitoring Nerve Regeneration
In peripheral nerves, axonal regrowth takes place at the rate of approximately 1 cm / week in humans. This is possible because macrophages remove cellular debris, and no inhibitory substances are present.
In contrast in the CNS, no macrophages are there to clear the cellular debris, and some powerful inhibitory molecules are present that prevent the regrowth of axons. Thus nerve regeneration is limited in the CNS.
In the CNS the lack of macrophages causes reactions from astrocytes which results in scarring.
Following peripheral nerve transection, some axons regenerate and make new connections with the muscle fibres.
When reinnervation occurs it is not uncommon to find that one axon innervates more muscle fibres in a small area of muscle than previously, resulting in an increase in the size of the motor unit. The size of motor units and the presence of denervated muscle fibres can be examined using Electromyography.
Regenerating nerve terminals are fine and much smaller than the normal axons. Once a regenerating neurone has contacted its post-synaptic cell, the axon expands, due to the synthesis of neurofilaments that are regulate the diameter of axons. These changes result in the speed of conduction of nerve impulses returning towards their normal level.