Injury and Resprouting of Axons in the PNS: Flashcards
Describe axonal transport and Differentiate between anterograde and retrograde transport::
Axonal transport - process by which neurons transport organelles, proteins, and other molecules along their axons
Anterograde Transport:
- movement of the materials away from the cell body
- same direction as signal propagation
- mediated by kinesin motor proteins moving along microtubules
- Delivers synaptic vesicles and neurotransmitters to the synapse via fast transport
Retrograde Transport:
- direction of transport is from axon terminal to cell body
- mediated by dyne motor proteins
- rate of retrograde transport is slow
- regulates metabolism of the cell
- when an axon is cut, the signal which induces the cell body to undergo chromatolysis is carried by retrograde transport
- some neurotropic viruses and neurotoxins enter peripheral nerve endings + ascend to infect cell body via retrograde
Explain the degrees of nerve injuries:
Neuropraxia:
- mildest form of nerve injury characterised by a transient conduction block without axonal disruption
- focal demyelination
- caused by mild compression or traction of the nerve
- 1st degree injury
2nd degree - axonotmesis with damage to axon only
3rd degree - axonotmesis with damage to axons and endoneurium
4th degree - axonotmesis with damage to axons, endoneurium and perineurium
Axonotmesis - Often due to severe crush or stretch injuries
Neurotmesis:
- complete nerve transection
- including disruption of the axon, myelin sheath, and surrounding connective tissue
- results from lacerations or severe trauma
- 5th degree
- surgical intervention is often required, functional recovery may be incomplete
Explain the influence of degree and location of nerve injury in recovery:
Location:
Close to neuronal cell bodies:
- proximal injuries
- poor prognosis for regeneration, reinnervation, functional recovery and neuronal survival
- due to longer regeneration distances
Close to target site of nerve fibres:
- distal injuries
- good prognosis for regeneration, reinnervation, functional recovery and neuronal survival
- Injuries farther from the cell body involve shorter regeneration distances, often resulting in better functional recovery
Degree of injury:
- Milder injuries like neuropraxia have a favourable prognosis with complete recovery
- Severe injuries such as neurotmesis have a poorer prognosis, often requiring surgical repair and resulting in incomplete recovery
Describe the steps for nerve repair and the importance of
Schwann cells in this process
Wallerian degeneration clears distal axonal and myelin debris
Schwann cells divide and align to form Bands of Büngner
Proximal axon generates growth cones that navigate towards distal targets, guided by Schwann cells
Schwann cells re-myelinate regenerated axons, restoring conduction properties
Release Neurotrophic Factors: These are chemical signals (e.g., NGF, BDNF) that promote axon growth and survival
Explain the functional consequences of nerve injury
Sensory deficits - loss or alteration of sensation
Motor deficits - weakness or paralysis of affected muscles
Autonomic dysfunction - Disturbances in sweating, vasomotor control, and other autonomic functions
Describe synaptic stripping:
Synaptic terminal withdraws from the neuronal cell bodies or dendrites of the chromatolytic neurons and are replaced by the processes of glial cells
Mechanism - activated microglia, astrocytes and glial cells physically displace presynaptic terminals from the neuronal soma and dendrites
Synaptic stripping can depress synaptic function and impair recovery of function
Transneuronal or transynaptic degeneration
Absence of NGF causes synaptic stripping
Describe end-organ response to denervation:
Muscle is paralysed and reflexes are lost
Hypotonia (little or no resistance to passive movement)
Atrophy of the muscle and spontaneous contraction set in fasciculations
Describe growth cone formation:
Several days after the injury to a peripheral nerve, the proximal axon stump begins to send out very thin axonal sprouts
The tips of these axons are a specialised, amoeba-like region filled with microtubules called a growth cone
Growth cones act as feelers for the intact endoneurial tubes
A growth cone will advance down the empty tube at a rate of 1-4mm/day, about the same rate as slow axonal transport
Describe Wallerian degeneration:
Following axonal injury, the distal segment undergoes degeneration, a process known as Wallerian degeneration
Mechanism:
- when axons is cut/ crushed, the axon segments distal to the lesion degenerate
- the myelin surrounding the distal parts of axon break down and become detached from oligodendrocyte (CNS) or Schwann cells (PNS)
- occurs in anterograde direction
- In the PNS, Schwann cells and macrophages remove the degenerating debris by phagocytosis over a period of 1-2 months
- Schwann cells proliferate forming empty endoneural tubes within Schwann cells and endoneurium known as the bands of Bungner
- in the CNS, glial cells phagocytose the degenerating debris and form glial scar tissue rather than the tubes formed in the PNS
Describe the anatomical structure of a nerve:
Epineurium - outermost dense connective tissue layer encasing the entire nerve, providing protection and structural support
Perineurium - intermediate layer surrounding each fascicle (bundle of nerve fibres), maintains blood-nerve barrier + contributes to nerve elasticity
Endoneurium - innermost layer of CT surrounding each axon, facilitates nutrient exchange and supports nerve fibre integrity
Axons - conducts electrical impulses, either myelinated or unmyelinated
Myelin sheath - lipid rich insulating layer produced by Schwann cells in PNS, enhances impulse conduction velocity
Describe chromatolysis:
First neural response to nerve injury
Retrograde reaction:
- cell body swells and becomes distended
- nucleus is displaced to periphery
- nissl bodies become dispersed into smaller ribosomal regroupings
- epigenetic changes to switch to a regeneration phenotype
Chromatolysis maximum at 12-24 hours after injury
Chromatolysis more prolonged the closer the injury is to the cell body
Describe the Potential Complications in Nerve Recovery and Mitigation Strategies:
Neuromas:
- scar (connective) tissue could block advancement of growth cones and will result in a mass of trapped and regenerating axons known as a neuroma
- surgical intervention to remove neuroma and ensure proper alignment of nerve ends
Misdirection of regenerating axons:
- axons may innervate incorrect targets resulting in functional deficits
- Suture them together using the epineurium to mitigate effects
Explain the importance of NGF:
When an axon of postsynaptic neurons is injured, presynaptic terminal retracts, however if exogenous NGF is supplied the presynaptic terminals are maintained
Mechanism - Binds to TrkA receptors on neurons, activating signaling pathways that support neuronal survival and axonal elongation
NGF is supplied to the cell body by microtubule dependent axoplasmic transport (this is blocked by colchicine)
Describe the steps of nerve repair:
1 - Chromatolysis
2 - Wallerian degeneration
3 - formation of endonueral tube + growth cone
4 - growing of growth cone
5 - reinnervation
