Neuroanatomy The Neuron Response to Injury

The Neuron Response to Injury

Retrograde response - the cell body reaction

Anterograde response - Wallerian degeneration

Competencies:

Describe the retrograde and anterograde response of a peripheral axon to injury.
Discuss how the responses of a peripheral nerve to injury contribute to nerve regeneration and functional recovery in the peripheral nervous system.
Discuss the effect of peripheral injury on the central nervous system.
Explain the evolutionary the concept of gain and loss of central nervous system plasticity.
Explain why the central nervous system is a "nonpermissive" environment when it comes to regeneration and recovery following injury.

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Injuries to axons and axon bundles were once thought to result in neuronal death and irreversible losses of function. We now know that neurons have the capacity to remodel and restructure their projections and synaptic connections. A challenge for modern neuroscience is to take advantage of the innate plasticity of the neuron and its connections to promote recovery and regeneration after injury.
The peripheral nervous system provides an excellent model for studying regenerative responses. The initiation of these responses by injured axons recapitulate many of the molecular and cellular events observed during development. As in development, successful axonal elongation and targeting is dependent upon the regulated sequential expression of appropriate signaling molecules that initiate neuronal differentiation, axonal elongation and guidance, and the accurate synaptic targeting of the neuron.
One key to regulating the regeneration and successful formation of new synapses is through the expression of tropic or trophic growthe factors. Growth factors can be "tropic" (promoting differentiation, guidance and synaptic targeting) or "trophic" (maintaining neuronal viability and survival).
Most growth factors are releasable substances similar to neurotransmitters and can be tropic or trophic depending upon the stage of maturation or physiological need of a particular system.
Membrane associated proteins as well as glycoproteins and proteoglycans that comprise the basal lamina or extracellular matrix can play significant roles in supporting and promoting the guidance and maintenance of neuronal connections.
Tropic and trophic substances have been classified as being either target-derived (promoting specific cell-cell synaptic connections), paracrine (promoting general cellular viability and maintaining projection pathways) or autocrine (promoting self-viability and phenotypic expression).
Target-derived and paracrine-like growth factors include the neurotrophins (nerve growth factor, BDNF, NT3), insulin-like growth factors (IGF1), fibroblasts growth factors (FGFs), glial-derived growth factors (GDNFs) and ciliary neurotrophic factor (CNTF). Other cytokines and lymphokines (e.g. transforming growth factors, interleukins, tumor necrosis factors) can also have specific neurotrophic functions.
The retrograde (cellular) response typifies the switching of cellular activity from neurotransmission to the activation of a development-like regenerative program.
- Vacuolation.
- Enlargement of the nucleus and formation of multiple nucleoli.
- Displacement of the nucleus from a central to eccentric cellular location.
- Dissolution of Nissle substance characterized by lightened somal staining (chromatolysis).
- Retraction of dendrites and stripping of synapses.
The anterograde (Wallerian degeneration) response depicts the clearance of proteins normally involved in maintaining cell-cell interactions that would inhibit neurite extension and elongation, developing an environment permissive to axonal regeneration and delivering signals to the neuron that would initiate the regenerative response.
- Varicose axonal swelling with ultimate fragmentation of the axolemma.
- Breakdown of the myelin sheath.
- Proliferation of Schwann cells (PNS) or astrocytes (CNS).
- Accumulation of fibroblasts and macrophages (PNS) or astrocytes amd microglia (CNS).
- Terminal degeneration.
Regeneration is initiated by:
- Phagocytosis of axonal and myelin debris that act as physical and chemical inhibitors of neuritic sprouting within the endoneurial tube.
- Release of cytokines from activated macrophages (e.g. interleukin-1) which induce Schwann cell proliferation as well as the synthesis and release of neurite growth promoting factors by these cells (e.g. nerve growth factor).
- Expression of proteins and proteoglycans of the Schwann cell basal lamina that provide a permissive microenvironment for neurite elongation.
- Neuritic sprouting and growth cone formation from the damaged stump. Under permissive conditions, neurites can cross transection gaps and reenter endoneurial tubes (this is easily accomplished following nerve crushes, but physical severing of nerves may require end-to-end suturing of the nerves in a process called “coaptation”.
The induction of the regenerative program is dependent upon the influx of calcium ions at the site of injury, an intitial depolarization "wave" back to the cell body and ultimately the transport of appropriate retrograde signals from the site of injury to the cell body. Following the initial depolarization wave, the nerve ending rapidly seals and trophic peptides (such as transforming growth factor β) bind to and activate receptors at the axonal stump. Activated receptors are actively incorporated into a signaling vesicle which is transported back to the cell body via retrograde axonal transport. The speed of retrograde transport (~100 mm/day) is intermediate between fast anterograde axonal transport (200 - 400 mm/day) and slow axonal transport (0.5 - 8 mm/day).
Axonal elongation occurs at the rate of ~1.0 - 4.0 mm/day. This rate, which may vary as a function of the distance of the sprouting neurite from the cell body, is dependent upon the delivery of membrane and cytoskeletal components which move along the axon by slow axonal transport mechanisms.
In contrast to the PNS, the mature CNS is often considered to be an environment that is hostile or "non-permissive" for axonal regeneration. Neuronal damage induced by injury or stroke induces reactive gliosis. This phenomenon of microglial and astrocytic activation represents an inflammatory response apparently designed to reestablish the blood-brain barrier around the site of damage, limit the spread of cellular damage and clear cellular debris. However, the formation of this "glia limitans", especially the expression of inhibitory extracellular matrix proteoglycans and the deposition of inhibitory proteins, limits the ability of regenerating axons to traverse the damaged area and reinnervate synaptic targets.

Consider the Following Questions ...

What will happen in a neuron cell body after its axon in a peripheral nerve is cut by a stab wound?
What happens in Wallerian degeneration? Where does it occur, relative to the site of nerve damage?
What is axonal transport? What role does it play with respect to a neuron's knowledge of its peripheral connection?
Following injury to a peripheral nerve, what signals initiate a regenerative response? What events occur distal to the lesion that promote successful reinervation of denervated targets?
If successful, regeneration of a nerve will take place at about what pace? What role does axonal transport play in the speed of a neuron's response to injury?
What stops neurons from regenerating in the central nervous system? Name some specific trophic substances. What role would each play in the regeneration of damaged neurons and in the guidance of regenerating axons to their appropriate targets?
Discuss some of the reasons that regeneration of axons in the CNS is more limited than in the PNS.