Regeneration of the Nervous System: Objectives
- Describe the process of axonal regeneration in the PNS
- Know how to estimate the time to recovery for PNS injuries
- Understand why atonal regeneration differs in the CNS
Reactions to Injury
- Axonal damage results in a series of degenerative changes: severed ends of axons seal severed ends retract, severed ends swell, failure of synaptic transmission, axonal terminals withdraw from targets
- Chromatolysis: and other changes in the cell body
- Wallerian Degeneration: fragmentation of the distal axon segment, myelin sheath degenerates, phagocytosis of degenerating cellular material by macrophages (PNS) or microglia and astrocytes (CNS), proliferation of Schwann cells that repopulate the endoneurial space if the nerve trunk is intact
Many degenerative changes result from a large influx of Ca++ into cell, which is toxic
In other circumstances related to injury, such as stroke, high levels of excitatory transmitters are released from terminals, which can raise Ca++ to toxic levels in other neurons
- After differentiation, nerve cells do not undergo further mitosis
- in a few locations, stem cells differentiate into neurons (olfactory neurons in olfactory epithelium, hippocampal neurons)
Regeneration in PNS
- functional connections can be restored by new growth of severed axons
- When a nerve trunk is damaged, the axons it contains are severed.
- The myelin in the damaged area degenerates, but the associated Schwann cells survive
- Peripheral nerve lacks glial stem cells so repair depends on dedifferentiation of Schwann cells
During repair Schwann cells have 2 key roles
- they proliferate to restore the damaged tissue
- they improve the environment for regrowth by removing myelin debris and they form tunnels that guide new axons to their targets
- **formation of tunnels depends upon interactions with fibroblasts. During this time, fibers sprout from the proximal ends of the severed axons. These fibers penetrate into the Schwann cell tunnels in the damaged site and continue into the distal nerve trunk, growing towards their targets. Eventually, the fibers contact their targets and the re-established axons are remyelinated.
the Condition of the nerve trunk
- has a great effect on regeneration
- Regeneration is most effective and accurate with crush injuries because the basal lamina between Schwann cells and axons remains to produce a gap that must be traversed by the growing axons
- When injuries transect nerve trunks, the cut nerve ends retract to produce a gap that must be traversed by the growing axons. This physical separation causes errors in guidance of the growing axons.
- Some axons may never find the distal nerve trunk. For successful regeneration, the epineurium of severed nerve trunks must be surgically reconnected.
- Nerve sheath implants also are used to re-establish connection
RATE OF REGENERATION
- varies with injury and location
- 1 mm/day for functional recovery: typically
- little or no recovery due to lack of axonal regeneration
- Because unlike the PNS, the extracellular environment in the CNS does not appear to support new growth
- CNS neurons will not extend axons within the CNS, but they will extend axons into transplanted PNS nerve segments
Why CNS environment will not support axonal growth
- Mammalian CNS myelin contains growth-inhibitory molecules on its surface
- CNS lacks extracellular matrix molecules
- Astrocyte proliferation can block outgrowth physically and through secreted molecules
- developmental signals not present
Axonal growth CAN occur
in some regions of the CNS (e.g. corpus callosum)
- can rescue dying neurons
- but which populations?
Neuronal proliferation continues in adult CNS in some areas
- neuronal stem cells exist (in subventricular zone) in the olfactory epithelium and hippocampus.
- In these areas, cell division contributes to new populations of neurons in adults that continually become integrated into circuits
Stem cells and Genetic engineering
- implantation of immature cells that differentiate into neurons or glia; implantation of transfected cells into the CNS with specific properties to repair damaged areas; transfection of resident neurons using viruses and other agents to alter their function
- Antibodies to CNS myelin
to reduce damage after spinal cord injury - timing is an important factor in treatment, which must be started before irreversible changes lead to neuronal degeneration