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Degree of regeneration of the NS will:
vary
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Is the PNS successful in regeneration?
very successful
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What makes up the PNS?
- CNs and spinal nn
- both motor or sensory (or mixed)
- autonomic system
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What surrounds the peripheral nerve in the PNS?
epineurium
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What surrounds the vesicles in the PNS?
perineurium
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What surrounds each axon in the PNS?
endoneurium (endoneurium tube) which is connective tissue
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Review Anatomy of Peripheral Nerve
see section 1
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Is the CNS successful in regeneration?
not very successful
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Regeneration:
replacement of cells or tissue w/ identical cells or tissue (occurs if cell body is not harmed)
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Repair:
replacement of living cells or tissue w/ cells or tissue of a more primitive nature (like scar tissue) --it is not the same
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Do we want regeneration or repair?
regeneration (we don't want scar tissue from repair)
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When can neurons regenerate?
after any kind of trauma or disease process
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What will vary after the injury?
functional success
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Why does functional success vary after the injury?
depends on location of damage
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Regeneration is generally successful in the ___, not the ___.
PNS, not the CNS
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What happens if you damage the motor neurons in the PNS?
paralysis
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What happens if you damage the sensory neurons in the PNS?
loss of general sensation
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A transected peripheral N will cut what?
motor and sensory properties
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When can regeneration occur in the PNS?
if the cell body is not permanently damaged
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Can regeneration occur in PNS or CNS if the cell body is damaged?
no
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When does Wallerian degeneration occur?
after a lesion in peripheral nerve
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Which part of a neuron undergoes Wallerian degeneration?
axon distal to lesion
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Wallerian degeneration:
- predictive, degenerative series
- Schwann cells on distal portion degenerate over a longer time
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In Wallerian degeneration, what happens to everything distal to the cut?
- degenerates in predictable manner
- -axons
- -Schwann cells (take longer)
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What is the inflammatory process from Wallerian degeneration?
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What happens to the endoneurium (endoneurial tube) during Wallerian degeneration?
stays in place (up to 30 days after initial injury) despite degeneration of axons and Schwann cells
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What do axons form during Wallerian degeneration?
filopoda (distal end) at the area of the lesion
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What do the filopoda make up?
growth cone
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What does one filopoda become?
dominant extension
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What happens to all filopoda besides the dominant extension?
they disappear
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What does the dominant extension do?
enters and grows down endoneurial tube to target structure
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What facilitates growth of the dominant extension?
NGF produced by target structures and Schwann cells
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Do Schwann cells remyelinate down the endoneurial tube?
yes
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CNS oligodendrocytes -> 1st order sensory neuron -> Schwann Cells (NGF, BDNF, Neurotrophins) ->
target recognition signals from target cells (NG, BDNF, Neurotrophins)
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Rate of regeneration is variable based on:
area of the body
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How fast does the upper forearm regenerate?
2.5mm/day
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How fast does the distal forearm regenerate?
2 mm/day
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How fast does the wrist and hand regenerate?
1 mm/day
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What can we predict from the different rates of regeneration at different parts of the body?
estimate how many months regeneration will take
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What determines the success of regeneration in PNS?
- depends on type of injury
- length of time b/w injury and repair work by surgeon
- general nutritional status and health of individual affected (health good then heals better)
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What are the possible types of nerve injury?
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Which type of injury has an easier time regenerating?
crush
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Crush injury:
endoneurial tubes are better preserved, they are only squished and the tube integrity is maintained
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Transected (cut) injury:
- interrupts integrity of the nn; there is an immediate inflammatory process w/ scar tissue
- resultant environment is difficult for regenerating axons to get through debris
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If you were naturally injured and you don't go to the dr. they will heal themselves overtime.
If you cut a nerve, you need surgical intervention
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Where does regeneration of the CNS occur?
in brain and SC
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Does mitosis occur in the CNS?
no
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What part of the neuron gets damaged in the CNS?
axons
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What happens when axons are damaged in the CNS?
interferes w/ development of synapses b/w axons and dendrites (communication dependent or integrity of synapses)
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What happens when neurons are damaged in the CNS?
very devastating damage
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What was the belief about why the CNS can't regenerate?
thought to be an intrinsic characteristic of neruons themselves
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What evidence is there to support that the inability to regenerate is not an intrinsic characteristic?
- CNS neurons could regenerate in vitro if environment was conditioned; sut up artificial conditions in the living organism (vitro) and gave them the appropriate culture and they grew
- same experiment was repeated with new techniques and definitely showed that CNS neurons can regenerate
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If there is evidence against it, why don't neurons regenerate in the CNS?
- there are CNS environmental characteristics which prevents significant regeneration as compared to regeneration in the PNS
- the failure to regenerate is not an intrinsic characteristic of the neurons as previously thought
- Recent research has shown that the oligodendrocytes produce inhibitory chemicals (NOGO factors), which prevent regeneration. Thus the problem is environmental, not genetic
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What does the evidence imply?
- there are no characteristics about the CNS environment that prevent significant regeneration as compared to regeneration in the PNS
- the failure to regenerate is not due to intrinsic characteristics of the neurons as previously thought
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So, what constitutes successful regeneration in the CNS?
- multi-step process which includes the following:
- -injured neuron must survive (cell body intact) [cells in cortex die, cell bodies die; cell in white matter will be ok b/c cell bodies are still intact]
- -damaged axon must extend across the cut or damaged process to original neuronal target
- once contract is made w/ target structures, axon needs to be remyelinated and functional synapses need to form on surface of target neurons
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How can the criteria for successful regeneration in the CNS be evaluated?
- 2 ways:
- descriptively (anatomically): anatomical tracers--colored markers in growing axon (amino acids)
- functionally (via physiological and behavioral outcomes): did they regain function? damage and then regenerated and function returns
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What is the major problem w/ CNS research?
other compensatory mechanisms (neuroplasticity) need to be ruled out as the reason for increase in function
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It is well established developmentally, that certain molecules (NGF, neurotrophins, etc) play a role in:
axon guidance and synaptogenesis
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What type of influence do some of these molecules (that play a role in axon guidance and synaptogenesis)?
inhibitory (inform axons when to stop, turn right, go at an angle, etc)
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Using monoclonal antibody techniques, inhibitory molecules in the adult CNS were shown to:
be produced by by the oligodendrocytes
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What are the inhibitory molecules that play a role in axon guidance?
chemicals called NOGO factors
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Are there other chemicals that do the same thing as NOGO factors?
yes
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NOGO:
- molecules that inhibit the progression of axons
- lie dormant under normal conditions
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When CNS is damaged, what happens with NOGO?
there is an increase in NOGO production by oligodendrocytes
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Why is NOGO a paradox?
- following trauma, NOGO are produced to prevent regeneration in the traumatized area
- normally, NOGO are used to suppress axons so you don't get too many
- under normal conditions they are very important in initial development and under pathological conditions they are harmful
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Research shows that these molecules (NOGO) are:
re-expressed after damage to CNS by oligodendrocytes
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What is a research area concerning NOGO and CNS regeneration?
the focus of molecular intervention is to develop drugs which will inhibit the action of the inhibitory molecules so that regeneration and synaptogenesis can proceed
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