What is the immediate reaction to an axon transection?
the function distal to the cut is lost
What happens within the first couple hours of an axon transection?
the ends of the cut are sealed
Describe the RETROGRADE effects of an axon transection.
these are the changes that occur proximal to the cut
you get an interruption of normal supply of retrogradely transported signals to the cell body
you also have the arrival of new signals elicited at the injury site
Describe the ANTEROGREADE effects of an axon transection.
it remains latent for a few days and then you get a sudden, extremely rapid fragmentation of the distal stump
within a week you have disintegration of myelin
within 2-3 weeks you have removal of axon remnants and myelin by macrophages and schwann cells
What is another word for anterograde degeneration?
What are the changes that occur specifically within the cell body after an axon transection?
you get swelling of the cell body and dispersement of ribosomes
What will happen to the TARGET neuron after an axon transection?
It will undergo atrophy and eventually cell death
What's special about the target "neuron" atrophy in ALS?
the muscle is the target and that's what atrophies
What happens in the presynaptic branchesto the damaged neuron in an axon transection?
they'll begin to contract
What does axon degeneration trigger in surrounding schwann cells of the PNS? How does this rank in terms of components of PNS regeneration capacity?
they start to "redifferentiate" - the #1 component of PNS regeneration!
1. they proliferate
2. they recruit macrophages fro the blood to help clean
3. promote axon regeneration
How do damaged neurons alter gene expression patterns in the PNS?
they alter gene expression such that genes requires for growth are upregulated
an example is GAP43
What is meant by "condiitoning" of axonal regeneration? Why can't it be used clinically?
found experimentally in animal studies...
specifically for pseudounipolar nerons of the DRG, if you cut the peripheral process first, then cut the central process, the central process will be more likely to regenerate than if you hadn't cut the peripheral process at all
can't do this clnically for obvious reasons
Which heals better - crush injuries or transection injuries? why?
crush injuries - because they still have some connective tissue connecting the two ends forming a "bridge" on which healing can occur
Why is the lack of guidance cues for neurons such an issue in the periphery?
you get the development of very painful neuromas as the axons grow and can't find their original targets, so just proliferate in space
When does regeneration tend to stop in the CNS?
about 1 month after the trauma
What does the myelin start to produce in response to trauma in the CNS?
produces inhibitors of axon regeneration like...
Myelin associated glycoprotein (MAG)
WHy is myelin clearance slower after axonal degeneration in the CNS than the PNS?
1. macrophages can't get there to clean as well because of the BBB
2. oligodencrotyes aren't as good as schwann cells at clearning out debris
What inhibitory extracellualr matrix molecules are produced by the glial scar that forms in CNS damage?
chrondroitan sulfate proteoglycan (CSPG)
What molecules will break down chondroitin sulfate proteoglycan (CSPG) to potentially aid regeneration?
In what two ways are CNS neurons intrinsically limited inr egenerating axons?
they actually have receptors for the myelin-derived inhibitors like Nogo-A and MAG
as they mature, they turn on some genes and turn off some genes such that they are unable to regenerate axons (especially specific transcription)
Where are the two places in the brain where physiological neurogenesis occurs?
1. hippocampus (dentate gyrus)
2. subventricular zone of lateral ventricle (olfacotry bulb neurons)
What are the three general strategies for helping regeneration int he CNS?
1. stimulation of axonal regeneration
2. cell replacement
3. promote CNS plasticity
How can you in theory neutralize myelin inhibitory molecules?
use antibodies against Nogo-A and MAG
How can you overcome inhibition of regeneration by breaking down the glial scar?
By getting rid of the CSPG with chondroitinase
How can you enhance the regenerative ability of axons by interfering with intracellular signaling pathways of inhibitory molecules
by increasing cAMP
What are the three strategies for cell replacement in encouraging CNS regeneration?
1. recruit endogenous neural progenitor cells with growth factors
2. transplant embryonic stem cells or induced pluripotent stem cells
3. supply oligodendrocytes to help funcitonal improvement (chaperone effects)
At what age does the "critical period" for greatest plasticity end?
Neurons producing what NT are especially repsonsible for the loss of plasticity potential in maturation?
they inhibit synapse prolieration, so inhibit plasticity
How can you in theory block the GABA-ergic neuron maturation, thus increasing the plasticity of the brain?
Interestingly enough, GABA neurons are helped to mature yb an aperineuronal net formed by CSPG.
so give chondroitinase, break down the aperineurononal net, and the GABA neurons can't mature