Regeneration in the Nervous System

Question 1

What is the immediate reaction to an axon transection?

Answer 1

the function distal to the cut is lost

Question 2

What happens within the first couple hours of an axon transection?

Answer 2

the ends of the cut are sealed

Question 3

Describe the RETROGRADE effects of an axon transection.

Answer 3

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

Question 4

Describe the ANTEROGREADE effects of an axon transection.

Answer 4

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

Question 5

What is another word for anterograde degeneration?

Answer 5

wallerian degeneration

Question 6

What are the changes that occur specifically within the cell body after an axon transection?

Answer 6

chromatolysis

you get swelling of the cell body and dispersement of ribosomes

Question 7

What will happen to the TARGET neuron after an axon transection?

Answer 7

It will undergo atrophy and eventually cell death

Question 8

What’s special about the target “neuron” atrophy in ALS?

Answer 8

the muscle is the target and that’s what atrophies

Question 9

What happens in the presynaptic branchesto the damaged neuron in an axon transection?

Answer 9

they’ll begin to contract

Question 10

What does axon degeneration trigger in surrounding schwann cells of the PNS? How does this rank in terms of components of PNS regeneration capacity?

Answer 10

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

Question 11

How do damaged neurons alter gene expression patterns in the PNS?

Answer 11

they alter gene expression such that genes requires for growth are upregulated

an example is GAP43

Question 12

What is meant by “condiitoning” of axonal regeneration? Why can’t it be used clinically?

Answer 12

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

Question 13

Which heals better - crush injuries or transection injuries? why?

Answer 13

crush injuries - because they still have some connective tissue connecting the two ends forming a “bridge” on which healing can occur

Question 14

Why is the lack of guidance cues for neurons such an issue in the periphery?

Answer 14

you get the development of very painful neuromas as the axons grow and can’t find their original targets, so just proliferate in space

Question 15

When does regeneration tend to stop in the CNS?

Answer 15

about 1 month after the trauma

Question 16

What does the myelin start to produce in response to trauma in the CNS?

Answer 16

produces inhibitors of axon regeneration like…

Nogo-A

Myelin associated glycoprotein (MAG)

Question 17

WHy is myelin clearance slower after axonal degeneration in the CNS than the PNS?

Answer 17

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

Question 18

What inhibitory extracellualr matrix molecules are produced by the glial scar that forms in CNS damage?

Answer 18

chrondroitan sulfate proteoglycan (CSPG)

Question 19

What molecules will break down chondroitin sulfate proteoglycan (CSPG) to potentially aid regeneration?

Answer 19

chondroitinase

Question 20

In what two ways are CNS neurons intrinsically limited inr egenerating axons?

Answer 20

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)

Question 21

Where are the two places in the brain where physiological neurogenesis occurs?

Answer 21

1. hippocampus (dentate gyrus)
2. subventricular zone of lateral ventricle (olfacotry bulb neurons)

Question 22

What are the three general strategies for helping regeneration int he CNS?

Answer 22

1. stimulation of axonal regeneration
2. cell replacement
3. promote CNS plasticity

Question 23

How can you in theory neutralize myelin inhibitory molecules?

Answer 23

use antibodies against Nogo-A and MAG

Question 24

How can you overcome inhibition of regeneration by breaking down the glial scar?

Answer 24

By getting rid of the CSPG with chondroitinase

Question 25

How can you enhance the regenerative ability of axons by interfering with **intracellular** signaling pathways of inhibitory molecules

Answer 25

by increasing cAMP

Question 26

What are the three strategies for cell replacement in encouraging CNS regeneration?

Answer 26

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)

Question 27

At what age does the "critical period" for greatest plasticity end?

Answer 27

5 years

Question 28

Neurons producing what NT are especially repsonsible for the loss of plasticity potential in maturation?

Answer 28

GABA-ergic neurons they inhibit synapse prolieration, so inhibit plasticity

Question 29

How can you in theory block the GABA-ergic neuron maturation, thus increasing the plasticity of the brain?

Answer 29

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