Lecture 42: How to repair the brain

Question 1

What type of recovery can we expect in the PNS?

Answer 1

• muscle cells regenerate
• axons are remyelinated (conduction is restored)
• motor axons sprout to reinnervate denervated NMJ
• axons can regenerate (but only for so long and getting lost is a problem)

Question 2

What is sprouting?

Answer 2

When intact nerve terminals grow new axons to innervated recently denervated NMJ’s adjacent to it

Question 3

What happens when you lesion the axon of a peripheral nerve?

Answer 3

They DON’T die

• degeneration distal to lesion
• cell body undergoes chromatolysis

Question 4

What is chromatolysis?

Answer 4

The process that occurs in cell body after there is a lesion in axons
-the neuron swells
-nucleus assumes an eccentric position
RER disperses

Question 5

What is Wallerian degeneration?

Answer 5

The term for changes that occur in nerves distal to the site of a lesion
-macrophages chew up broken down myelin sheath
But the basal lamina of schwann cell remains intact!

Question 6

What is the role of denervated Schwann cells (the ones that are cut off away from the cell body)?

Answer 6

-schwann cells appear to transform themselves into adhesive cells that make multiple growth factors for regenerating axons
Potential adhesive factors: N-cadherin, L1, NCAM
Trophic factors (neurotrophins, cytokines)

Question 7

What is Cajal’s neurotropic theory?

Answer 7

Regenerating axons are drawn to the denervated Schwann cells in the distal nerve stump

What happens if nerve is completely severed?
The cut would interrupt the Schwann cell highway in nerve
-also if you put a dead nerve next to an axon, the axons don’t regenerate towards the dead nerve

Question 8

What is the key principle in axon regeneration?

Answer 8

Successful regeneration requires rejoining of the separated ends of proximal and distal nerve stumps

Question 9

What needs to happen in order for successful regeneration to occur?

Answer 9

The rejoining of the separated of the proximal and distal nerve-stumps

Question 10

What is a pitfall in axon regeneration?

Answer 10

Axons can potentially misroute at the site of injury as cut axons enter the wrong basal lamina

Question 11

Why is it better to join individual fascicles together rather than whole nerves?

Answer 11

To prevent rerouting or misrouting

Question 12

Why is axonal regeneration in the CNS so limited?

Answer 12

Intrinsic
-cell body dies after axon is cut
Extrinsic
-Loss of trophic support from the target
-glial scar at site of injury
-presence of specific inhibitors of axon outgrowth, e.g. on central myelin

Question 13

How can you prove that the CNS, when in the right environment, can regenerate?

Answer 13

If you replace a piece of spinal cord with a piece of peripheral nerve, it reveals that CNS can regenerate into the PNS
-however, the neurons do not extend to the oppositely attached part of the spinal cord (CNS)
Conclusion: peripheral nerve is a “permissive” environment for axonal regeneration
CNS is hostile

Question 14

What is the barrier in CNS injury?

Answer 14

Astrocytic glial scar

-oligodendrocytes also express repellents on their surface which discourage axonal contact or growth

Question 15

What molecules do oligodendrocytes express to inhibit axon growth?

Answer 15

Nogo
OMGP
MAG

Question 16

Do blocking oligodendrocyte molecules work with regeneration?

Answer 16

No (cat)

Question 17

Where can you find neuro stem cells?

Answer 17

can be found in the Olfactory epithelium (because sensory neurons in the nose turns over every 2 weeks)
-Olfactory sensory neurons can grow from olfactory bulb all the way back to the cortex!

Question 18

What is chemo-brain?

Answer 18

Fog-like condition related to chemotherapy’s effect on “new brain cells”
-so if chemo makes you have neurologic symptoms, and chemo kills proliferating cells…do we have a transitive property here?
Scherer is skeptical

Question 19

It is almost impossible for central neurons to re-establish connections with distal targets. List four reasons why

Answer 19

1. glial scar
   
   2. release of oligodendrocytes of inhibiting factors like Nogo
   3. Loss of trophic support from the target
   4. Injury induced cell death (cell body dies after lesion in axon, unlike PNS cell body that undergoes regenerative chromatolysis)

Question 20

When peripheral axons are disconnected from their targets, they re-grow but struggle to establish functionally appropriate connections. Why?

Answer 20

Because of lack of neurotrophic and adherence factors

Question 21

New neurons are continually being generated in selected portions of the CNS. Why is this significant from a medical perspective?

Answer 21

-because we can potentially use existing regenerating mechanisms and apply them elsewhere in the CNS

Question 22

Why would it be advantageous to use reprogrammed somatic cells (as compared to fetal tissues) to produce differentiated cells for transplants into the CNS?

Answer 22

Problems with the fetal tissue approach
-heterologous grafters require immunosuppression
-inflammation and immune rejection may damage grafted neurons
-impractical and unethical (you can’t mass produce this
Somatic cell advantages
-you can produce it on a mass scale and it would be ethical
-no immunosuppression required

Question 23

Can endogenous stem cells fix the CNS?

Answer 23

No because patients aren’t getting better on their own