Naka: Regeneration

Question 1

What is the cellular response to axon transection?

Answer 1

1. Functions distal to the cut is lost immediately
2. Resealing of cut axon ends (hours later)
3. Retrograde effects
4. Anterograde effects

Question 2

What are retrograde effects?

Answer 2

Refers to area PROXIMAL to the cut end.

1. Interruption of normal supply of retrogradely transported signals to the cell body
2. Arrival of new signals are elicited at the injury site

Question 3

What are anterograde effects?

Answer 3

The distal stump of the cut axon undergoes Wallerian degeneration.

1. Rapid (1 hr) fragmentation of distal stump after latent phase
2. Disintegration of myelin (1 week)
3. Removal of axon remnants and myelin by macrophages and Schwann cells (2-3 weeks)

Question 4

What is chromatolysis?

Answer 4

Changes in the cell body of the injured neuron.

1. swelling cell body
2. dispersed ribosomes

Question 5

What may happen to the target nueron after the axon going to it has been cut?

Answer 5

May undergo atrophy/death.

In ALS the motor neuron degenerates–> target muscle undergoes atrophy.

Question 6

Could pre-synaptic input be affected by an axon transection?

Answer 6

Yes!

Question 7

What are the components of PNS axon regeneration?

Answer 7

1. Axon degeneration
2. Triggers surrounding schwann cells to “redifferentiate”.
3. Damaged neurons change gene expression patterns
4. Physical bridges form at injury site
5. Lack of inhibitors that are produced by CNS myelin and glial scars

Axons in the PNS are easier to regenerate than axons in the CNS

Question 8

What is redifferentiation?

Answer 8

1. Schwann cells proliferate
2. Recruit macrophages from blood stream
3. promote axon regeneration

Question 9

How do damaged neurons change gene expression patterns?

Answer 9

Damaged neurons increase the expression of GAP43

Question 10

What is “conditioning” of axonal regeneration?

Answer 10

Occurs in DRG (sensory neurons)

Pre-injury to a peripheral axon stimulates sensory neurons to regrow in the CNS.

Question 11

Is axon regeneration faster for a crushed axon or a cut axon?

Answer 11

Axon regeneratin is FASTER for a crush injury because tissue remeains that aids in regrowth.

Axon regeneration is SLOWER for cut injuries because no tissue remains.

Question 12

What is a major limitation to PNS regeneration? What can this cause?

Answer 12

A lack of guidance cues to lead axons to their former destinations.

Traumatic Neuroma–when axons don’t reach their targets

Question 13

Why is CNS repair limited in the CNS?

Answer 13

1. CNS myelin produces inhibitors of axon regeneration
2. Myelin clearance affter axonal degeneration is also very slow compared to PNS
3. Injury causes local production of excess astroctyes that form a glial scar
4. CNS neurons are intrinsically limited in regenerating axons
5. Neuronal production is limited in adut CNS

After injury, CNS axons begin to grow but make little progress. CNS axons abort further growth at 1 month.

Question 14

What are CNS inhibitors of axon regeneration?

Answer 14

Nogo-A

MAG

(Myelin Assoc. Glycoprotein)

Injury–> release Nogo/MAG –> inhibition of axon growth

Question 15

What produces a glial scar? What does a glial scar do?

Answer 15

Injury > production of excess astrocytes > glial scar

1. Acts as a barrier to growing axons
2. Produces inhibitory extracellular matrix molecules like CSPG (protein core + unbranched polysachaaride)

Question 16

What gets rid of CSPG?

Answer 16

Chondroitanase gets rid of CSPG (produced by glial scars)

Question 17

Why are CNS neurons limited in regenerating axons?

How do genes play a role in this?

Answer 17

CNS neurons are limited in regenerating axons because they have receptors for myelin-derived inhibitors:

NogoR and p75NTR

(NogoR is a myelin produced inhibitor of axon regeneration–when it finds a receptor on a CNS neuron it will stop the regneration of its axon!)

Genes show increased or decreased expression as the neurons mature and become unable to regenerate axons (Transcription Factors).

Question 18

How is neuronal production limited in the adult CNS?

Answer 18

Physciological neurogenesis only occurs in 2 regions of the adult brain

Ectopic (abnormal place) neurogenesis in pathological conditions (ischemia/neuronal death) is also limited.

Question 19

What are the 2 (3) places neurogenesis can occur in the adult brain?

Answer 19

1. Hippocampus- dentate gyrus
2. Subventricular zone of the lateral ventricle > olf bulb of neurons
3. POSSIBLY the hypothalamus

Question 20

What are three strategies for regeneration of the CNS?

Answer 20

1. Stimulate axonal regeneration
2. Cell replacement
3. Promote CNS plasticity

Question 21

What happens in axonal regeneration?

Answer 21

Neutralize myelin inhibitory molecules: Anti-NogoA and Anti-MAG antibodies try to block inhibitory effect.

Overcome inhibition of glial scar by removing CSPG with chondroitanase.

Enhance regenerative abilities of axons by interfering with the intracelular signaling pathways of inhibitory molecules. An increase in cAMP can block the NogoA pathway.

Question 22

How does cell replacement work?

Answer 22

Recruit endogenous neuroal progenitor cells: growth factors –> stimulate neurogenesis

Transplant exogenous cells

1. ES cells (have been used for regeneration of motor neurons in the spinal cord and dopaminergic neurons in the midbrain)
2. Induced pluripotenet stem cells

Question 23

What promotes CNS plasticity?

Answer 23

Most injuries are INCOMPLETE leaving some axons passing through the lesion site. It is possible to INCREASE the synaptic strength of the remaining connections.

Question 24

What do we see occuring to CNS plasticity with age and what is the critical period?

Answer 24

A decline

The critical period is a period of GREAT plasticity that terminates at about age 5.

Question 25

What facotrs contribute to the closure of the critical period?

Answer 25

Maturation of GABA neurons It may be possible to **block the maturation of GABA neurons** and maintain plasticity. **CSPG** is bad because it **enhances the maturation** of **GABA neurons.**

Question 26

What are treatments that enhance plasticity?

Answer 26

**Chondroitinase** **Physical therapy**