13. Regeneration

· True regeneration

o Formation of axonal growth cone

o Axon elongation

o Reformation of synapses

o Restoration of function

· What regenerates? What does not? (Axons can regenerate under certain circumstances)

o Peripheral portions of spinal or cranial nerves regenerate

o Central portion elongates up to CNS but do not regenerate

o CNS does not elongate, does not regenerate

o Optic nerve: does not have peripheral distribution (does not elongate, does not regenerate)

o Cell body location is not as relevant as passageway of axon

	PNS	CNS
Cell Body Response	- Chromatolysis - Increase in protein synthesis - Increase and fast-axonal transport of growth-associated proteins (GAPS)	- Chromatolysis - Increase in protein synthesis - No sustained increase or transport of GAPS
Proximal segment	- degeneration 1-2 nodes of Ranvier (myelinated); 1-2mm (unmyelinated) - growth cone (w/ filopodia) - elongation (1-2mm/day)	- degeneration - injury bulb - no elongation - requires axon collaterals to sustain
Injury site	- compromise of blood/nerve barrier - fast removal of debris by phagocytes - Schwann cells form scars	- compromise of blood/nerve barrier - relatively slow removal of debris - astrocytes form scars (may also phagocytose) - relatively dense scars
Distal segment	- phagocytosis of myelin and axon debris (rapid and efficient) - Bands of Von Bungner – tunnels (proliferation of Schwann cells) - suturing facilitates process - axons elongate and regenerate	- debris removal is much slower - no formation of “tunnels” - no elongation, no regeneration

Generalizations (w/ exceptions):

1. There is no mitosis of neurons in CNS

a. Primary olfactory neurons mitose and regenerate throughout life (only example of regenerative mitosis)

b. Low level of mitosis in some structures

i. granule cells of dentate gyrus (part of hippocampus)

2. There is no regeneration of CNS axons within CNS

a. Some neurons in reticular formation (which use monoamines: NE, DA, 5HT)

i. nucleus coeruleus (NE)

ii. raphe nuclei (5HT)

3. The optic nerve cannot regenerate

a. fish, amphibians

b. retinal ganglion cells in rats can be “tricked” (not true regeneration: no return of function)

4. Axons will regenerate if injured in peripheral distribution

- cell bodies must not be damaged; vasculature must be intact

- post-synaptic structures must be intact and “healthy”

- better if crushed (if cut: suture)

- inappropriate connections often made

a. sympathetics and VII regenerate better than most

Why do we see return in function?

1. Partial occlusion during ischemic stroke: further damage can be prevented by

o anti-ischemic drugs

o collateral circulation

2. Acute phase: shock and edema (return of function of undamaged axons)

3. Unmasking: post-synaptic cells may adjust excitability; “silent” synapses may à expressed

4. Sprouting: degeneration may induce sprouting of collaterals in undamaged axons

a. results in loss of specificity (as in polio)

5. Undamaged areas can take over functions (e.g. hemispherectomy, best example: language functionality in young girls)

Theories: why CNS axons do not regenerate

	Evidence for	Evidence against
1. Barrier Theory - astrocytes and very dense collagenous scars (CNS)	- axons don’t appear to grow through/across scars - scars less dense in PNS - regeneration better when anti-inflammatory drugs are given	- dense scars not an obstacle in non-mammalian vertebrates - when very dense scars in PNS: not a total barrier - does not explain barrier of PNS central portion upon reaching CNS
2. “Inadequacy” of CNS periaxonal environment - astrocytes/oligodendrocytes vs. Schwann cells - Bands of Von Bungner	- CNS myelin breakdown products inhibit growth - PNS myelin breakdown products do not inhibit - central portion of PNS (VIII, etc.) stop growing - possible to “trick” CNS axons by providing PNS environment (e.g. w/ a sciatic nerve graft) - (axons in graft will die; Schwann cells remain) - (possible to restore light reflex in rats)	- non-mammalian vertebrates have vigorous CNS growth - olfactory axons - monoamine fibers
3. “Intrinsic” inability of CNS to regenerate axons	- discovery of GAPS (expressed in PNS and developmental CNS); major: GAP-43 - increase GAP in olfactory neurons, hippocampus, neo-cortex, cerebellum	- cell lines exist that do not require GAP - ability to “trick” does not require GAP
4. Trade-off of regeneration for plasticity	- GAP-43 in non-mammalian vertebrates: regeneration - modified GAP-43 in mammals: plasticity