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In what way are neurons fragile cells?

- energy demand high
- obligate aerobic metabolism (O2 critical)
- totally dependent on glucose supply (via blood)
- Brain (2% of body) gets 15% of blood
- loss of O2 for a few minutes, glucose for 10-15 min, is fatal to neurons


What is the most vulnerable part of the neuron?

the axon


What do nervous system injuries often involve?

- axons: trauma, demyelination
- axons are the largest and most vulnerable part of a neuron
- 20µ diameter cell and 30cm axon more like a cortical axon that will extend from the top of the head down into the neck


What is the response to damage of the nervous system?

- different outcome in peripheral or central nervous system


What is axotomy?

- cutting an axon


What happens when we cut an axon?

- gives a distal segment and a proximal stump
- result of cutting an axon in periphery is Wallerian degeneration (loss of peripheral (distal) part)


What occurs in Wallerian degeneration I?

- severed axon degenerates and is phagocytosed (4 days)
- chromatolysis of cell body (swelling, loss of organelles
- neuron can die or survive


What occurs during Wallerian degeneration II?

- if it survives, the axon sprouts (1-3 days)
- sprouts can reconnect to target (if axon is in the peripheral nervous system)


What occurs during Wallerian degeneration III?

- bad trauma leads to scarring, sprouting axon may not find its way back
- painful neuroma results - sensory endings trapped in the scar tissue that generates chronic pain


How does axon find its way back and reconnect to target cell?

- axon reconnects poorly across break
- best if cut nerve (nerve being whole structure/bundle of neurons and connective tissue) stitched back together
- sprout extends down surviving endoneurium and perineurium to target


Who is Henry Heads?

- surgeon interested in recovery from injury
- cut own nerve in arm
- recovery over 2 years mostly successful
- ' the art of self-experimentation'
- late 1800s


What are the endoneurium and perineurium?

- outer connective tissue sheath (epineurium)
- bundles of axons wrapped in connective tissue (perineurium)
- individual axons wrapped in Schwann cells and basal lamina (endoneurium)
- hopefully when you cut a nerve you are left with the endoneurium and other connective tissue that provides a 'runway' or 'track' for a newly growing/regenerating axon to follow


What is the role of distal nerve in neuron healing?

- acts as an axon guide
- sprouting axons can grow along empty tubes formed by epi- and perineurium
- leads them to target
- crush better than cut - tubes intact all the way


What is nerve repair?

- sewing nerves together can misalign distal and proximal tubes
- sometimes a piece of nerve is destroyed
- need a bridge to guide sprouts to empty endoneural tubes
-- can be nerve transplant
-- can be artificial


What are important things to consider in regards to peripheral axon regeneration?

- only a minority make it back to target (10% in case of cut nerve)
- functional recovery is never perfect
- bad injuries rarely recover
- but they try


Why do cell bodies sometimes die?

- after losing an axon, neurons die by apoptosis
- apoptosis - programmed cell death
- internal biochemical cascade
- doesn't damage surrounding cells (cf. necrosis)


What is the trigger for apoptosis?

- signal from target cell suppresses apoptosis - no signal, apoptosis occurs
- signal carried retrogradely up the axon
- cutting axon interrupts signal
- outcome depends on neuronal size and age


How does central regeneration differ from peripheral?

- cut sensory, motor and autonomic axons in the periphery can often regrow
- Axons in the CNS never regrow


What do rat spinal grafts show us?

1. normal spinal projections.
2. create spinal lesion in adult rat - no recovery
3. graft sciatic nerve bridge across lesion, axons regrow down graft, stop at spinal cord

- this shows that it is the central nervous system environment that prevents regrowth of nerves


What are the inhibitors of CNS axon regrowth based on current understanding?

Three things
- glial scar
- lack of attractive cues/trophic factors
- central myelin is inhibitory


What is glial scarring?

- glial cells retain ability to divide
- will increase division at site of injury
- tend to fill damaged area (glial scar)
- non-neuronal cells invade (microglia, macrophages, fibroblasts)
- sprouts don't like growing on glial scar


What are some of the known inhibitory components of scar?

- chondroitin sulfate proteoglycans (GAGs)
- remove GAGs with enzymes - glial scar no longer inhibitory
- GAGs bind signalling molecules (semaphorin 3A?)


Why do we have a lack of attractive/trophic factors in the CNS?

- in embyro, many mechanisms guided growing axon
- in adult, distances much greater, environment more complex and guidance mechanisms may be lacking
(perhaps a weaker argument for why we don't get regeneration in CNS)


What is the evidence for myelin being inhibitory?

- central axons can regrow until myelin forms in embryo
- oligodendrocytes (myelinating glial cells of CNS) can prevent axon regrowth in vitro
- destroying myelin in rat allows functional regrowth of spinal cord axons


What about myelin is inhibitory?

1. Myelin associated glycoprotein (MAG1)
2. oligodendrocyte myelin glycoprotein (OMgp)
3. Nogo A

- all work through the same receptor: Nogo receptor


Why is myelin inhibitory in the first place?

- CNS is complicated and circuitry is crucial
- uncontrolled axonal growth likely to scramble circuits
- develop brain and then clamp down on change


What are some diseases that cause death of the whole neuron?

- Alzheimer's
- Parkinson's
- Huntington's
- Motor neuron disease


Why is it hard for the brain to make new neurons?

- neurons are terminally differentiated cells (can't divide)
- some tissues have small numbers of undifferentiated cells (stem cells) that keep dividing to generate new tissue cells e.g. skin
- brain may contain neural stem cells


What was a non-human species that provided some evidence that we have stem cells in the brain? How?

- song birds learn new songs each year
- rebuild "song centre" in brain annually
- new neurons from stem cells
- migrate long distances, integrate into new neural circuits


Do mammals have neural stem cells?

- yes
- neural stem cells exist in subventricular zone
- supply new neurons to olfactory bulb (in rats)