lecture 5 Flashcards
nervous system injury and repair
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?
- normal spinal projections.
- create spinal lesion in adult rat - no recovery
- 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?
- Myelin associated glycoprotein (MAG1)
- oligodendrocyte myelin glycoprotein (OMgp)
- 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)
How do stem cells function in the olfactory system?
- in rats: not something that happens in humans
- stem cells in ventricular zone generate new neurons that migrate to olfactory bulb
- travel via RMS (rostral migratory stream)
- become new interneurons in olfactory bulb
- new olfactory neurons generated in olfactory epithelium (nasal cavity)
What role to stem cells have in the hippocampus?
- hippocampus involved in memory
- also site of generation of new neurons from ventricular zone
- new neurons are granular cells
- seem to be involved in the making of new memories in rats/mice etc
- sure if vital for laying down memories but somehow they contribute towards it
What is the role of new neurons in the brain?
- new neurons detected in brain of experimental animal after damage
- existing neural stem cells seem insufficient to repair damage
- new cells hang around for weeks but not integrated into circuits
new hippocampal cell in humans
- hippocampus crucial for human learning
- learning occurs throughout life
- very difficult to prove - no experimental data
- use natural experiment
How did scientists use nuclear bombs to study stem cells?
- above ground nuclear bomb testing common in 50s and 60s
- filled atmosphere with 14C
- if no generation of neurons then 14C should reflect time of birth (low in 30s and 40s, high in 50s and 60s)
- however it was seen in the brains of people who were born before the increased levels of C-14 that they had higher amounts of C-14 then was in the atmosphere at the time they were born seemingly proving that they made new cells well into their life
What are some features of new neurons in old hippocampi?
- evidence that dentate neurons turn-over in human hippocampus
- continues with modest decline into old age
- generation of new neurons may have functional significance (unsure yet)
What are some questions regarding the use of exogenous stem cells?
- can additional stem cells be added to damaged brain?
- source? (fetal brains, embryonic stem cells, non-neural stem cells)
- how many do you need?
- need to grow them in cell culture to increase numbers?
What are some problems with using exogenous stem cells?
- tumorigenesis (teratomas: a tumour which has aspects of every single type of cell in the body)
- allodynia (pain due to sprouting of sensory endings)
- unwanted phenotypes
- but these complications rarely reported (why?)
- rejection (lifelong immune suppression)
Give an example of a problem that occurred with exogenous stem cell therapy
- Donor-derived brain tumour following neural stem cell transplantation in an ataxia telangiectasia patient
- ataxia telangiectasia (AT) treated with intracerebellar and intrathecal injection of human fetal neural stem cells
- four years later was diagnosed with a multifocal brain tumour
- tumour was of non-host origin - from the transplanted neural stem cells
- first report of a human brain tumour complicating neural stem cell therapy
- generally though stem cells seem to be pretty safe
What is medical tourism?
- popular for stem cell therapy
- often a last resort
- gives access to experimental treatments prior to scientific and clinical validation
