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(Molly) NEUR30003 - Principles of Neuroscience > lecture 5 > Flashcards

lecture 5 Flashcards

nervous system injury and repair

1
Q

In what way are neurons fragile cells?

A
  • 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
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2
Q

What is the most vulnerable part of the neuron?

A

the axon

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3
Q

What do nervous system injuries often involve?

A
  • 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
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4
Q

What is the response to damage of the nervous system?

A
  • different outcome in peripheral or central nervous system
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5
Q

What is axotomy?

A
  • cutting an axon
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6
Q

What happens when we cut an axon?

A
  • gives a distal segment and a proximal stump

- result of cutting an axon in periphery is Wallerian degeneration (loss of peripheral (distal) part)

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7
Q

What occurs in Wallerian degeneration I?

A
  • severed axon degenerates and is phagocytosed (4 days)
  • chromatolysis of cell body (swelling, loss of organelles
  • neuron can die or survive
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8
Q

What occurs during Wallerian degeneration II?

A
  • if it survives, the axon sprouts (1-3 days)

- sprouts can reconnect to target (if axon is in the peripheral nervous system)

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9
Q

What occurs during Wallerian degeneration III?

A
  • 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
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10
Q

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

A
  • 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
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11
Q

Who is Henry Heads?

A
  • surgeon interested in recovery from injury
  • cut own nerve in arm
  • recovery over 2 years mostly successful
  • ’ the art of self-experimentation’
  • late 1800s
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12
Q

What are the endoneurium and perineurium?

A
  • 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
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13
Q

What is the role of distal nerve in neuron healing?

A
  • 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
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14
Q

What is nerve repair?

A
  • 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
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15
Q

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

A
  • 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
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16
Q

Why do cell bodies sometimes die?

A
  • after losing an axon, neurons die by apoptosis
  • apoptosis - programmed cell death
  • internal biochemical cascade
  • doesn’t damage surrounding cells (cf. necrosis)
17
Q

What is the trigger for apoptosis?

A
  • 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
18
Q

How does central regeneration differ from peripheral?

A
  • cut sensory, motor and autonomic axons in the periphery can often regrow
  • Axons in the CNS never regrow
19
Q

What do rat spinal grafts show us?

A
  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
20
Q

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

A

Three things

  • glial scar
  • lack of attractive cues/trophic factors
  • central myelin is inhibitory
21
Q

What is glial scarring?

A
  • 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
22
Q

What are some of the known inhibitory components of scar?

A
  • chondroitin sulfate proteoglycans (GAGs)
  • remove GAGs with enzymes - glial scar no longer inhibitory
  • GAGs bind signalling molecules (semaphorin 3A?)
23
Q

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

A
  • 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)
24
Q

What is the evidence for myelin being inhibitory?

A
  • 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
25
Q

What about myelin is inhibitory?

A
  1. Myelin associated glycoprotein (MAG1)
  2. oligodendrocyte myelin glycoprotein (OMgp)
  3. Nogo A
  • all work through the same receptor: Nogo receptor
26
Q

Why is myelin inhibitory in the first place?

A
  • CNS is complicated and circuitry is crucial
  • uncontrolled axonal growth likely to scramble circuits
  • develop brain and then clamp down on change
27
Q

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

A
  • Alzheimer’s
  • Parkinson’s
  • Huntington’s
  • Motor neuron disease
28
Q

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

A
  • 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
29
Q

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

A
  • 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
30
Q

Do mammals have neural stem cells?

A
  • yes
  • neural stem cells exist in subventricular zone
  • supply new neurons to olfactory bulb (in rats)
31
Q

How do stem cells function in the olfactory system?

A
  • 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)
32
Q

What role to stem cells have in the hippocampus?

A
  • 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
33
Q

What is the role of new neurons in the brain?

A
  • 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
34
Q

How did scientists use nuclear bombs to study stem cells?

A
  • 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
35
Q

What are some features of new neurons in old hippocampi?

A
  • 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)
36
Q

What are some questions regarding the use of exogenous stem cells?

A
  • 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?
37
Q

What are some problems with using exogenous stem cells?

A
  • 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)
38
Q

Give an example of a problem that occurred with exogenous stem cell therapy

A
  • 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
39
Q

What is medical tourism?

A
  • popular for stem cell therapy
  • often a last resort
  • gives access to experimental treatments prior to scientific and clinical validation

(Molly) NEUR30003 - Principles of Neuroscience (35 decks)

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