Lecture 5-Nervous system injury and repair Flashcards

1
Q

How are neurons fragile cells?

A

-have high energy demands(burn up energy fast) -obligate aerobic metabolism (O2 is critical) -totally dependent on glucose supply via blood -brain= 2% of body weight, gets 15% of blood -loss of O2 for a few minutes= fatal to neurons -glucose loss for 10-15 minutes= fatal to neurons

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2
Q

Which part of the neuron is the most vulnerable and why?

A

-axon -because it is much longer than the cell body so more likely to be damaged -thus nervous system injury often involves axons (trauma, demyelination)

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3
Q

What is cutting an axon called and what does it give (PNS)?

A

-axotomy -gives a distal segment(the disconnected bit of the axon) and proximal stump(the bit with the neuron body) -result of cutting an axon in the periphery is Wallerian degeneration (loss of peripheral(distal) part) -the peripheral part is going top starve to death as it is the cell body that provides it with energy

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4
Q

What is Wallerian degeneration? (if clean cut)

A

-in the PNS when axon cut -severed axon degenerates and is phagocytosed- by macrophages (4 days) -Schwann cells are activated -chromatolysis of cell body (swelling, loss of organelles) -neuron can die or recover -if it survives the axon sprouts (1-3 days) -sprouts can reconnect to target (if axon is in the PNS)

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5
Q

What is Wallerian degeneration (messy cut/crush)?

A

-in the PNS -when axon crushed or messily cut (more common than clean cut) -at the site of the cut= lot of connective tissue, scar tissue, so the twigs get caught up in this and form a neuroma= this can become very sensitive= so the scar can be painful= from these neuromas

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6
Q

What are the layers in a nerve?

A

–outer layer= epinerium(outer connective tissue sheath) -middle layer= perineurium(bundles of axons wrapped in connective tissue) -inner layer= ednoneurium (individual axons wrapped in Schwann cells and basal lamina) -a

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7
Q

How can the two cut bits of an axon reconnect? (PNS)

A

-best if cut nerve is stitched back together -sprout extends down surviving endoneurium and perineurium to target (the tracks act as guides) -this is because the axons are bundled up by Schwann cells, basal lamina and connective tissue -sprouting axons can grow along empty tubes formed by epi- and perineurium -they lead them to target -crush better than cut= tubes intact all the way

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8
Q

What is the story of Henry Heads and his self-experimentation?

A
  • surgeon interested in recovery from injury -cut own nerve in arm and observe recovery -over 2 years mostly successful -wallerian regeneration occured
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9
Q

What happens to the endoneurium after axonomy?

A

-when you kill the axon, then space surronded by basal lamina -left with these tracks -you hope some of the sprouts find their way there

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10
Q

How do you repair a nerve (surgically)?

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 transplants from elsewhere in the body or other body =can be artificial

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11
Q

How successful is recovery from PNS nerve injury?

A

-the nerves can regenerate -only a minority make it back to target (10% in case of a cut nerve= this is enough to return sensory and motor function but not as good as before) -functional recovery is never perfect -bad injuries rarely recover -the worse the injury the worse the recovery

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12
Q

How do the cell bodies die sometimes after the axon is cut/damaged?

A

-neurons die by apoptosis (programmed cell death) -result of internal biochemical cascade -doesn’t damage surrounding cells (like necrosis would)

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13
Q

How does apoptosis occur in neurons when axons damaged?

A

-signal from target cell suppresses apoptosis, no signal (due to disconnection) apoptosis occurs -signal carried retrogradely up the axon -cutting axon interrupts the signal -outcome depends on neuronal size and age -(the l need you signal)

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14
Q

Can the CNS axons regrow?

A

-no, never -the PNS you can damage autonomic, sensory and motor and often they regrow

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15
Q

Is it the environment or are the neurons in the CNS different and that’s why they don’t regrow?

A
  • it is the environment - tested by rat spinal garfts, created a spinal lesion in a rat= no recovery, they put in a sciatic nerve bridge across the lesion, the axons regrew there but as soon as they hit the spinal cord= stop growing= therefore CNS environment doesn’t let the axons grow
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16
Q

What are the 3 things that inhibit axonal regrowth in the CNS?

A

-glial scars -lack of attractive cues/trophic factors -central myelin is inhibitory

17
Q

What is glial scarring?

A

-Glial cells retain the 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

18
Q

What are the inhibitory components of the glial scar?

A

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

19
Q

What is the lack of attractive/trophic factors in the CNS (axonal regrowth)?

A

-in embryo many mechanisms guided growing axon -in adult, distances much greater, environment more complex and guidance mechanisms may be lacking -less persuasive as an argument

20
Q

What is the evidence that in the CNS mylein is inhibitory to axonal regrowth?

A

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

21
Q

What is on myelinated axons that is inhibitory to axonal regrowth? (CNS)

A

-inhibitory proteins on oligodendrocyte membrane 1. Myelin associated glycoprotein MAG1 2.Oligodendrocyte myelin glycoprotein (OMgp) 3. Nogo A -all work through the same receptor= Nogo receptor -Nogo A most important

22
Q

Why is myelin inhibitory?

A

-CNS is complicated and circuitry is crucial -uncontrolled axonal growth likely to scramble circuits -develop brain and then clamp down on change -you don’t want random changes, so you keep your synaptic connections -maybe you have to have this system to have an efficient brain that is sustainable

23
Q

What diseases kill the whole neuron?

A

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

24
Q

Are neurons able to divide?

A

-no, terminally differentiated cells, can’t divide

25
Q

Do some tissues in the adult body have cells that are able to divide?

A

-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

26
Q

What is the story with bird song?

A

-song birds learn new songs every year -rebuild song centre in brain annually= new neurons from stem cells -migrate long distances,integrate into new neural circuits -so birds have to have brain stem cells -this led to the idea that maybe humans do too

27
Q

Where are the neural stem cells in the rat?

A

-subventricular zone -supply new neurons for the olfactory bulb -hippocampus (involved in memory=converts short term memory to long term, also site of generation of new neurons, from ventricular zone = new neurons are granular cells)

28
Q

How are the neurons in the olfactory bulb of the rat replaced?

A

-stem cells in ventricular zone generate new neurons that migrate to olfactory bulb –every time you smell something the neurons die, lot of them a one-off type of cell, so have to be replaced -travel via RMS (rostral migratory stream) -become new interneurons in olfactory bulb -new olfactory neurons generated in olfactory epithelium (nasal cavity)

29
Q

What is the role of new neurons (rats)?

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 week but not integrated into circuits and then just disappear

30
Q

What is the nuclear bomb experiment that test if humans form new neurons after maturation?

A

-new hippocampal cell in humans -hippocampus crucial for human learning -excess of C14, naturally there but nuclear bombs put more in, then carbon goes into every cell -now wait for people born before the nuclear bomb to die= how much 14C is there -people born before the nuclear bombs still had more 14C than they should if the brain was finished growing when young -so the brain must contibue to make new neurons, 1/3 of neurons in hippocampus replaced every year -we don’t know if capable of repair

31
Q

Can additional stem cells be added to damaged brain?

A

-source: -fetal brains -embryonic stem cells (64 cell stage -non-neural stem cells -not clear how many are needed

32
Q

Where would you inject the exogenous stem cells?

A

-Ventricles? -Subventricular zone? -Damaged part of the brain? -will they work out what type of neuron they have to become? -will they make the correct connections?

33
Q

What are the potential ways of using stem cells indirectly?

A

-may be used as aids to keeping sick neurons alive –inject genetically modified glial cells that release trophic factor -use glial cells derived from stem cells or other sources to repair axonal loss in CNS

34
Q

What are the potential problems with using stem cells as treatment?

A

-tumorigenesis (teratomas) -allodynia (pain due to sprouting of sensory endings) -unwanted phenotypes -but these complications rarely reported (Why?) -rejection (lifelong immune supression)

35
Q

What is the example of a patient who did get a tumour from stem cells?

A

-Ataxia telengiectasia (AT) treated with intracerebellar and intrathecal injection of human fetal neural stem cells -four years later diagnosed with a multifocal brain tumour -tumour was of nonhost origin= from the transplanted neural stem cells -first report of a human brain tumour complicating neural stem therapy

36
Q

Is there medical tourism with stem cell use?

A

-yes -last resort, people seek alternative therapies -China