Lecture 5-Nervous system injury and repair Flashcards
How are neurons fragile cells?
-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
Which part of the neuron is the most vulnerable and why?
-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)
What is cutting an axon called and what does it give (PNS)?
-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
What is Wallerian degeneration? (if clean cut)
-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)
What is Wallerian degeneration (messy cut/crush)?
-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
What are the layers in a nerve?
–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
How can the two cut bits of an axon reconnect? (PNS)
-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
What is the story of Henry Heads and his self-experimentation?
- surgeon interested in recovery from injury -cut own nerve in arm and observe recovery -over 2 years mostly successful -wallerian regeneration occured
What happens to the endoneurium after axonomy?
-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
How do you repair a nerve (surgically)?
-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
How successful is recovery from PNS nerve injury?
-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
How do the cell bodies die sometimes after the axon is cut/damaged?
-neurons die by apoptosis (programmed cell death) -result of internal biochemical cascade -doesn’t damage surrounding cells (like necrosis would)
How does apoptosis occur in neurons when axons damaged?
-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)
Can the CNS axons regrow?
-no, never -the PNS you can damage autonomic, sensory and motor and often they regrow
Is it the environment or are the neurons in the CNS different and that’s why they don’t regrow?
- 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
What are the 3 things that inhibit axonal regrowth in the CNS?
-glial scars -lack of attractive cues/trophic factors -central myelin is inhibitory
What is glial scarring?
-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
What are the inhibitory components of the glial scar?
-chondroitin sulfate proteoglycans (GAGs) -remove GAGs with enzymes= glial scar no longer inhibitory -GAGs bind signaling molecules (sempaphorin 3A)?
What is the lack of attractive/trophic factors in the CNS (axonal regrowth)?
-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
What is the evidence that in the CNS mylein is inhibitory to axonal regrowth?
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
What is on myelinated axons that is inhibitory to axonal regrowth? (CNS)
-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
Why is myelin inhibitory?
-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
What diseases kill the whole neuron?
-Alzheimer’s -Parkinson’s -Huntington’s -Motor neuron disease
Are neurons able to divide?
-no, terminally differentiated cells, can’t divide
Do some tissues in the adult body have cells that are able to 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 is the story with bird song?
-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
Where are the neural stem cells in the rat?
-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)
How are the neurons in the olfactory bulb of the rat replaced?
-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)
What is the role of new neurons (rats)?
-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
What is the nuclear bomb experiment that test if humans form new neurons after maturation?
-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
Can additional stem cells be added to damaged brain?
-source: -fetal brains -embryonic stem cells (64 cell stage -non-neural stem cells -not clear how many are needed
Where would you inject the exogenous stem cells?
-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?
What are the potential ways of using stem cells indirectly?
-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
What are the potential problems with using stem cells as treatment?
-tumorigenesis (teratomas) -allodynia (pain due to sprouting of sensory endings) -unwanted phenotypes -but these complications rarely reported (Why?) -rejection (lifelong immune supression)
What is the example of a patient who did get a tumour from stem cells?
-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
Is there medical tourism with stem cell use?
-yes -last resort, people seek alternative therapies -China
