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
