Lecture 3: Self-Repair Capacity of Peripheral Neurons Flashcards
What factors determines the size of axon diameters
Some regions include:
1) How much neurotransmitters are needed, for example, if there are hundreds of muscle fibers controlled by one motor neuron then all those unpaved region need to be supplied by fresh neurotransmitters since the axon is transport mechanisms (for neurotransmitters precusor?), it needs to be able to carry a certain volume
2) conduction velocity, larger axons are faster conducting meaning the brain will get the message sooner from faster fiber
Why cats have larger axon diameters than humans?
Speculative Guess:
Cats are predators, and their survival relies heavily on their ability to respond rapidly to environmental stimuli, such as chasing prey or escaping danger. Larger axon diameters allow for faster conduction of electrical signals, which enhances their reflexes and reaction times
Practice Question: What are typical conduction velocity ranges for human motor and sensory axons? How does CV scale with axonal diameter?
Motor axons: up to 55 m/s
Sensory axons: up to 60 ms
CV scaling factor (gives you estimate of conduction velocity based on size of axons: 6 m/s per micrometer
What are specialized transport systems?
What provides transport mechanisms?
It is a system that moves material between soma and axon terminals in both directions along the axons, such as proteins synthesized in the soma that are needed at terminals
Parallel arrays of microtubules and microfilaments provide transport mechanisms (and maintain cytoskeleton)
List the fast axoplasmic transport
- Fast Anterograde Transport
- Retrograde Transport
Describe fast anterograde transport
Transport away from the cell body (towards axont terminal). It is mediated by kinesin. In synaptic vesicles, it carries neurotransmitters, enzymes and lipid, manufactured in the nucleus of the cell body) and then transported out at a rate of 200 - 400 mm/day.
It also carries mitochondria, it is transported at a rate of 50 - 100 mm/day (slower may be due to mitochondria constantly attaching and detaching (to the transport machinerary)
Describe retrograde transport
Transport towards the cell body, mediated by dynein, transport occurs at a rate of 100-200 mm/day
It brings back empty synaptic vesicles for refilling
It brings back trophic factors (chemical signals like nerve growth factor), which are produced by postsynaptic cells and taken up at the synapse. These factors are crucial for the neuron to receive feedback, such as signals from muscle fibers, allowing the neuron to monitor its connections. If ie, muscle gets damaged, the neuron can detect disconnection or damage because tropic factors are not providing the feedback via RT potentially leading to cellular responses.
It also carries toxins and viruses that enter through nerve terminals. These undesirable agents, such as tetanus toxin, can be transported back to the central nervous system, leading to diseases or poisoning the brain and spinal cord.
Describe slow axpolasmic transport
It’s is only (slow) anterogade transport. Involves a different mechanism. Mainly carries cytoskeletal elements, neurofilament and microtubulues units that are assembled in cell bodies prior to transport. They are ie, sent out to repair membrane if there was a damage, kind of like maintenance. The rate is ~1mm/day, due to that particles get detached from transport mechanism and then attach again
Describe slow axoplasmic transport
It’s is only (slow) anterogade transport. Involves a different mechanism. Mainly carries cytoskeletal elements, neurofilament and microtubulues units that are assembled in cell bodies prior to transport. They are ie, sent out to repair membrane if there was a damage, kind of like maintenance. The rate is ~1mm/day, due to that particles get detached from transport mechanism and then attach again
Why is the rate ~1mm/day in slow anterogade transport significant?
It is the rate at which axons can repair themselves and build new projects if the axon is damaged (regenerate) but the rate is limited by this physical capacity if bringing the material to the site of injury
What did Ramon y Cajal infer about axonal growth and development
He imagined the process of regeneration, he described the growth cone, which is the tip of a cut nerve axons that has multiple sprouts, where eventually one would be the main sprouts
The growth cone in a nerve that is injured has a way of finding in which direction it should grow because it picks up mechanical guidance and chemical cues from tissues.
What are the three most common ways in which nerve can be mechanically damaged?
(Increases in severity)
- Compression
- Degree if compression matters, if it minutes, then limbs go to sleep, then you feel tingling as it wakes up, you shake it, and get blood to circulate again —> recovery
If it’s compressed for hours ie, in a paralyzed individual, then it leads to compression neuropathy - Crush
- After a crush two things can happen, in a simple crush axons are still aligned, the proximal surviving portion of the axons that are still connected to the cell body survive but the crush causes interruption in flow and the axon distal to the crush die very quickly. Axons will be disconnected from the target and have to regeneration, but it eventually reaches to its correct target
- Crush that also distorts the nerve, axons will regenerate, but it will go down to wrong target (doesn’t follow the path of the previous axons ghost) - Transection
- Nerve completely cut, axonal growth will always be attempt, but there could be a neuroma that forms (tangled of nerve terminals) that get lost and bundle up) or there could be a gap where the nerve is separated from the distal portion.
What are other sources of injury that not traumatic injury
Interruption of blood flow (indirect damage)
Degenerate diseases ie, affect myelin, multiple sclerosis
In a 3 neuron set up, one has a leison along the length of the middle axons, what happens in response
- The proximal part of the axons still connected to the cell body survive but suffers
- Distal portion that gets disconnected by the cell body degenerates/ Loss of axonal structure distal to the leison
- Myelin degenerates leaving debris (myelin “ghost”)
- The synaptic terminal degenerates (distal to the leison) which then has implications on the postsynaptic cells
- Postsynaptic cells stop receiving synaptic drive and can undergo anterogade transneural degeneration. It doesn’t necessarily die (degeneration doesn’t necessarily equal death in this case), but it is affected by the lack of normal input
5.Presynaptic neuron undergoes retrograde transneural degeneration. The terminal retracts because postsynaptic cells is damaged, therefore some synaptic input is withdrawn but not all
None of the 3 neurons dies but they are damaged.
What does the latent period of variable duration in terms of axonal regeneration depend on?
It depends on the distance from where the leison happens to the cell body, ie a motor neuron that supplies the foot muscle and is a meter long then the cell body in the spinal cord will not find out right away.
How does the cell body know it needs to take action after injury
The cell body eventually gets the message for two reasons 1)because there’s a change in the mixture of things that comes back (retrograde) those things were lack of empty vesicles because nothing is sending them 2) or chemical messages produce by the postsynaptic cells are no longer coming back. It takes time to process and regenerate an axon. Cell body start producing building materials to build membrane and transport mechanisms (slow anterogade?)
What 4 things happen to the proximal axons when there is an injury and why?
The first thing that happens pretty fast is that 1) the proximal axon shrinks in diameter. It shrinks because it has a lack of material coming back. 2) and it can swell near the ends because there is an accumulation of transported materials that are not moving, shape of axons changes. 3) And then eventually it starts to produce growth cones and send them out, 4) then it manages to produce a long thin axon but it thins out along the entire length (not just the new distal portion). This happens because it’s not containing the same thing that it normally does. It puts all the efforts in producing new axon and not to maintain the proximal axon until it makes a new connection–> regeneration is successfully complete
Explain Hoffer’s research in determining what happens to the proximal axons size after a peripheral injury
They measured compound action potential from nerves by implanting electrodes, left it there, and monitored week to week changes in the size of the compound action potential when they stimulated that nerve. Like conduction velocity is proportional to diamerer, so is action potential proportional to diameter. So, if fibers shrink, the compound action potential will be smaller. Compound means the sum of the axonal nerves.
The research found that proximal to a nerve crush or transection, the axonal cross- sectional area (lumen) declines exponentially (30 to 45 days) while the axon elongates (successfully regenerated)
However, once the growing axon successfully makes the new connection, the cross-sectional area of the entire proximal axon increases again (100 to 200 days: rate 3 times slower). Because now that axon gets to send out the normal amounts of material.
The lumen of the proximal may or may not return to its original size
Explain Hoffer’s research on injured sensory and motor axons
Looked separately at the fate of sensory and motor axons in the same nerve. The nerves were the tibial nerves or the peroneal nerve, branches of the sciatic. Put a cuff(?) on the sciatic nerve and stimulated one of the braces (?) and recorded on the other one.
Open the spinal cord in the animal to reveal the dorsal and ventral roots and measure compound action potential separately.
The findings were that after the injury, the sensory axon declined at an exponential rate. The motor axon also declined exponentially but at a slower rate, and motor axons were three times larger than the sensory axons because they atrophy was less.
Why was the atrophy less? There were 2 hypotheses:
1) sensory fiberes were more dependent on getting tropic information from their distal targets that they were no longer getting
2) sensory fiberes were immediately and completely silenced after the injury however the motor fibres took a long time understanding an injury has occurred, and were still giving some descending input (even when they reliazed),they were not silenced. Had a better chance surviving because they were electrical active.
Reinnervation
After leison every 2 weeks after stimulated and recorded the nerve. At first there was nothing by after a while (I think months) there was suddenly signs of EMG (when stimulated the nerve) because the motor fibres started to reinnervate the muscle, and it then improved (got fully reinnervated). It also gave opportunity for motor axons and sensory axons to recover in size, although not to its original size, their compound action potential got bigger.
The cell body learned that it’s axons made a new connection because it was receiving normal information through retrograde transport (feedback from periphery) hence it started to ie regain production of neurtransmiiter. Sensory fibers have reinnervated their receptors, once this occer, the proximal axon increased in diameter (because it was originally shrunk)
Explain Hoffmans study in neurofilament gene expression determining axon size
Looking at the level of NF68 mRNA, which were reduced after nerve crush while the levels of tubulin and actin mRNAs were increased. This was because the cell switched its plan and priority. Aside from this, they too found that there was diminished conduction velocity. Their finding support the hypothesis that the expression of a single set of neuron specific genes (encoding neurofilaments) directly determines axonal caliber.
They also found somatofugal atrophy meaning caliber reduction in the proximal stumps begins near the soma and proceeds distally at the slow axonal transport rate.—> They found that the axon eventually got thinner all along the length but it started to get thinner near the (soma?) and then eventually towards the distal. That’s because the soma stops producing material and stop sending i5 through slow transport axons. So the axons closest to the cell body were depleted first, which then progressed distally