Lecture 3: Self-Repair Capacity of Peripheral Neurons Flashcards

1
Q

What factors determines the size of axon diameters

A

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

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2
Q

Why cats have larger axon diameters than humans?

A

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

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3
Q

Practice Question: What are typical conduction velocity ranges for human motor and sensory axons? How does CV scale with axonal diameter?

A

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

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4
Q

What are specialized transport systems?
What provides transport mechanisms?

A

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)

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5
Q

List the fast axoplasmic transport

A
  • Fast Anterograde Transport
  • Retrograde Transport
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6
Q

Describe fast anterograde transport

A

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)

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7
Q

Describe retrograde transport

A

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.

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8
Q

Describe slow axpolasmic transport

A

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

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9
Q

Describe slow axoplasmic transport

A

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

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10
Q

Why is the rate ~1mm/day in slow anterogade transport significant?

A

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

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11
Q

What did Ramon y Cajal infer about axonal growth and development

A

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.

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12
Q

What are the three most common ways in which nerve can be mechanically damaged?

A

(Increases in severity)

  1. 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
  2. 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)
  3. 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.
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13
Q

What are other sources of injury that not traumatic injury

A

Interruption of blood flow (indirect damage)
Degenerate diseases ie, affect myelin, multiple sclerosis

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14
Q

In a 3 neuron set up, one has a leison along the length of the middle axons, what happens in response

A
  1. The proximal part of the axons still connected to the cell body survive but suffers
  2. Distal portion that gets disconnected by the cell body degenerates/ Loss of axonal structure distal to the leison
  3. Myelin degenerates leaving debris (myelin “ghost”)
  4. The synaptic terminal degenerates (distal to the leison) which then has implications on the postsynaptic cells
  5. 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.

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15
Q

What does the latent period of variable duration in terms of axonal regeneration depend on?

A

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.

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16
Q

How does the cell body know it needs to take action after injury

A

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?)

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17
Q

What 4 things happen to the proximal axons when there is an injury and why?

A

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

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18
Q

Explain Hoffer’s research in determining what happens to the proximal axons size after a peripheral injury

A

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

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19
Q

Explain Hoffer’s research on injured sensory and motor axons

A

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)

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20
Q

Explain Hoffmans study in neurofilament gene expression determining axon size

A

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

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21
Q

What happens to myelin after nerve injury

A

Gillespe research gound that the shape of the axons changed after nerve transection. They found axons of different shapes, i.e., fully squished , or partially squished axons, however they found the thickness of myelin remain unchanged, (axon got thinner because the lumen of the axon got emptied reducing its conduction velocity).

22
Q

What is the history of the process of nerve regeneration

A

Cajal 1928, questioned how does the axon know where to grow? Hence he hypothesized that in the PNS, there must be some kind of guidance factors for regenerating axons and that these factors are supplied Schwann cells (axons grows through the ghost of myelin sheath) and that there were growth factor

Levi-Montalcini 1950s discovered Nerve Growth Factor (it was the first of several NGF)

Barde 1988 discovered a factor that acts on different nerve cells than NGF caller “brain derived neurotrophic factor”

Currently, the term neurotrophin is used as a synonym for neurotrophic factors but is generally reserved for:

  1. NGF
  2. BDNF
  3. Neurotrophin 3
  4. Neurotrophin 4

These are species specific. Different types of neurons responds to different types of neurotrophic factors, ie NGF specific to afferent nerves (not motor nerves)

Above are example of chemical guidance

23
Q

Practice question: What two mechanisms did Ramon y Propose were need to to support successful regeneration?

A

Mechanical Guidance
Chemical Guidance

24
Q

How do nerves grow and innervate muscles during development

A

During development, growth cones at the tips of nerve fibers navigate through the cellular environment, detecting signals from other cells or proteins in the extracellular matrix. These signals guide the growth cones along specific pathways, such as existing muscle planes, promoting nerve growth. As the nerves extend, they first innervate proximal muscles and continue growing until they reach more distant, immature muscles that have not yet been innervated. In this way, nerves systematically travel down muscle fibers and across the body, ensuring that every muscle is eventually connected to the nervous system.

may need some clarity

25
Q

What are cell adhesion molecules ?

A

A type of promoter, when cells touch CAM on their surface stick

26
Q

How do Schwann cells contribute to nerve regeneration after injury, and how does this affect axonal function?

A

Schwann cells & other peripheral cells elaborate signals that promote and guide axonal growth

Axonal sprouts from the proximal nerve stump may enter the distal nerve stump & grow towards target end organs

Once there is successfully regeneration, the schwann cell will remylinate regenerating axons. The myelin will never get thick as the original one so the myelinated axon will have less myelin and will not conduct at the same old velocity

27
Q

What happens when there is a successful axonal regeneration?

A

There are many sprouts, but only one will be the surviving one.

If and when a suitable connection is made distally, the cell body will find out and axon will gradually increase its lumen along its entire length.
Extrasprouts that did not make connections are withdrawn and usually one will be ariving to the muscles

28
Q

What happens when there is a successful axonal regeneration?

A

There are many sprouts, but only one will be the surviving one.

If and when a suitable connection is made distally, the cell body will find out and axon will gradually increase its lumen along its entire length.
Extrasprouts that did not make connections are withdrawn and usually one will be arriving to the muscles

29
Q

What happens with unsuccessful axonal regeneration?

A

Axonal sprouts can easily lose their way. Processes often grow down blind alleys or in inappropriate directions and cannot find suitable end-organs.

It may take years for axons to give up, they are persistent, they keep looking for a target. When axons don’t make it that leads to neuroma formation

30
Q

Practice question:
What is a neuroma? Where does it develop? Why does it develop? Why is this often a problem?

A

Neuroma is a tangling of fibers of nerve ending and fibers tissue. Creates a bulging end to a peripheral nerve that is not able to grow

Sometimes you have a neuroma along a nerve, because part of the axons were successful in regenerating, but others are not, so it makes a local neuroma

Neuromas are painful because some of the fibers the innervate the neuroma are pain fibers and pain fibers are “happy” in fiberous tissues because they don’t have end organs (?) They are usually free nerve ending that attach to neuroma

Vibration, changes in temperature, movement then it may sent shooting pain.

31
Q

What causes phantom limb pain and how do neuromas form in amputees

A

Shooting pain happens to amputee. Peripheral nerves with dead end have neuroma

They have phantom pain. It is interpreted from coming from the missing limbs where fibers used to connect

In amputee, the surgeon tie up the nerve in an attempt to inhibit pointless axonal regeneration but since the growth cones are very persistent, so they double up and will start going back inside the nerve sheets, hence it’s difficult to prevent to neuroma formation

32
Q

How does surgical intervention aid nerve regeneration, and what are the key factors for successful nerve repair?

A

We want to make the task of regenerating as simple as possible for a nerve, so if a person has a nerve damage, sometimes surgical innervation can help repair the site and make it better for the nerve to regenerate successfully.

Two things must happen
1) the natural process of the body uses to repair itself has to proceed
2) the appropriate functional connections need to be made
(Because ie if a nerve goes down “the wrongs highway” and ends up “successfully” innervating an ie antagonist muscle, the brain will have a hard time with controlling. It may be able to but it has to learn how to deal with this.

33
Q

Describe what happens there’s a gap between two ends of a nerve

A

If the gap is small (mm or so) then due to nerves elastic nature (they change length all time). They will be able to stretch and connect

If there is a long gap, a gap with more than a few mm, you cannot just stretch those nerves to bring the close to each other. At this point, you need to provide a bridge to fill that gap so that nerve axons will grow through and enter the otherside

34
Q

Give an example of when surgical realignment suturing can be used

A

Surgical realignment suturing
Nerve completely cut, two portions of the nerve turn in respect to each other and then those fasicles are not aligned lead to poor function, although regeneration can occur, so we want peripherally realign the nerves so the fasicles are normal aligned

35
Q

If there’s transacted median nerve (supply’ first three fingers) at the level of the wrist, what may be (surgical solution]

A

Soultion; decompressed the area by cutting a ligament, allowing more access to the median nerve. Then, you want to align individual fascicles (surgical realignment suture) to ensure that fingers function properly)

36
Q

What is one operation you can do if the ulner gets damaged

A

Ulner nerve, which is very superficial, it runs along the elbow and can get easily damaged

One common operation is to decompress, to give more slack to the nerve by taking it out of the pathway and making is a shorter pathway, so you can bring the ends together more easily and suture them

37
Q

Give an example of peripheral nerve autograft

A

When a nerve is compressed, you may cut it to get a fresh end of the nerve because growing nerves would have had a hard time going through this compressed portion.
But if there’s a long gap, you need to provide a bridge, and the best material is a nerve from some other part of your body, ie the sural nerve (in the distal leg), you can use piece of that nerve to fill the gap. However, the media nerve is much larger, so you will need several sural nerve side by side, this is called graft

With this procedure only a small number of axons (~10%) may make functional and physiologically correct connection, however at least there is some functional recovery

38
Q

What is an autograft?

A

Often the graft of choice is an autograft formed by a segment of donor nerve that is removed from another part of the body.

39
Q

What are some disadvantages of an autograft?

A

-need for an additional surgical procedure in another location
- limited availability of donor nerves, might not be enough if you have a larger cross-sectional area nerve to repair (however you can still access the other legs sural nerve)
-permanent denervation at the donor site

40
Q

Why is there not a high success rate in autograft

A

due to the fascicular exchange, which is the rearrangement of nerve fibers along the length of a nerve, it’s difficult to ensure that the axons grow into the correct pathways.

Even when you use nerve grafts, like sural nerve grafts, to bridge a damaged nerve, the axons may not always find their original target due to this misalignment. This is one reason why nerve regeneration surgeries don’t have a 100% success rate—many axons may regenerate but end up misrouted, leading to improper innervation of the organs or tissues.

The fascicular exchange complicates the repair because it involves sorting fibers within the nerve that align based on their destination. This process is hard to replicate artificially, meaning that some axons may grow through a graft but fail to connect with their intended target, resulting in partial or incorrect functional recovery

41
Q

Explain allograts

A

If the autograft are not available, then allografts can be used, i.e., another living species, a cadaver, different animal species.

If you treat a nerve in such a way that makes it less likely to produce an immune response, then you will have a better success

42
Q

What biological materials have been used as conduits for nerve regeneration, and how successful are they?

A

Autologous blood vessels and muscle fibers have been used as
conduits (for nerves to go through), but with varying levels of nerve regeneration success

43
Q

How do synthetic materials like collagen tubes impact nerve regeneration, and what factors affect their effectiveness?

A

You can use synthetic material such as collagen tube as conduits.
- The size of the tubes and the permeability matters: regenerative capacity can improve with more permeable tubes (pore
size 80-100 nm) compared to semi-permeable tubes (pore size 22 nm). You want permeability so that it can reach the nerves
- quality of nerve regeneration increased for tubes with intermediate in-vivo degradation rate

44
Q

How has the use of nonabsorbable synthetic tubes, like silicone, evolved in medical implants, and what improvements have been made to reduce complications

A

Nonabsorbale synthetic tubes such as silicone (rubber?) used a synthetic conduit. It is a really good implantable material where the body doesn’t react badly to. In the past it was failed, but today it doesn’t contain liquid silicone material. In the past if the silicone was puncturd the liquid material would infiltrate the body, get into the cell, and cause pain. Now the silicone bag is filled with saline solution, if it burst it won’t hurt you

Nonabsorbale is not necessarily a good thing, because some weeks after the surgical implant for the nerve to regenerate, you really want it to go away, because if not it is constraining the ability of the nerve to grow back out and it too tight, and the nerve can compress itself trying to grow inside this tube. So this silicone have to be remove via another surgery

45
Q

Why are bioabsorbable synthetic tubes a better choice?

A

bioabsorbable synthetic tubes made from polyglycolide, this can get digested inside in the body and there non toxic: so they last as long as you need them to and naturally go away

46
Q

Benefits of artificial graft

A

Artificial grafts can provide directional guidance to prevent neuroma formation, reduce cellular invasion and scarring of the nerve (if scars are produced then the nerves has to fight scars tissue in its way and prevent recovery), prevent branching, and concentrate neurotrophic factors.

47
Q

Working on a q

A

Silicone tubing placed around a nerve, if there’s a big gap, you can dope it with fluid and make sure fibrin, fibroblast cab get there, and swchann cells are available for regenerated

48
Q

List the 5 phases of the regenerative sequence

A

Regenerative sequence occurring within a hollow NGC occurs in five main phases:
(1) the fluid phase: plasma exudate fills the conduit resulting in accumulation of
neurotrophic factors and ECM molecules
(2) the matrix phase: an acellular fibrin cableforms between proximal and distal nerve stumps and align
(3) the cellular phase: Schwann cells, endothelial cells and fibroblasts migrate (from
the proximal and distal nerve stumps), align and proliferate along the fibrin cable forming a
biological tissue cable
(4) axonal phase: re-growing axons use this
biological tissue cable to reach their distal
targets
(5) myelination phase: Schwann cells switch to a
myelinating phenotype and associate with
regenerated axons to form mature myelinated
axons

49
Q

Explain the hand transplant

A

Donor hand kept frozen, to prevent it from regenerating
Once you bring it back to room temperature, you have to prevent it from going bad so you need to first connect the bloody supply, stich up the veins and arteries. The second thing you need to attach the bones to give it structures. And then the tendons and muscles. Then the last thing to do is reattach the nerves, and then closed the skin again.

The extinisic muscle are available and can do some motion earlier than it takes for the nerve to regenerate to the hand, however the intrinsic musle will take longer because the nerves have to find the right muscles. Some sensations will come back from the proximal reinnervation soon then from the distal fingertips. Gradual and progressive

While Zolfi is no longer haunted by what’s known as phantom pain related to the loss of her lower arm, she now suffers a different kind of
pain caused by the growth of her nerves into the muscles of the donorarm

50
Q

Role of electrical stimulation on peripheral nerve regeneration

A

After an experimental nerve cut and microsurgical repair, brief (1 h) low-frequency (20 Hz)
electrical stimulation (ES) accelerates axon regeneration.
Acceleration with ES is seen for regenerating motor fibers; ES is ineffective for sensory fibers.
• ES contributed an earlier start of regeneration (alerted the cell body that they will be switching from maintain to regeneration) but did not increase the rate of regeneration (limited the capacity for axon to sustain slow axoplasmic transport)
If it’s given for longer (electrical stimulation) it has diminishing returns
And it only works if action potential are generated and travel to the soma, it then kickstart the process of regeneration

51
Q

Role of exercise on peripheral nerve regeneration (in mice)

A

1 h treadmill walking starting 3 days after surgical repair enhanced axon regeneration in male
mice only. Females required interval training (2 min running, 5 min rest, repeated 4x/day).