CSB332 Lecture 5
- Nerves are bundles of axons that are located outside of the CNS.
- Tracts are bundles of axons that are located within the CNS (e.g., spinothalamic tract).
- Ganglia are clusters of cell bodies that located outside of the CNS.
- Do not memorize the cranial nerves.
- Most nerve injuries that you experience are introduced in the spinal nerves.
- The motor neuron axons and the sensory neuron axons fuse together to form the spinal nerves.
The spinal nerve is a combination or aggregate of sensory neuron axons and motor neuron
- A cross-section of a spinal nerve contains a lot of bundles. This slide is depicting one bundle. This
is a collection of the axons. The red areas are blood vessels. The yellow circles are either sensory
neuron axons or motor neuron axons. The green areas around the axons are myelinating
Schwann cells. All of the axon fibers are collectively called fascicle. Fascicle is a bundle of many
axons. Fascicle is enveloped or protected by an epithelial connective tissue layer called the
perineurium. The perineurium is a protective sheath around fascicles. The area that immediately
surrounds each axon that contains Schwann cells is called endoneurium. Endoneurium is the
protective connective tissue around each axon. The perineurium is the protective epithelial
tissue that surrounds bundles of axons.
- What happens to a severed axon? Will it grow back or will It regenerate? It depends on where
the injury occurs.
- If the injury occurs on a spinal nerve in the PNS, it will most likely regenerate, but it has to
undergo certain cellular events before regenerating. The sequence of events that comes after
axotomy is called Wallerian degeneration. Wallerian degeneration pertains to degeneration and
regeneration that comes after degeneration.
2) Wallerian degeneration
- Consequences of spinal nerve injury:
Most often, sensory impairments and motor impairments (e.g., paralysis) go
hand in hand because the sensory axons and the motor axons are bundled
together within a fascicle within the spinal nerve. When you injure the spinal
nerve, then most often you are injuring sensory fibers and motor axons.
o Fasciculation and fibrillation
Usually benign. However, if recurrent and associated with other major
symptoms, then it could underlie severe damage to the nerves.
- Muscle fibers tend to become overactive when motor axons are denervated. Slide 6
- The events that describe Wallerian degeneration:
o The distal region of the axon fibers degenerates rapidly.
o The proximal end of the axon that is closest to the cell body degenerates a little bit.
o In response to the injury, the immune system is activated. Macrophages delivered by
blood capillaries, including microglia, would approach conglomerate in the lesion site.
Macrophages are scavenger cells that clear up the debris that is left by the
degeneration of the axon, including some disconnected myelin sheaths. Macrophages
invade the site of lesion and clear out the lesion site from debris left by the
degenerating axon and by the degenerating myelin sheaths.
o The cell body undergoes chromatolysis. Chromatolysis refers to injured neurons
losing its ability to stain purple with a basophilic staining method. Basophilic stains are
basic dyes that, when applied to a neural tissue, would stain mainly cell bodies. They
react to acidic components of the cell, which are RNA, DNA, and nucleic acids that are
mainly located in the cell bodies. Ribosomes and RER have a lot of acidic components.
In response to a basophilic stain, you would stain the cell body with a purple or
blue colour. The substances that is used for the stain reacts with the RER and
ribosomes in the cell body that are enriched with nucleic acids.
In an injured neuron cell body, the neuron loses its ability to be stained by the
basophilic stain. This indicates that the integrity of the RER and mRNA in
ribosomes is degenerated.
- The distal segment of the axon will degenerate, along with myelin sheathes that wrap around it.
- In response to the inflammation resulting from the lesion, macrophages (coming from the blood
stream) and microglia (immune cells that are within the brain) will invade the site of the lesion.
They will clear out the remnants left by the degenerating myelin and distal region of the axon.
o Inflammation is an active, pro-growth process.
o Acute inflammation is a protective process. Acute inflammation is able to activate the
macrophages to clear out any debris that would get in the way of the regrowth of the
axons. You have to clear out the debris so that once the denervated axon
degenerates, it can smoothly go through the region and synapse with the original
o Macrophages and microglia also functions to stimulate the dedifferentiation of
Schwann cells, which happens later on during regeneration. Once invading
macrophages reach the site of the lesion, it will release cytokines that will signal
Schwann cells to dedifferentiate. The Schwann cells will go into the precursory mode
and be able to multiple. They will proliferate in response to the cytokines released by
o Later on, the cytokines will also induce the Schwann cells to synthesis BDNF and NGF
(which are growth factors that are able to stimulate the growth of axons and
stimulate the development of a cell). LIF is released by the invading macrophages,
stimulates the synthesis of BDNF by Schwann cells. BDNF and NGF are released by
Schwann cells and bind receptors that are located on the cell membrane of the
Schwann cells. BDNF and NGF are held on the plasma membrane of the Schwann cells
(the same Schwann cells that synthesize and release BDNF and NGF). o Later on, during regeneration, Schwann cells will proliferate and have BDNF on the
plasma membrane. Schwann cells that have BDNF on the plasma membrane are able
to guide the regenerating proximal region of the growth cone.
o Macrophages also stimulate the proximal region of the axon to release another
signalling molecule called Reg2. Reg2 is able to guide the growth cone along, to
sustain the health of the growth cone, to stimulate and contribute to the signaling
that allows Schwann cells to synthesize BDNF.
o Reg2 and LIF stimulate the synthesis of BDNF by Schwann cells.
- Wallerian degeneration usually continues to proceed without any interference in the PNS (e.g.,
- Muscle fibers and postsynaptic cells also synthesize BDNF and NGF. BDNF and NGF synthesized
by the muscle fiber will not be able to reach the cell body because BDNF has to travel through
the axon terminals. BDNF binds receptors on the plasma membrane of the axon terminal. BDNF
is carried by axoplasmic transport back into the cell body. BDNF in the cell body will synthesize
proteins that are responsible for the maintenance of the structure and the health of the neuron.
If you denervate the axon, then the cell body is unable to pick up the BDNF released by the
postsynpatic cell (myofiber).
o The consequences of not being able to accept BDNF:
The cell body bloats, and then shrinks. Atrophy.
The nucleus will get displaced and translocated to an eccentric area of the cell
body. Initially, the nucleus is located in the center of the cell body, but in
response to axotomy, the nucleus will get displaced and will be found close to
the edge of the cell. The translocation of the nucleus indicates that some
regenerating process is happening within the cell body. The nucleus is located in
the periphery of the cell body. The nucleus is located at the center of the cell
body in a normal neuron.
The Nissl bodies in the cell body denote the aggregate of RER and ribosomes.
Nissl bodies are rich in ribonucleic acids. Axotomy will result in some degree of
degeneration of the Nissl bodies and dispersal of the remaining Nissl bodies.
An indication that Nissl bodies are dissolve would be apparent if you observe
the cell under a basophilic stain, which would stain the Nissl bodies
purple/violet. A cell that has undergone axotomy would result in the loss of the
purple/blue stain, indicating that Nissl bodies have dispersed and some have
degenerated. This process is called chromatolysis (loss of color).
- Macrophages do two things: (1) clears up the debris, and (2) releases cytokines (e.g., LIF). LIF
stimulates the dedifferentiation and proliferation of the remaining Schwann cells in the
endoneurial tube. LIFE stimulates the Schwann cells to synthesize BDNF. BDNF is important for
the guidance of the growth cone within the intact endoneurial tube back to its original synaptic
connectivity with the muscle fibre.
o Wallerian degeneration will undergo completion rapidly if the endoneurial tube is
intact (e.g., when the nerve is crushed). If you sever the fiber and the endoneurial
tube, then the Schwann cells will spill out. It will not be effective to guide the growing
growth cone back to its original target. If the ends are totally far apart from each
other, then the axon would have to leave the endoneurial tube of the distal region. If
the growth cone of the axon leaves the endoneurial tube, then you won’t find any
Schwann cells in the vicinity. There will not be any Schwann cells or any molecules
released by Schwann cells to guide the growth cone back to its original target.
Two scenarios: The growth cone can travel a few millimeters and then stop.
There are postsynpatic cells (e.g., muscle fibres) within the vicinity, so
the growth cone will synapse with the closest muscle fibre. It will not be
able to synapse with its original muscle fibre target.
- LIF stimulates the release of Reg2. Reg2 stimulates the Schwann cells to proliferate and to
- In response to the slowly degenerating cell body of the axotomized neuron, the presynaptic
axon terminals undergoes synaptic trimming. Inputs of healthy neurons that synapse with the
degenerated cell body slowly retracts and recedes from the area of innervation of the cell body.
o Why do axons retract away from degenerating cell bodies?
If the cell body is undergoing degeneration, then there will be a decrease in the
synthesis of growth factors, BDNF and NGF, which help to sustain the health of
the presynaptic axons.
- If Schwann cells become successful in their proliferation (stimulated by macrophages) and are
able to synthesize BDNF, then BDNF is able to maintain the health of the growth cone and to
guide the navigation of the growth cone within the endoneurial tube back to its original muscle
- The basal lamina or the endoneurial tube (connective tissue that ensheathes a single axon)
must be intact for complete Wallerian degeneration to take place. The completion of Wallerian
degeneration terminates in the actual re-growing back of the axon and the synapsing of the
axon to its original muscle fiber target.
- These are the events that happen in the postsynaptic cell (e.g., muscle fiber) in the spinal
nerves. In response to a denervated axon, the muscle fiber undergoes supersensitivation. The
muscle fiber becomes supersensitive to stimulation by ACh and supersensitive with the absence
of ACh. The muscle fiber generates action potentials by itself, even without ACh to activate the
receptors on the muscle fibers. This explains why muscle fibers undergo fibrillation and
- (A) Fetal form of a single muscle fiber.
o Fetal form contains cholinergic receptors. The cholinergic receptors and the mRNA of
the cholinergic receptors are in an embryonic form. The embryonic form of
cholinergic receptors is different from the subunit composition of the adult form of
cholinergic receptors. The embryonic form of cholinergic receptors is composed of
two alpha subunits, one beta subunit, one delta subunit, and one gamma subunit.
During fetal development, the fetal form of cholinergic receptors are seen
everywhere in the muscle fiber and start to concentrate on the motor endplate
(postsynaptic region of the NMJ; opposite to the presynaptic axon). During embryonic
development, muscle fibers express the fetal form of cholinergic receptors along the
entire extent of the muscle fiber.
- (B) Adult form of a muscle fiber with axons coming from motor neurons.
o The adult form of cholinergic receptors on muscle fibers consists o