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Overall, there’s no
functional regeneration of axons within the CNS, whereas there is some
regeneration of axons in the PNS.1
In the CNS, proximal
stumps will start to regenerate a few millimetres, however the axons sprout
into the lesion, causing them to stall and form retraction bulbs. On the other
hand, the proximal stumps in the PNS will bypass the lesion; regrowth is
vigorous and long-distance.2,4,10 A significant number of sprouting axons
(PNS) will enter neurilemmal tubes, these lead to motor or sensory terminals,
restoring some function.3 Oligodendrocytes are the cells responsible for
myelinating CNS neurons, and Schwann cells are responsible for myelinating PNS
neurons.1 Figure 1 shows how PNS axons are able to regenerate whereas CNS
axons aren’t. Following Wallerian degeneration of the distal stump (PNS),
axonal sprouts from the proximal segment will enter the distal portion of the
neuron and will grow along the nerve until reaching its target. Schwann cells
are responsible for attracting axons to the distal stump, as well as
remyelinating axons after new, functional nerve endings have been formed.10Schwann
cells align in tubes known as Bünger bands and express surface molecules that
guide regenerating fibres. They also fill the endoneurial tube at the cut end.9,12
Oligodendrocytes die after CNS injury, meaning they can’t remyelinate axons.1
Essentially, there’s two reparative mechanisms occurring simultaneously in the
PNS. Branchlets extend distally from the distal stump, the tips of these
branchlets are known as growth cones. In the distal stump, Schwann cells will
send processes in the direction of the cones. The cones develop surface
receptors that will anchor to complementary cell surface adhesion molecules on
the basement membrane of Schwann cells. Filaments of actin surmounted on the
cones become attached to these points of anchorage, where they’re able to exert
onward traction on the growth cones.13 This process allows for axons of the
PNS to grow roughly at a rate of 3-4mm/day after injury.9 More chromatolysis
occurs in neurons found within the CNS and the PNS neurons survive the process
with greater efficacy; chromatolysis occurs near the nucleus of the neurons
found within the CNS and the periphery of neurons found within the PNS.4
Overall, the differences could be summarised in a simplistic manner: there’s no
functional regeneration of axons within the CNS following injury whilst there
is some functional regeneration within the PNS.

 

It’s fair to say
that it’s an interplay of mechanisms that contribute to these differences.1
The ineffective and aggressive immune response seen in the CNS following injury
is a massive contributing factor to the lack of axon regeneration. The biggest
inhibitor of axon regeneration following injury in the CNS, is the formation of
non-permissive glial scarring.1,13 ECM glial scarring is the result of a
glial reaction that recruits microglia, oligodendrocyte precursors, meningeal
cells and astrocytes.1 Chondroitin sulfate proteoglycans (CSPGs) are the main
inhibitory molecules found in glial scars, CSPGs are upregulated by reactive
astrocytes following CNS damage.4 A review of CSPGs demonstrated that after
CNS injury, CSPG expression was increased, indicating this increased expression
contributes to the non-permissive nature of glial scarring.5 It’s also been
reported that CSPGs’ inhibitory action can be reduced by the enzyme
Chondroitinase ABC (ABC); ABC cleaves glycosaminoglycan side chains attached to
core proteins, further revealing the non-permissive nature of CSPGs in axon
regeneration.4 ECM glial scarring not only provides a physical barrier for
axonal sprouting, but a biochemical one as well, contributing to the cytotoxic
environment.1 Figure 2 shows the non-permissive nature of glial scarring, as
well as the components of the scar. It’s visible that the scar acts as a
physical and biochemical barrier to regenerating axons. The highly vascularised
CNS means that a large influx of immune cells occurs following injury, immune
cells contributing to the non-permissive environment. Cytokines also contribute
to inflammation. The debris produced following injury proves toxic to
macrophages that aren’t able to clear the debris and migrate, like they do in
the PNS. The macrophages then turn into foam cells as they aren’t able to break
down myelin lipid, adding to the inflammation about the injury.1 It’s
understood that CNS axons are able to regenerate when in a permissive
environment, indicating that it’s the non-permissive environment above all else
that inhibits axon regeneration in the CNS, following injury. Oligodendrocytes
express myelin-associated inhibitors, a component of myelin that has been shown
to impair in vitro neurite growth, and are believed to do the same in vivo,
following injury. This class of inhibitor includes but isn’t limited to Nogo-A,
myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein
(OMgp). MAG gets cleared away rapidly in the PNS but not in the CNS. Nogo-A
interacts with the Nogo-66 receptor to inhibit axon growth, Nogo-A isn’t
normally seen in the PNS.4 The CNS has an inadequate pattern of expression of
 neurotrophic growth factors for axon
growth.1 The environment following injury in the PNS is conducive for
regeneration; the immune response is fast and effective and is able to clear
the debris; there’s no inflammation or cytotoxicity. Schwann cells are better
myelinators than oligodendrocytes, and they produce many growth factors.1
Studies indicate that Schwann cell migration to facilitate elongation of axons
is mainly driven by neurotrophic growth factors like NGF, or by cytokines and
laminin, highlighting the importance of the molecular interactions between Schwann
cells and its environment.8 After PNS axotomy, neurons up-regulate
regenerative-associated genes (RAGs), they activate transcription factors that
produce growth-associated proteins. Over-expression of these genes has been
shown to cause neurite outgrowth. CNS neurons don’t express these genes in the
same manner.4 Figure 3 highlights the importance of RAGs and the
myelin-associated inhibitors of Oligodendrocytes in axon regeneration/lack of
regeneration. Along with this, neurotrophins and cell-adhesion molecules are
up-regulated following axotomy.9 Neurotrophins act as dimers that activate
downstream signalling pathways that activate RAGs, promoting survival.11
Overall, the differences in the mechanisms can be understood when looking at a
range of contributing factors, ranging from production of growth factors,
permissive/non-permissive environments and even regulation of gene
transcription.

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During early,
post-natal life, brain circuitry is remodelled in accordance with experience,
so we’re able to adapt to the challenges of the world. It’s important for the
brain to stabilise, so that constancy can be maintained when we’re exposed to
small changes in the environment; we don’t want brain remodelling in all
instances.10. Studies have highlighted parallels between mechanisms
preventing axonal repair and those that limit experience-dependent plasticity.
14 Earlier it was mentioned the Nogo receptor pathway inhibits axonal
regeneration; the pathway also restricts adult neural plasticity.15 It’s been
observed that supressing nogo receptor signalling enhances neural repair; it
can be inferred neural repair involves plasticity.16 Perhaps limited CNS
regeneration is a price to pay for higher intellectual capabilities.10

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