Neural Plasticity And Neurotrophic Factors II: The Central Nervous System
There is now mounting
evidence that regeneration and reorganization can occur in the adult central
nervous system (CNS). However, plasticity in the CNS is probably not due to a
major production of new neurones, as most neurones in the mature CNS are postmitotic,
but to their ability to extend branching new axons. The
time at which this is
most florid is in the early postnatal period when the systems of the brain are
developing, and it is during this time that major modifications can be
made.
The mechanisms
underlying this plasticity are not fully known, but the production and uptake of
factors promoting neuronal growth and survival (neurotrophic factors)
are important.
Plasticity in the
developing visual system In their pioneering studies, Hubel and Wiesel demonstrated that at birth
the input to lamina IV of the primary visual cortex (V1) is diffuse, and that
it is only during the critical period of development (in cats this is up
to 3–14 weeks of postnatal life while in humans it may be several years) that
these inputs segregate and form the basis of ocular dominance columns (see
Chapter 26).
The segregation of input
is dependent on the amount and type of activity within the afferent pathway
from each eye; the greater this is, the more likely it is that the afferent
input will gain control over those cortical neurones. Thus, ocular dominance
(OD) columns will form in the absence of competition between the input from the
two eyes but will not develop when there is no afferent input from either eye.
Hubel and Wiesel
experimentally manipulated the inputs by initially depriving one eye of an
input by suturing it shut (monocular deprivation) and then reversing the
procedure in later experiments (‘reverse suturing’). Monocular deprivation
created an expansion of the thalamic influence from the unsutured eye in layer
IV with a subsequent shift in OD columns so that more cortical cells were under
the control of the open eye. This pattern could be rapidly changed by ‘reverse
suturing’ during the critical period, which implies that the initial shift in
thalamic influence on cortical cells is caused by the activation of synapses
that were present but functionally suppressed as there is not enough time for
any axonal outgrowth. However, in time, the initially suppressed synapses from
the uncompetitive eye would be physically lost as the active thalamic input
takes over the control of cortical cells.
The correct segregation
of the ocular inputs into V1 as OD columns is important for the generation of
many of the other visual functions in V1. However, once outside the critical
period the ability to modify the visual cortex in such a fashion is reduced,
but not lost.
Plasticity in the
adult state
Somatosensory system
and the vestibulo-ocular reflex It is now known that the somatosensory system is capable of being
remodelled in the face of alterations in the input from the peripheral
receptors. Thus, the loss of input from a digit (e.g. by amputation) does not
lead to a permanently silent area of cortex, but instead the adjacent cortical
areas with sensory inputs from adjacent digits would sprout axons and exert
influence over this initially silent cortical area.
Conversely, increased
afferent information in a sensory pathway results in an expansion of the
cortical area receiving that input. Simplistically, it can be imagined that the
activity in a given afferent induces the production of a neurotrophic factor in
the postsynaptic cell, which then binds to the appropriate receptor in the
active presynaptic terminal, promoting its growth and survival. In this way the
CNS is constantly remodelling itself based on the amount and type of ongoing
afferent information.
Subsequently, it was
discovered that major sensory deficits, such as the deafferentation of a whole
limb, produces similar results, which implies that the reclaiming of cortical
areas by adjacent inputs is not solely achieved by the local
sprouting of axons in the cortex.
Occasionally, this
plasticity may go awry in certain situations, such as in dystonia.
In this condition, abnormal plasticity in the primary motor and sensory
cortices is thought to cause abnormal activation of muscles, and this results
in abnormal posturing of a body (see also Chapter 42). A further example of the
plasticity of the mature CNS is seen with the vestibulo-ocular reflex (see Chapters
29 and 40). The vestibular system provides a signal to the CNS on head velocity
and this is relayed to the cerebellum via mossy fibres. However, the other
input to the cerebellum – the climbing fibre – can provide information on the
degree to which the image is slipping across the retina (the degree to which
eye movements are compensating or not for head movement). This input from the
climbing fibre is not only important in providing a signal on the degree to
which the reflex is working or not (i.e. provides an error signal), but also
gives a critical input to correct it. Thus, if one alters the relationship
between ocular and head movements by having the patient wear prisms, for
example, the reflex adapts with time to compensate for the new relationship and
this adaptation is possible because the climbing fibre input can modify the
parallel fibre (and so indirectly mossy fibre) input to the Purkinje cell (see
Chapter 40). The basis for this latter modification at the level of the
Purkinje cell is an intracellular process and is termed long-term depression
(LTD; see Chapter 45).
Neural stem cells
In many adult tissues,
cell loss occurring through natural attrition or injury is balanced by the
proliferation and subsequent differentiation of stem cells. In the adult CNS
this was thought not to be the case, but recent evidence has shown that neural
precursor cells are to be found in the mature CNS of mammals including humans.
These cells are mainly found in the hippocampus and around the ventricles (in
the subventricular zone) and appear to be able to form functionally active
neurones. However, their role in plasticity and repair is unknown, but in the
dentate gyrus of the hippocampus these cells may have a role in memory and
mediating the effects of various hormones (e.g. cortisol/corticosterone) and
drugs (e.g. antidepressants) on CNS function.
Limits on the
regenerative capacity of the adult central nervous system
The regenerative
capacity of the CNS is limited by:
· neurones are postmitotic in the
mature CNS, and the stem cell population is small and localized to certain
sites;
· glial cells in the CNS are generally
inhibitory to axonal out- growth (see Chapter 13).
Astrocytes produce
signals that stop axons growing and oligodendrocytes produce a number of
factors that repel axons or even cause the approaching axonal growth cone to
collapse. Attempts to overcome these inhibitory signals are now entering early
clinical trial in patients with spinal cord damage.
