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.