Plasticity in the adult and neonatal central nervous system.

British Journal of Neurosurgery (1990) 4, 253-264

REVIEW ARTICLE

Plasticity in the adult and neonatal central nervous system

Br J Neurosurg Downloaded from informahealthcare.com by Chulalongkorn University on 01/08/15 For personal use only.

ADRIAN J. BOWER

Department of Anatomy, University of Queensland, Australia

Abstract The adult nervous system is capable of plastic change; studies have shown that plasticity is part of normal adaptation to daily life as well as being part of the response to trauma. The structural substrates of plastic change are described, and the hypotheses for explaining functional recovery in adults following trauma are reviewed. Events in normal brain development are summarized, and experiments designed to investigate the processes involved are described. The brain of the neonate is a much more plastic structure than that of the adult, both in normal development and in response to trauma. Activity in pathways is an essential component for consolidation of connections, whether normal or compensatory. Experiments which elucidate the mechanisms of axonal/target recognition are described. Recent work on the possible development of therapeutic agents to enhance recovery from trauma, in both adults and neonates, is reviewed. An attempt is made to link the findings from basic research to the clinical field.

Key words: Plasticity, neonate, adult, compensato y pathway, melanocortins, glucocorticoids, gangliosides.

Introduction The stimulus for this review is that in the last decade there has been an enormous amount of basic research into brain plasticity and the mechanisms that produce it. Some of the findings have implications for clinical practice. The adult brain is not a fixed, unalterable structure, but is plastic and malleable, capable of profound alterations as a result of changes either to its structure or to its environment. Neurons are post-mitotic, and once destroyed are not capable of regeneration, but this does not mean that they cannot adapt to changing circumstances; they can. Also, any recovery from trauma to the brain is extremely variable, depending on the timing and extent of the injury, but this does not mean that neuronal connections cannot adapt; they can. There is now good evidence that reorganization of neuronal circuitry after trauma is the rule rather than the exception. The brain is capable

of changes, both during development, whether pre- or post-natal, and after normal development is complete. Such changes, either in neurons or in their connections, are given the general term of plasticity. For the purposes of this review plasticity is defined as changes that occur in neuronal anatomy, physiology or biochemistry in response to alterations to those neurons or their environment. These changes may be the result of normal development, or as part of everyday living, or due to pathology, trauma and experiments involving the nervous system. The changes are not random, but are extremely ordered in an attempt to adapt to the new circumstances. There are two areas of particular interest. One is the considerable amount of work being carried out on plasticity in the adult brain. Plasticity in the neonatal or embryonic brain has long been acknowledged and researched, but adult plasticity is a relatively new area.

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The other area of much research activity is the effect that various chemical agents have on the speed of growth and the quality of new connections. The results are very exciting and promise new advances in the treatment of brain trauma. Plasticity in the central nervous system (CNS) is such a vast subject, with many books written about it, that this review cannot cover all the aspects and developments that have occurred. Therefore, my aims are (1) to present the evidence for plasticity in the adult brain; (2) to review some of the evidence for neonatal plasticity and how it differs from the adult, and (3) to show how basic scientific research into plasticity and its mechanisms may have a bearing on clinical practice. The aim in the various sections will be to present the work which may explain the phenomena seen by clinicians in patients recovering from CNS trauma. I do not propose to cover regeneration and plasticity in the peripheral nervous system. This is well known and is outside the scope of this review.

Adult plasticity

Plasticity in vestibulo-ocular reflexes It could be said that a series of classical experiments first showed that the adult CNS is capable of plastic changes in response to an altered input. These are the experiments in which human volunteers wore prisms which reversed the visual field.' At first the volunteers were not able to walk or react properly because they found it impossible to interpret their visual input. After a period of several weeks the visual image was seen as being the right way round. The correction was so good that the volunteers were able to take part in sport, or one volunteer was able to ride his motorbike around town! This compensation must have entailed changes to the synapses somewhere in the visual system, and it is probable that they involved morphological alterations. This is indicated by the fact that the plasticity was long term, because when the

goggles were removed it took a further period of time before the visual field reverted to normal; in other words removal of the goggles had the effect of reversing once more the visual image. Therefore we can conclude from this that input to, and activity in, synapses is important in the generation of plastic changes in the CNS. The fact that when compensation for the goggles occurred, the volunteers were able to take part in sport must also mean that the vestibulo-ocular reflexes (VOR) had altered. With the visual fields reversed, the normal V O R would be opposite to that required for retinal image stabilization. Therefore, for the images to have been stabilized to an extent which allowed sport to be played, plastic changes must have occurred in the VORs.This phenomenon has been investigated in more detail by Melvill Jones: who used a series of human volunteers and animal models, all involving image reversal and measurements of the changes to the VORs. Since then, plasticity in the V O R has been the subject of further research, much of it involving manipulations to the vestibular, rather than the visual part of the VOR. The results illustrate some of the difficulties in interpreting basic research in clinical terms. The choice of experimental animal seems to be important. Squirrel monkeys will recover full V O R again following unilateral plugging of the semicircular canals.) On the other hand, rabbits show no recovery of function following unilateral labyrinthect ~ m y In . ~cats some do and some do not show recovery,5 which is also found in humans who have had resection of an acoustic neuroma.6 Experiments with primates indicate that visual input and therefore activity within the system is an essential part of the recovery process. Animals kept in the dark after unilateral labyrinthectomy did not display the same degree of recovery as those which were exposed to light after the operation.' Because removal of an acoustic neuroma is a relatively common operation, and because alterations to V O R input can be undertaken in a noninvasive manner in both animals and humans, plasticity in the V O R is one of the few areas

Plasticity in the central nervous system


where experiments (animal and human) can be compared with clinical findings. When such comparisons are made, they show that basic research on animal models can be used to understand processes occurring in humans. Unfortunately it is not possible to obtain any data from humans about the structural correlates of VOR plasticity, and there does not appear to have been much research in animals on this aspect.

Memory As can be seen from the preceding section, input to, and activity in, synapses can cause plasticity leading to changes in function in the CNS. However, little information has been obtained about the structural correlates of neuronal plasticity. One area of research which has produced much information about structural changes to the neuron and its synapses in plasticity, is that involving memory. Memory is one of the most obvious examples of what can legitimately be called plastic changes in the CNS which occur as a result of altered input, and is such an everyday event that it is not often thought of in these terms. In order to be able to establish memory in such a form that it may be retrieved when needed, there must be alterations to the neurons involved; either in their morphology, including the structure of synapses, their connections, their biochemical and physiological characteristics, or a combination of all these features. Modern research using a variety of animal models from aplysia to cats is beginning to show that alterations in ionic channels are part of the processes of memory formation. It is now quite clear that definite structural changes occur to synapses during the process of memory acquisition.s-’O A key event is an activation-induced entry of calcium into the pre- and post-synaptic nerve terminals. This activites protein kinase C, which in turn forms new proteins involved in synaptic synthesis.11v12This matches earlier evidence that if protein-synthesis blocking-agents are given during a learning task, then memory is not laid down.I3

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Further confirmation of the structural nature of memory learning is that the number and sizeeJ4 of synapses change as a result of the learning process. Following repetitive neuronal activation or visual training, an increase in synaptic number has been o b ~ e r v e d . ’ ~The J~ opposite effect has also been reported; underuse of the brain leads to a reduction in the number of synapses,. This has been observed in Down’s syndrome children,” and in animals exposed to lead.’* This latter finding is interesting because lead is a powerful inhibitor of calcium activity.

Reorganization mechanisms in the CNS As has been shown in the previous two sections, the CNS can modify its organization as a result of trauma, e.g. within the VOR, as well as in response to normal activity, e.g. memory formation. Whatever the mechanism underlying plasticity within the CNS following trauma, it does not involve regeneration of the damaged neurons or axons. As far as I know, there is only one paper which claims to demonstrate regeneration of the damged CNS axons them~elves.’~ Therefore other explanations must be sought to account for restoration of function. One possibility is that the restored function is carried out in more than one area of the brain, and any disability is very temporary while reorganization takes place. A second is that other areas of the brain may take over the “lost” function. This is seen when the speech area is lost in young children and the right hemisphere takes over speech function.20 A third possibility is that there is growth and adaptation within the remaining structure to compensate for what has been lost. Most of the work in this area has been carried out on animal models where the experimental lesions can be finely controlled in terms of site and extent (in contrast to the random nature of human pathology). Also, results of microanatomical changes can be studied more easily because the brain tissue can be better preserved. Interested readers are referred to Ref. 21.

The kind of neuronal reorganization, as


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opposed to the extent, will depend on the completeness of the lesion. For example, in cats, the subsequent functional recovery of limb movement after partial lumbar dorsal rhizotomy is quite different from that found after complete dorsal rhizotomy.22 The implication of this is that the CNS has more than one way to achieve functional compensation, and the one chosen will depend on the severity of the lesion. There have been reports which show that in some systems central neurons which have lost their normal input may be able to respond to alternative information. Normally, the somatosensory system is the experimental model, with digit amputation or nerve crush as the deafferenting lesion. Reorganization of neuronal responses following such deafferentation have been seen at all levels within the system, the dorsal horn of the spinal cord, the thalamus and the cerebral cortex. One of the most interesting findings is that it is possible for the reorganization to be “instantaneous”, although the normal finding is that deafferentation is immediately followed by silence of the affected neurons. Only later is activity seen in those neurons which respond to other areas of the body not normally associated with those neurons. Possible mechanisms of reorganization are discussed below.

transport for repair processes. This seems an extraordinary waste of energy for something that is not normally used. It is difficult to believe that such synapses are present just in case something happens to the CNS to render them necessary! However, Calford 81 Tweedale24have reported immediate changes in the somatotopic map in the somatosensory cortex of the flying fox following digit amputation. This would indicate that some plastic changes have such a rapid time course that growth of other connections is excluded as an explanation. It may be that in these “instantaneous” changes it is a loss of tonic inhibition to the now active synapses which is the reason for their emergence from “hibernation”. However, this still does not account for their existence.

Somatotopically inappropriate synapses. In contrast, there has been a series of papers which have shown that the time course for a cortical area, which has lost its normal input, to respond to a totally different peripheral input is six weeks. The somatosensory (Sl) cortex can and does undergo reorganization after nerve crush, ligature or digit amputation. This reorganization can occur in both primates and sub primate^.^^-^^ (It should be pointed out that it has recently been proposed that the flying fox should be considered to be a primate.) Such reorganization has also been Normally ineflective synapses. In 1977 Wall shown in the SII area of the cerebral One possible explanation of the above represented a paper to the Royal Society describing the existence of ineffective synapses and sults showing plasticity in the adult CNS the circumstances that unmask them.23 The following trauma has been provided by Snow thrust of the report was that there are synapses and his colleagues. They have shown that in which are normally silent, but which can the spinal cord of the cat, 42% of the collaterals respond to inputs if the normal pattern of of the different fibres of the hair follicles are afferent activity is disrupted. This was pro- somatotopically inappropriate to the area in posed as an alternative mechanism to sprouting the dorsal horn grey matter in which they of collateral axons, or opening up polysynaptic terminate.30 They postulate that, following pathways as the means whereby plasticity of single digit amputation, the somatotopically connections was achieved in adult brains. One inappropriate collateral axons sprout, thus of the problems of the hypothesis is the becoming powerful enough to cause a postdifficulty of corroboration. Another is deciding synaptic potential in the neurons on to which Such inappropriate collaterwhat is the purpose of such ineffective they te~minate.~’ therefore this synapses in the normal brain. In order to als exist throughout the ~ystem;~’ remain viable, the axons with these ineffective mechanism could also explain the reorganizasynapses must have the full range of axonal tion seen in the cerebral cortex following digit


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amputation. So although they seem to agree development of the CNS which involve plastiwith Wallz3that there are ineffective synapses, city. they disagree in that they consider that such synapses have to sprout in order to become Proliferation. More neurons are produced for effective. any given area of the brain than are present in In summary of the above section on adult the adult animal. Exceptions to this are the plasticity, it is clear that plasticity is a real locus coeruleus and some of the pontine event in the adult brain. It is more common nuclei:3 although some of the areas in the than usually supposed and the type of recovery CNS with large numbers of neurons have not depends on the system affected and the size of yet been examined.34There would appear to be the injury. It is also clear that plasticity a patterned programme of cell death which depends on activity in the remaining pathways ensures that the adult CNS has the right and s y n a p s e ~ ; ~ Jtherefore ~,~' passive treatment number of neurons. Neuronal death is not of patients with pathology or trauma, whether disordered, but is so arranged that, in any given accidental or elective, should be avoided. area, there is a balance between production and There are contradictions and controversies loss. Within any system, the number of neubetween different groups working on different rons which survive is related to the size of the animal models, but they all agree that the adult target to which their axons project. If the size brain is a highly adaptable and plastic strucof the target is increased then the number of ture. surviving neurons projecting to it also inc r e a s e ~ .There ~ ~ is competition between the axons of different neurons for post-synaptic Neonatal plasticity target sites; the losers die. The final number of Although the adult CNS is capable of adapting neurons is therefore a complex interaction to alterations in its circumstances, by far the between the production by precursor cells and greater degree of plasticity is seen in the the neuronal/target interplay by the neurons developing nervous system. This plasticity so produced. (It is now generally accepted that may be part of the normal developmental the apparent loss of neurons throughout life is processes of the CNS, or it may be in response an artifact of the counting methods used, to experimental manipulations undertaken to which did not take into account changes in the investigate some part of the maturing CNS. size of neurons occurring during life.36-38See The usual reason for manipulating the neona- also d i s c u ~ s i o n . ~ ~ ) tal CNS, is to understand better the normal neuronal development. The findings may have Migration. It is a truism that all neurons in the important lessons in the way the neonatal CNS are produced at sites distant from their nervous system adapts to pathology or trauma. eventual adult location. Therefore the neurons The neonatal brain is not a miniature adult must receive a signal to start migrating, brain, it generally has more and different information about the route to follow, and know connections and more neurons. Therefore the when the destination has been reached. The next part of this review will be a brief signals that are used for these three processes recapitulation of some of the events that occur are still not understood. There is much evidence in the normal development of the CNS, most that the route for migration is shown by radially of which involve some kind of plastic change, orientated glial although this cannot either permanent or temporary. explain the guidance of, for example, the precursors of the inferior olive traversing the brainstem:' or the precursors of the external Features of the normal development of the CNS granular layer of the foetal and neonatal There are several features about the normal cerebellum travelling to their destination.


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Establishment of connections. In many areas of ences, e.g. malnutrition and hormone imbathe brain, transient pathways, which usually lances. They can also be manipulated in order degenerate by the third postnatal week, have to understand further the mechanisms which been demonstrated. Examples of these are: the produce the normal adult CNS. However, it is visual system has transient connections still not resolved, whether or not the events that govern normal embryogenesis and develthrough the corpus c a l l o ~ u m ; ~the ~ *pyra~~ midal tract arises, for a short time postnatally, opment of the CNS, are the same as those that from the visual cortex as well as the normal govern plasticity seen in response to pathology, sites of rigi in;^^,^^ the olivo-cerebellar path- trauma, or altered inputs. The section below way, normally crossed and unilateral, has, in will describe some of the many experiments, on those from which general the neonate, an ipsilateral c ~ m p o n e n t ; ~ ~ ,concentrating ~' there is a transient projection directly from the rules about CNS development may be decerebral cortext to the c e r e b e l l ~ m .The ~ ~ duced. purpose of these transient pathways is unclear. It may be that their elimination has a role to Expm'mentally induced plasticity play in the shaping of final adult topography,45,49especially since the elimination is of Activity related changes. One of the classic collateral branches of the normal system, examples of experimentally induced plasticity rather than death of neurons giving rise to the is that seen in the ocular dominance columns of abnormal This latter hypothesis the visual cortex. When the physiological may not be true of all systems; for example, the responses of the cells in the visual cortex are elimination of the transient olivo-cerebellar studied, it is found that cells respond maxipathway may be due to neuronal death in the mally to one eye or the other, with a few cells inferior olive.52 It is interesting to note that responding to both.46 The neurons that remany of these pathways have an ipsilateral spond to a given eye are arranged in columns projection in a normally crossed system. This which are called ocular dominance columns. If an animal has an eye-lid sutured in the may be of importance in view of the changes first few weeks of life, changes are seen in the that can be seen following elimination of arrangement of the ocular dominance columns. normal pathways in different systems, vide Eye-lid suture is used rather than enucleation infia . because then problems of transneuronal degenMaturation. Maturation does not usually occur eration do not occur. The principal change that before migration has taken place. Therefore, occurs is that the ocular dominance columns once neurons have arrived at the correct place, from the unsutured eye expand and take over and the right number has been established, the the territory of those columns from the sutured process of maturation can begin. Before it can eye. This has been demonstrated both physio. ~ ~the expansion become a useful, functioning unit within the logically and a n a t ~ m i c a l l yFor to occur the suturing has to be carried out CNS the neuron has to acquire its correct within a certain specific time. In kittens this is morphology, and its physiological and biochefrom the fourth postnatal week until the end of mical characteristics, and to form connection the third month.53 This implies that there is, with the right target cell as well as receive the during the development of the visual system, a correct afferent input. In summary, the neuron needs to have critical period in which it is vulnerable to migrated to the right place, established the changes in its input. The other major implicaright connections, have competed successfully tion of this work is that there must be activity for post-synaptic sites and perhaps also have in a system for consolidation of the normal the right trophic factor to ensure survival connections. In this model the only change was rather than death. This is a complicated set of the lack of activity in one eye; nothing events, which are vulnerable to outside influ- structural had been removed. Therefore it


Plasticity in the central nervous system appears to be of paramount importance that connections must be used in order to survive. Other experiments have shown that the input to the visual system has to be normal, otherwise, although the connections may remain, the activity within them will be abnormal. If, in the critical period, an animal is presented with an abnormal visual image, e.g. stripes with only one orientation, then the animal is blind to stripes of any other orientat i ~ nTranslating . ~ ~ this to the clinical sphere, it means that in the neonatal period normal input to the CNS should be maximal.

Pathway removal. The paragraphs above illustrate how inactivity caused changes in the connections seen in the visual system. It is also possible to cause changes by removing entire pathways. This has been carried out in, for example, the olivo-cerebellar system, the cerebello-rubral system and the corticospinal tract. By collating the results, lessons can be learnt about the mechanisms of target recognition by axons and the use of plasticity by the neonatal brain to achieve restitution of function following trauma. Critical periods. By an easy operation via the foramen magnum, it is possible to cut the cerebellar peduncles in one side in the neonatal rat:5 thus removing the climbing fibres on that side. This results in the remaining inferior olive sending axons across the cerebellar midline to reinnervate the denervated hemisphere. If the removal is carried out before postnatal day 3 (P3), then the new fibres form a good mirror image of the normal pathway, i.e. it appears to be normally o r g a n i ~ e d .If~ how~-~~ ever, the removal is carried out at P7 the compensatory innervation is much less well organized;57 and if carried out after P10 there is no compensatory pathway.57. The neuronal output of the cerebellar hemisphere is from the deep cerebellar nuclei (DCN) and this is mainly to the contralateral red nucleus and thalamus.58 If one cerebellar hemisphere, including the DCN, is removed, then there is a reorganization of the efferents from the remaining DCN. The obvious change

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is that the projections from the remaining DCN are now bilateral.59 This will not occur if the cerebellar hemisphere is removed after P 10. That the corticospinal tract is capable of plasticity is shown by the fact that after lesions of the cerebral hemisphere, children were able to use the affected hand. Even in cases with the largest lesions, the children were able to reach out and grasp objects.60 The model used to study the basis of such plasticity is removal of a cerebral hemisphere in the neonatal rat. The corticospinal tract in this animal is normally entirely crossed. Studies have shown that following postnatal hemispherectomy, the remaining cerebral hemispheres will grow an ipsilateral pathway6’q6*and this does not occur after P10. In all three examples described above, there is a critical time in which plasticity will occur.

Somatotopic organization. New axonal growth is not random but is topographically ordered. This is seen in the compensatory olivocerebellar p a t h ~ a y , 5 ~ the . ~ ’ ipsilateral outflow from the DCN,63 and the ipsilateral corticospinal fibres.6’*6z The interpretation of this is that the stimulus for compensatory fibres to grow is not just the presence of vacant synapses. In each of the above examples, the growing axon will have had to pass vacant synapses to reach its destination. However, it is not clear what is the stimulus for compensatory fibres to grow. Origin of compensatory axons. The compensatory olivo-cerebellar pathway is not formed by collateral branches of the normal axons, but arises from a separate population of neurons in the inferior o l i ~ e .A~ similar ~ , ~ ~result has been shown for the ipsilateral cerebello-rubral pathway.64This is confirmed by the finding that there are more neurons in the remaining DCN after hemicerebellectomy than in control anirnal~.~’ The origin of the ipsilateral corticospinal axons has recently been investigated.66 The findings were that the density ofneurons givingrise to the ipsilateral axons was low, but their distribution was from a much wider area of the cerebral cortex than the normal corticospinal tract.

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One may conclude that the ipsilateral compensatory fibres arise from a small discrete population of neurons.

causes not only growth of compensatory axons, but also reorganization of remaining pathways. The CNS therefore uses a wide range of responses to obtain the maximally efficient Non-retention of transient ipsilateral fibres. The functional response. findings described in the previous section In summary, the potential for functionally imply that compensatory fibres are not simply useful plasticity in neonates is much greater the retention of transient ipsilateral pathways than in adults. However, there is a definite (vide supra, normal development). This is time in which maximal changes can occur. confirmed by the fact that the compensatory Trauma or pathology outside that time will not olivo-cerebellar pathway has a route com- result in such functionally good plasticity. The pletely different from the transient ipsilateral work on the visual cortex shows that activity in p a t h ~ a y . ~ The ~ , ’ ~ipsilateral cerebello-rubral a system is vital for the consolidation and pathway is much larger than that seen in the maintenance of synapses and connections. The normal animal, which implies growth of new work involving removal of pathways shows axons, not simply retention of a neonatal that the plasticity that occurs is functionally orientated; it is not just a question of filling the pathway The only area of cerebral cortex which did first vacant synapse that the growing axon not give rise to the ipsilateral corticospinal reaches. The termination of new pathways pathway was the visual cortex.66This indicates very often mirrors the topography of the that the new pathway could not have been normal pathway. It is of interest to note that in retention of the transient pathway from the the three examples given above the new visual cortex which has been described by pathways arise from their own set of neurons; Stanfield & O ’ L e a r ~ . ~ ~ they are not simply retained transient pathways. Putting together the findings described in the Perhaps the survival of such neurons is further previous two sections it is clear that compensa- confirmation of the interplay between axons tory pathways arise from their own population and target sites; the neurons now have a target of neurons. It also seems clear that, if they are to innervate so they survive. Also, whatever the not needed, these neurons die. The intriguing function of transient pathways, it is not to provide a back-up system should there be question is therefore, why are they there? trauma to the CNS. There is no reason to Efect on other pathways. Removing one set of suppose that the new pathways do not also need afferent fibres to a structure can have the effect activity to consolidate their survival. Therefore, of reorganizing other axons projecting to the the message must be to maximize activity in the same region. For example, as well as receiving a CNS after trauma, no matter how seemingly large input from the DCN, the red nucleus also hopeless the situation. receives an input from the cerebral cortex. This normally terminates on the distal dendrites of Pharmacological agents a n d plasticity the red nucleus neurons. However, when the normal DCN input to the red nucleus is One of the intriguing new areas of research is removed, the cortical synapses move down the the possibility of using pharmacological agents dendrites to occupy the regions previously to enhance post-trauma plasticity, either in the number of new connections, their speed of taken up by cerebellar efferent fibres.67 Another effect of removing a cerebellar growth, or their functional quality. It has been hemisphere in the early postnatal period is that known for some time that noradrenaline is the contralateral pontine nuclei are reduced in essential for plasticity during the early postnasize. The cortical afferents which normally go to tal period.69 Recently, acetylcholine has also that nucleus are routed to the opposite side.6s been implicated as being necessary for neonaIt is clear that the removal of pathways tal p l a ~ t i c i t yHowever, .~~ this is not the same as

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Plasticity in the central nervous system finding a substance which will actively promote plasticity. The main substances in the latter category that have been investigated are melanocortins, glucocorticoids and gangliosides.


Melanocortins

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the hippocampus in the rat. What is important is the circulating level of glucocorticoids. High levels inhibit axonal sprouting:’ whereas low levels are essential for the normal postnatal development of the brains2 The former point is of importance if glucoconicoids are used for the management of brain oedema; the negative effect on neuronal plasticity and recovery should be kept in mind.

Melanocortins are peptides related to the piNitary hormones ACTH and a-MSH and are also now known to be neuropeptides, i.e. Gangliosides they are found in neurons and have an effect on neuronal metabolism and can enhance Gangliosides are protein molecules which are repair of peripheral nerves.” Administration is major constituents of cell membrane and may by subcutaneous infusion72 and needs to be play a role as cell membrane receptors.83 At given in the first few days after injury.73 Not least 60 such molecules have now been identionly is the speed of recovery enhanced by these fied. In vitro studies have shown that gangliosubstances, but also the quality of recovery. sides facilitate survival, morphological and Following crush injury to the rat sciatic nerve, biochemical differentiation, increase synapse the speed of conduction returned to normal formation and enhance neurite o ~ t g r o w t h . ~ ~ ~ after 90 days with administration of melano- Using this information, the effects of systemic cortins instead of the 200 days in control administration of the ganglioside GM1 has been tested in several types of nerve injury. In animals.74 In addition to the actions on the peripheral all cases it improves the temporal and qualitanervous system described above, melanocor- tive recovery following experimentally intins also have an affect on the CNS. Lesions to duced nerve damage in adult animals. various areas have been studied; v e s t i b ~ l a r ; ~ ~ If the nigrostriatal path was partially severed on one side, it was found that administration of ~ e p t a l ;h~i p~p ~ c a m p a land ~ ~ parafasci~ular.~~ All the reports agree that administration of GM1 facilitated recovery of dopaminergic melanocortins improves recovery from CNS activity and also increased the survival of nigral dopaminergic neuron^.^^,^' GM1 also trauma, even in adult animals. mitigates the effects of neurotoxic The mechanisms involved are being investie.g. the degenerative effects of 6-hydroxydogated in ~ i t r o . ’The ~ findings indicate that one pamine on serotonergic and noradrenergic of the main effects is the enhancement of systems are reduced.89 The above results were neurite outgrowth and the rapid formation of all obtained after chronic administration of neural aggregates. GM1, but it has also been shown to be effective in the early phase after CNS damage. Glucocorticoids Gangliosides limit cerebral electrolyte imbaGlucocorticoids are secreted by the adrenal lance and oedema and improve blood f l o ~ , 9 ~ * ~ l cortex in response to stress and are the last resulting in less morphological damage and less product in the chain of events organized in the severe neurological deficits.92 It is hypothehypothalamus-pituitary-adrenal axis. They sized that the mechanism by which GM1 elevate blood glucose levels, promote fluid alleviates the sequelae of CNS trauma may be excretion, have an immunosuppressive and an by minimizing the effects of neurotoxic amino anti-inflammatory action and influence mood acids which are released as a result of brain and affect.s0 They also have an effect on post- injury.93 They may also have an effect by increasing neuronal responses to neuronotrolesion plasticity in the CNS. The experimental model is denervation of pic factors, which are released normally after


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injury, but in insufficient quantity to have much effect.94 In summary, although the work described in this section on the pharmacology of plasticity has been on animal models and cell culture, there are glimmers of hope that therapeutic agents will be available to mitigate the effects of CNS trauma in both neonates and adults. Meanwhile, there have been results that should provide food for thought, especially the finding that glucocorticoids may have a negative effect on neurite outgrowth and recovery from damage. In conclusion, basic scientific research can provide knowledge which can be important in a clinical context. Plasticity in the adult and neonatal brain is important both as part of normal development and in functional recovery from injury. Experimental findings indicate that activity is an important part of these processes, and this has implications for the clinical field. One hope for the future is the development of therapeutic agents to enhance recovery. Another, which I have not covered in this review, is the development of transplantation of nervous tissue to compensate for disease and trauma. That needs a review in itself.

Acknowledgement I am grateful to Dr R. M. Sherrard for critically reading this manuscript. Address for correspondence: Adrian J. Bower, Development Neurobiology Laboratory, Department of Anatomy, University of Queensland, St Lucia, Queensland 4067, Australia.

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Melville-Jones G . Plasticity in the adult vestibulo-ocular reflex arc. Phil Trans R SOCLond Ser B 1974; 278:319-34. Paige GD. Vestibuloocular reflex and its interaction with visual-following mechanisms in the Squirrel monkey. I1 Response characteristics and plasticity following unilateral inactivation of the horizontal canal. J Neurophysiol 1983; 49:152-68.

Baarsma EA and Collewiln H. Vestibulo-oculo and optokinetic

reactions to rotation and their interaction in the rabbit. J Physiol (Lond) 1974; 238:603-25. 5 Maioli C, Precht W, Reid S. Short and long term modification of vestibuloocular response dynamics following unilateral vestibular nerve lesions in the cat. Exp Brain Rrs 1983; 59:259-74. 6 Hart CW, McKinley PA, Peterson BW. Compensation follow-

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Leptin sustains spontaneous remyelination in the adult central nervous system.

SOD1 Lysine 123 Acetylation in the Adult Central Nervous System.

Decoding transcriptional repressor complexes in the adult central nervous system.

Coxsackievirus-induced acute neonatal central nervous system disease model.

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Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection.

Central nervous system regeneration.

Central nervous system toxicity.

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Central nervous system tuberculosis.

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Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination.

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