the influence of environment and experience on neural grafts

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Neural tissues can survive transplantation into the adultmammalian brain and spinal cord, integrate and con-nect with the host nervous system, and influence thehost’s behaviour. Indeed, several clinical trials have nowshown that embryonic tissue grafts can alleviate symp-toms — at least partially — in Parkinson’s disease1,2, andrelated strategies are under evaluation for Huntington’sdisease, spinal cord injury, stroke and other disorders ofthe central nervous system3–7.

Nevertheless, there are concerns that current trans-plantation procedures could be considerably improved.There is a need both to enhance the survival and to con-trol the integration of implanted embryonic tissues, andto identify alternative sources of suitable cells or tissuesfor transplantation that can be expanded and selectedin vitro, to yield precisely specified cells on demand8.Considerable advances have been made over the pastdecade in understanding the causes of cell death intransplanted tissues, and in developing strategies toimprove cell survival9, differentiation10,11 and long-distance axon growth12 within the host brain. However,the factors responsible for enabling a well-integratedgraft to provide effective and efficient recovery of func-tion have been less well studied. Clearly, one such factoris that the grafts need to establish afferent and efferentconnections with the host brain that are appropriate tothe particular function that needs to be restored13–15.

But it is becoming increasingly apparent that circuitreconstruction at an appropriate level might not be suf-ficient for full functional recovery. During ontogeny, thegrowing animal must not only develop the rightanatomical structures and systems, but also acquire andrefine appropriate patterns of behaviour through learn-ing and experience. Similarly, to aid spontaneous recov-ery, or after surgical repair of damage in the adult brain,patients (and animals) need appropriate rehabilitation,and they benefit from experience, practice and retrainingin reacquiring lost function16–18. Although still limited,experimental evidence is accumulating that experienceand training are also important in the plasticity of, andfunctional recovery provided by, neural grafts (TABLE 1).We review this evidence here.

The mechanisms by which environment and expe-rience can influence brain structure and function firstreceived direct experimental attention after Hebb’sobservations and theoretical proposals that learning isrepresented in the brain by synaptic changes inresponse to repeated concurrent activation19. Thesefundamental concepts were subsequently shown atcellular and molecular levels in various simple organ-isms, such as the molluscs Aplysia and Hermissenda20.In mammals, synaptic plasticity of the Hebbian typehas been widely investigated through the phenome-non of long-term potentiation21,22, and there is limited

THE INFLUENCE OF ENVIRONMENT AND EXPERIENCEON NEURAL GRAFTSMàtè D. Döbrössy and Stephen B. Dunnett

Environmental enrichment, behavioural experience and cell transplantation can each influenceneuronal plasticity and recovery of function after brain damage, and each has been extensivelyinvestigated in its own right. However, the degree to which housing conditions or behaviouraltraining can modify the survival, integration or function of transplanted tissues is less wellestablished. Here we review the limited literature available, and suggest that this factor should beconsidered and integrated into the postoperative care that follows the clinical application ofneural transplantation.

School of Biosciences,Cardiff University,Museum Avenue Box 911,Cardiff CF10 3US,Wales, UK.Correspondence to M.D.D.e-mail:[email protected]

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HEBB–WILLIAMS MAZE

An open field with moveablebarriers that challenges theanimal’s learning and memorycapabilities in locating a boxfrom a given starting position.

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Cholinergic grafts in cortex and hippocampus. Grafts thatare rich in cholinergic neurons derived from the embry-onic basal forebrain can reverse various cognitive deficitsthat are associated with cholinergic depletion in the ratcortex and hippocampus, caused by ageing or explicitlesions38,39. In the first model system to be investigatedunder such conditions, cholinergic fibre outgrowth frombasal forebrain tissues, implanted as dissociated cell sus-pension grafts into the dorsal neocortex, was greater inrats that were housed in an enriched environment thanin rats kept in standard cages40. The difference was partic-ularly marked at 4 weeks after grafting, but had waned by10 weeks, indicating that the greatest effect might be onthe initial stimulation of neurite growth, rather thanasymptotic expansion of the grafts.

Further studies analysed the effects of enriched orstandard housing on the ability of basal forebrain graftsto alleviate maze-learning deficits in rats with hippo-campal cholinergic lesions41,42. In the first study, onlyrats housed for 10 months in an enriched environmentafter receiving lesions and grafts showed significantattenuation of the profound lesion-induced deficit inrelearning a HEBB–WILLIAMS MAZE task; neither the trans-plant nor enrichment was effective alone41. By contrast,a shorter period of enriched housing over 2 months wasnot sufficient to benefit even the grafted rats. In a secondstudy, rats experienced standard housing alone, stan-dard housing with daily handling and training in a watermaze spatial navigation task, or environmental enrich-ment, before being retested in the Hebb–Williamsmazes42. Again, neither enrichment nor graft alone wassufficient to sustain recovery over a shorter, 5-monthpost-surgery period, whereas the specific handling andspatial training did produce selective recovery in thegrafted animals. This observation is akin to the finding

evidence that this plasticity can be influenced bybehavioural experience or explicit training23–26.Although this topic still receives much less attentionthen it merits, experimental data is now available fromstudies of the effects of environmental enrichment ongraft differentiation, outgrowth and recovery, of placeconditioning on motor activity, and of specific trainingon various learned tasks. Here we consider the ways inwhich these manipulations can influence graft integra-tion and function.

Environmental enrichmentOne of the simplest ways of enhancing the behaviouralexperiences of an experimental animal is to house it inan ‘enriched’ environment (FIG. 1a), allowing greateropportunities for activity, play and social interactionthan is provided by conventional housing (FIG. 1b).Rosenzweig, Diamond and colleagues pioneered studiesin the 1960s, showing that such experiences producesignificant changes in the structural anatomy of thebrain, including the thickness of the cortex, sizes of cellsomata, branching of dendrites, and the density ofsynaptic spines on cortical neurons27. There is alsorecent evidence that environmental enrichment canpromote neurogenesis within the small population ofresting stem cells in the adult brain28. Such structuralchanges were associated with changes in brain neuro-chemistry, physiology and function, and, most notablyfor our purposes, with enhanced performance in a vari-ety of behavioural tasks29–33. Moreover, environmentalenrichment can enhance recovery from brain injury atboth the structural34 and functional levels35–37. It isappropriate, therefore, to ask whether similar experiencecan promote the structural integration and functionalcapacity of neural grafts.

Table 1 | Effects of environmental enrichment and other training conditions on graft survival and function

Lesion Graft Target Treatment Anatomical Tests Behavioural Referencestissue effects effects

NBM ibo ACh Neocortex Environmental Increased rate – – 40enrichment of outgrowth

Fimbria fornix ACh Hippocampus Environmental Increased rate H–W mazes Improved graft 41enrichment of outgrowth performance

MCAO Cortical Neocortex Environmental Decreased Rotation/posture Improved 51,52ischaemia enrichment thalamic atrophy

Skilled reaching No effect

Cortical Cortical Neocortex Environmental No effect Beam walking Additive but 54aspiration enrichment independent

NSP 6-OHDA DA Striatum Environmental Increase in Rotation, delayed No effect 58enrichment and dopamine neurons alternationbehavioural training

NSP 6-OHDA DA Striatum Place conditioning/ – Rotation Conditioned 65behavioural training rotation

Enucleation Retina Tectum Behavioural training – Operant conditioned Learned 69suppression

Open field Required conditioning

Striatal quin Striatal Striatum Behavioural training – Choice reaction Task-specific 78time learning

–, not investigated; ACh, acetylcholine-rich (septal) tissues; DA, dopamine-rich (nigral) tissues; H–W mazes, Hebb–Williams maze tests; MCAO, middle cerebral arteryocclusion; NBM ibo, ibotenic acid lesion of the nucleus basalis magnocellularis; NSP 6-OHDA, 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway; striatal quin,quinolinic acid lesion of the striatum.

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connections seen in neonatal hosts47, so such grafts mighthave little influence on host neuronal function48–50.Nevertheless, behavioural improvements have been seenwhen grafted animals have been given the added benefitof housing in enriched environments, in particular onsimple tests of motor asymmetry, such as rotation, pos-tural position and balance on a rotating rod (FIG. 1c–e)51,52.However, recovery was not seen on tests of skilled motorcoordination, such as the skilled forelimb reaching task52,in which functional effects of grafts seem to depend onthe re-establishment of cortical and basal ganglia connec-tions15,53. So, the behavioural benefits that were providedby a combination of cortical grafts and environmentalenrichment in the ischaemic cortex might be attributableto secondary protection against thalamic atrophy ratherthan primary cortical reconstruction51.

Cortical grafts have also been reported to yieldbehavioural benefits in a different model that involvesaspirative lesions of the somatosensory cortex54. In thisstudy, housing the animals in enriched conditions led toenhanced recovery on a beam-walking task in all groups.Whereas grafts implanted into frontal sensorimotor cor-tex promoted early recovery, they had little further long-term benefit, irrespective of whether they were com-bined with environmental enrichment. So, this studyindicates two separate influences: an early trophic effectof the grafts on spontaneous recovery processes54,55, andan independent process of enrichment that promotesbehavioural compensation in the foot-slip tests on thebeams, rather than reconstruction54,56,57.

Nigral grafts in the striatum. Given the number of stud-ies of dopamine-rich nigral grafts in laboratory studiesof Parkinson’s disease models over the past 20 years, it isperhaps surprising that the investigation of environ-mental effects on dopamine grafts in this model hasbeen so limited. M.D.D. carried out a study in which theinfluences of environmental manipulation on intra-striatal dopaminergic grafts in the rodent parkinsonianmodel were examined under two extreme conditions:collective and enriched housing with extensive trainingon various behavioural tasks, and individual housingwith limited behavioural testing58. Although the animalshoused in enriched conditions were not spared from thebehavioural deficits induced by unilateral 6-hydroxy-dopamine lesions, a significantly higher number ofgrafted dopaminergic neurons survived under theseconditions58. As most cell death in nigral grafts occursduring the first week after implantation59, the enhancedgraft survival in enriched animals is likely to be attribut-able to induced neuroprotective changes in the host cel-lular environment. For example, the upregulation oftrophic factors or corticosterone levels can influenceneuronal survival, and such systemic changes areknown to be influenced by housing conditions34,60,61.

Together, these studies emphasize that maximal grafteffects will be determined not only by the technical con-ditions of implantation. Rather, graft survival, growth,integration and functional responses are themselves allmodulated by extrinsic influences on the experienceand behaviour of the host animal.

that hippocampal neurogenesis is particularly related toopportunities for increased activity, rather than to envi-ronmental enrichment per se 43. As in the earlier corticalstudy40, in both these graft studies, asymptotic choliner-gic outgrowth from the basal forebrain grafts was simi-lar in animals housed in enriched and standard environ-ments41. This indicates that enrichment is not the soledeterminant of recovery, and agrees with other struc-tural–functional correlations showing that cholinergicreinnervation is necessary, but not sufficient, for graft-derived recovery38. In each case, grafts were effective inalleviating deficits in the ability to learn complex spatialmazes only when the grafted animals received furthertraining or experience over a protracted period.

Cortical grafts in stroke and lesion models. The observa-tion in human stroke victims of spontaneous functionalrecovery over several months after the incident offersstrong evidence for brain plasticity44. In rodents, the func-tional integration of cortical tissue has been widely stud-ied in a particularly well-controlled model of ischaemia,induced by middle cerebral artery occlusion. Corticalgrafts implanted into the infarcted area receive extensivefunctional afferent host connections from somatosensoryand other pathways45, as demonstrated by an increase inglucose uptake in the graft in response to stimulation ofthe contralateral vibrissae46. Reciprocal projections backto the host are sparse in adult rats, in contrast to the rich

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Figure 1 | Environmental enrichment can enhance functional recovery associated withcortical grafts in ischaemic rats. a | Group-housed rats in an enriched environment. b | Comparison condition in which rats are housed singly or in small groups in standard laboratorycages. c,d | Ratings of posture on stationary or rotating rods51, illustrating normal posture andbalance, scored 5 in a normal rat (c), or severe postural impairment, scored 2 after unilateralintracerebral ischaemia (d). e | Median postural scores of ischaemic rats (I), subgroups of whichhad received further cortical transplants (T) and were housed in either standard control (C) orenriched (E) environments. Based on data from REFS 51,52.

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amphetamine in one environment, and control injec-tions of saline in a second environment, then a subse-quent injection of saline will induce strong rotation(and in the same direction: ipsilateral for lesioned rats,contralateral for grafted rats) in the environment thathas become associated with amphetamine treatment. Bycontrast, administering the drug in the environmentthat was previously paired with the control injection hasno effect65. So, the rate and direction of conditionedrotation are not due to previous treatment with ampheta-mine per se, which was matched between the groups, butare determined by specific place conditioning to establishan association between the environmental cues associatedwith a particular location and a specific response.

Learning to use the transplant. A specific aspect not onlyof the effects of, but also of the absolute requirement for,conditioning on graft function is seen in the phenome-non known as ‘learning to use the transplant’. In this sit-uation, it is not sufficient for the transplanted tissues tosurvive and be anatomically well established, as appliesin the restitution of cholinergic activation of cortical orhippocampal circuits (see above), or dopaminergicactivation of striatal motor routines66,67. Rather, the ani-mal must undergo specific training for the graft to exerta functional influence, as applies in situations in whichthe graft provides essential transduction of sensory

Behavioural experience and trainingNigral grafts. The effects of experience on nigral graftfunction have been investigated more extensively in a dif-ferent context: the interaction between conditioningexperiences and the expression of motor asymmetries ingrafted rats. When rats with unilateral nigrostriatallesions are activated either pharmacologically (usingdirect or indirect dopamine agonists, such as apomor-phine or amphetamine, respectively) or by a stressor(such as a tail pinch), the spontaneous motor asymmetryinduced by the lesions is manifested in a quantifiable andvigorous head-to-tail rotating response62. Rotation itselfcan be modified by experience. Repeated treatments withamphetamine or apomorphine induce behaviouralcompensation through a pharmacological process63.More interestingly, repeated association of an ampheta-mine treatment with a particular apparatus yields a con-ditioned response, such that if the animal is subsequentlyinjected with saline in the same location, it now rotates inthe same direction as had been elicited by the drug64.

The history of drug treatments can similarly influ-ence the expression of rotational behaviours in graftedanimals, by a process that seems to involve both phar-macological sensitization and behavioural conditioning.So, if lesioned or grafted rats receive a series of ampheta-mine injections, the rotation response increases fromtest to test65. Moreover, if they receive repeated doses of

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Figure 2 | ‘Learning to use the transplant’ in the retinotectal system. Rats were prepared by unilateral enucleation and a retinaltransplant positioned over the tectum. A transparent Perspex window was implanted into the skull to allow direct illumination of thetransplant, and normal vision could be excluded by placing a patch over the remaining eye. In the first phase of testing in the openfield, only rats that viewed the world through the intact eye showed a normal response, spending an above-chance proportion oftime in the dark segment (chance level of 100 s in a 300 s test is indicated by dashed lines). After training to associate illuminationwith footshock, and then testing to view the arena through the transplant, the animals trained to illumination of the transplant spent ahigher proportion of time in the dark segment than the control group trained to illumination of the normal eye, and a similar time toanimals viewing the arena through the normal eye. Based on data from REF. 69.


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Striatal grafts. We have found a similar phenomenon ina different system. In the quinolinic acid lesion model ofHuntington’s disease, striatal grafts survive, establishafferent and efferent connections with the host brain,and alleviate deficits in a variety of motor and cognitivetests15,72. Functionally, the striatum has been consideredas the neural substrate for habit formation and motorlearning73,74. The experiments used a ‘nine-hole box’apparatus that allows the precise presentation of stim-uli, and registration of the animals’ responses, in multi-ple spatial locations provided by an array of nine holesin the back wall of the apparatus (FIG. 3a,b). In the ‘Carli’task75, animals are trained to hold a nose poke into thecentral hole in the array, and then to respond rapidly tobrief light stimuli on the left or right side. Animals weretrained to respond to either the same side as the lightstimulus, or the opposite side. Unilateral lesions ofeither the dopamine afferents to the striatum, or intrin-sic striatal neurons, disrupted the initiation of responseson the contralateral side. The lesions specifically affectinitiation, without affecting the animals’ ability to detector attend to the eliciting stimulus75–77. Similarly, whenunilateral striatal lesions and striatal grafts are made inrats that have been trained to respond on the oppositeside to the stimulus, both groups (lesioned and grafted)show profound deficits in responding on the contra-lateral side when returned to the test 4 months later.However, whereas the lesioned rats cannot relearn thetask, the grafted animals do relearn with training78–80.The relearning takes place over a similar period to thatrequired by naive rats to learn the task de novo. So, simi-lar to the phenomenon described by Coffey andLund69,70, the re-formation of appropriate connectionsby the striatal grafts was not by itself sufficient for func-tional recovery; rather, the rats had to be retrained touse the reconstructed graft–host circuitry to performthe relevant stimulus–response association.

The need for relearning to use the transplant indi-cates not only functional plasticity, but also a structuralrepresentation of that process within the reconstructedgraft–host circuit. Motor skills and habits are acquiredand refined throughout development and a lifetime ofexperience. To the extent that motor learning (whetherexpressed in the language of habit formation, proceduralor stimulus–response associative learning) is mediatedby the striatum, it is not surprising that striatal lesionsgenerate such lasting impairments in a variety of skilledmotor tasks. More remarkable is the fact that recoverycan be achieved by a process as apparently crude asembryonic striatal cell transplantation, and that theimplanted cells not only organize themselves and projectappropriately15,81, but retain the physiological plasticityto act as a substrate for new learning78. The first chal-lenge is to determine whether more direct evidence canbe obtained that the relearning is actually subservedwithin the striatal circuitry, before considering furtherthe cellular mechanisms involved.

The fact that striatal grafts transduce afferent infor-mation arriving through cortical and pallidal inputs,and project to primary outputs in the globus pallidus,has been shown using a variety of methods, including

experience, the interpretation of which is dependent onconditioning, or when it actually constitutes the neuralsubstrate for the conditioning itself. This phenomenonhas been investigated in two main model systems —retinotectal grafts and striatal grafts.

Retinotectal grafts. Grafts of retina implanted into themidbrain of enucleated rats not only survive and con-nect anatomically with the host brain, but can trans-duce a light stimulus (by direct illumination of the graftlaying on the tectal surface) to drive a pupillary reflex68.But does the grafted rat actually use the transplant to‘see’? Coffey and Lund69,70 tested rats in two paradigms:a simple open field avoidance chamber and an OPERANT

CONDITIONED SUPPRESSION test (FIG. 2). The open field com-prised a circular arena, divided into three equal seg-ments with opaque, transparent and open ceilings. Abright light was positioned overhead. When allowed toexplore, a normal rat spends most of the time underthe shade of the opaque roof, whereas a blind rat doesnot distinguish between the zones. The experimentalrats had their normal vision obscured by eye patches,and were prepared surgically with a Perspex window inthe skull over the retinal grafts. When first exposed tothe open field, they showed no differences in the timespent in each quadrant (FIG. 2). However, it seemed thatthe failure was not in their ability to detect the light, butthat they still had to learn to attach meaning to this newchannel of sensory input. This was confirmed by pro-viding specific training, in which light was paired with afootshock in the training phase of a conditioned sup-pression task. Effective learning was shown by a pro-gressive reduction in lever pressing for food rewardduring light (but not control tone) stimulation, indicat-ing that the rats could detect the visual stimulus. Moreimportantly, when the rats were placed back into theopen arena, they avoided the bright segments whenviewing the world exclusively through the transplantedretina (FIG. 2), so they had clearly learned to use the stim-ulus to control behaviour69,70. This bears intriguing sim-ilarity to the long-established principles of visual devel-opment, in which animals (and people) have to learn tointerpret the visual world. A parallel can also be madewith the rare cases of restoration of sight in the congeni-tally blind, in which learning to interpret the signalsderived from the new channel of input in adulthood hasproved to be remarkably difficult71.

The main challenge for the retinotectal graftingexperiments is still to demonstrate that the effects arespecific. As the operant training conditioned the animalto avoid the light70, it could be that the animal simplylearned to evade the novel arbitrary stimulus input,rather than learning to interpret it as a new visual chan-nel. The latter, specific interpretation would be appro-priate if rats still avoided the bright segments in theopen field after a different form of operant training inwhich the light illumination was conditioned as a posi-tive signal to be approached rather than an aversivesignal to be avoided. This has apparently been found(P. J. Coffey, personal communication), but unfortunatelynever published.

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A classical conditioningparadigm in which a stimulus(e.g. light) that predicts an event(e.g. mild shock) interrupts alearned behaviour (e.g. leverpressing for food).


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Figure 3 | Retraining in a choice reaction time task by rats with striatal lesions and grafts. a,b | The nine-hole box testapparatus is illustrated (a) and shown in plan view (b). c | The ‘Brasted’ version of the lateralized choice reaction time task, in whichthe rats are trained to discriminate between two holes on the left side of the central hole (illustrated), or between two holes on theright side of the centre hole, on alternate days. MT, movement time; RT, reaction time. d | After training on both sides, all rats receiveunilateral (right, R) striatal lesions, and half receive further striatal grafts into the lesioned striatum. Four months later, all animals areretrained either immediately on the side contralateral to the lesion (left, L), or on the contralateral side after 30 days of further trainingon the ipsilateral side. Lesioned rats are unable to perform the task on the contralateral side (showing close to 100% ipsilateral bias),however much retraining they receive. e,f | By contrast, when retrained on the contralateral side, grafted rats are initially as impairedas lesion controls, but show relearning of the task contingency with repeated training over a period of 3–6 weeks (e), an effect wehave called ‘learning to use the transplant’. The grafts show identical relearning on the contralateral side, even after 6 weeks offurther training on the ipsilateral side (f), indicating that the training effect is side-specific, in agreement with the hypothesis that therelearning must take place specifically within the grafted striatal circuitry. Based on data and adapted with permission from REF. 79

© 1999 National Academy of Sciences, USA.


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Similarly, at the anatomical level, various markersare available to identify axonal growth and synapticplasticity; for example, growth-associated protein 43(GAP43), neural cell adhesion molecule (NCAM),synaptophysin and neurofilament light polypeptide.These markers are expressed in striatal and othergrafts101–103, and now provide the means to investigateanatomically the dynamic changes in both internal graftorganization and graft–host connections associatedwith different conditions of training and experience.

Rehabilitation and therapyThe implications of our developing understanding ofgraft plasticity for neurological rehabilitation are likelyto be profound, but have hitherto been almost totallyneglected throughout the cell-therapy field104. The stan-dard approach has been to consider biological strategiesfor repair (whether of neurodegenerative disease,trauma or ischaemia) at the cellular and systems levels,with little further attention given to the patient as awhole organism. Physiotherapy and rehabilitation havetypically been considered as a quite separate process,intended to assist patients in finding new strategies tocope with and compensate for disability. The data dis-cussed here indicate that a different approach isrequired: postoperative experiences, including physio-therapy and explicit behavioural retraining, can havemarked direct as well as secondary effects on the inte-gration and function of grafted cells into the host neuralsystem. After demonstrations that enriched housingconditions or activity training regimes promote notonly functional recovery from brain damage, but alsothe intrinsic plasticity of the brain itself 28,33,43, prelimi-nary but convincing evidence is now becoming avail-able that similar factors influence the integration andfunction of neural grafts. The benefit of forced limb useand training on recovery from stroke85–87,105 or after spinalcord injury106 has been clinically validated, showing sub-stantial improvements in motor performance, even inchronic stroke patients. The expertise developed in pro-moting intrinsic recovery processes needs to be com-bined with neurobiological and surgical strategies forrepair at both the experimental and clinical levels. Withproof of principle now established, a rich area for innova-tive research with profound therapeutic application isnow wide open for investigation.

ConclusionsFor any cell-based treatment, replacing lost cells andreconstructing damaged circuits of the brain are neces-sary, but not sufficient, for functional therapy of neuro-degenerative damage and disease. Futhermore, the effi-cacy of these treatments is dependent on the behaviouralexperience and training of the host animal (or patient).These processes are not independent, but complemen-tary. Not only do behavioural training and experiencepromote behavioural and functional compensation (thetraditional realm of rehabilitation medicine), they alsoinfluence plasticity at the cellular and systems levels ofneuronal reorganization and graft integration. Until now,this research area has not been thoroughly exploited.

the induction of IMMEDIATE-EARLY GENE expression82–84, theelectrophysiological identification of monosynapticprojections85–87, and in vivo monitoring of changes inneurotransmitter turnover in the grafts and their tar-gets88–90. Brasted and colleagues undertook a series ofexperimental manipulations to explore the limits of therelearning effect at the behavioural level. First, as hostcortical and other afferents slowly retract after excitoxicremoval of their striatal targets, we reasoned that delay-ing the lesion–graft interval would reduce the opportu-nities for the grafts to establish afferent innervationfrom the host brain. We found that extending the inter-val from 9 days to 10 weeks abolished the ability of thegrafted rats to relearn the Carli task80. Moreover, in arelated task designed to allow separate training on theipsilateral and contralateral sides on alternate days77

(FIG. 3c), training the animals on both sides beforesurgery, and then providing extensive postoperativetraining on the ipsilateral side, did not transfer to thecrucial tests carried out on the animals’ abilities torespond on the contralateral side79 (FIG. 3d–f). This indi-cates that the relearning involves specific stimulus–response associations that are mediated by the trans-planted striatum, and is not achieved simply by generaltraining in task performance79,91.

The search for mechanismsWe do not know the mechanisms by which a graft thatis integrated anatomically into the host neuronal systemrepresents the variety of signals that encode stimulusexperience or motor responding, let alone the adapta-tions that take place at the cellular level to represent thetransduction of information or the learning of newassociations. Our understanding of similar processes, atthis level of organization, within the normal brain isequally limited. However, there is convincing evidencefrom both clinical and experimental sources that neu-ronal reorganization in the adult is a dynamic processthat is driven by experience, including environmentaland training conditions92–95. After brain damage, theprocesses that drive neuronal reorganization have beencompared to the plasticity observed in development,involving sprouting and pruning stages, each underexperience-dependent control96,97. An appropriate starthas been made in trying to shed light on these mecha-nisms by behavioural experiments, probing not onlywhether similar functions can be sustained in graftedanimals, but also whether acquisition and performanceseem to engage similar processes79.

In recent years, electrophysiological analyses of neu-ronal activity in the striatum have become increasinglysophisticated74, which should allow the evaluation ofwhether similar processes are observed in striatal grafts,as have been observed in the hippocampus98. For exam-ple, as a starting point, not only do we know that graftedstriatal neurons can show appropriate monosynapticresponses to cortical stimulation85,86, but we can now askwhether those neurons show similar adaptation bylong-term potentiation or depression, depending on theparameters of repeated stimulation, as do intrinsic neu-rons in the intact striatum99,100.

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Genes that are expressed as oneof the earliest responses of cellsto factors that initiate thetransition between the quiescentand activated states.


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technologies. Careful and increased attention must alsobe paid in the future to how appropriate regimes of post-operative care can be more centrally integrated into neu-rological and surgical practice. The emergence in bothNorth America and Europe of new centres with a multi-disciplinary scientific approach to brain repair heralds therapid development of this new perspective.

However, experimental data indicate that the goals offunctional recovery can be optimized only when surgicalrepair is integrated with an appropriate programme ofpostoperative care and training. So, as experimentalstrategies of cellular repair progress from the laboratoryto the clinic, it is not sufficient simply to establish neuro-biological and surgical expertise in the new cell-based

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2. Lindvall, O. & Hagell, P. Clinical observations after neuraltransplantation in Parkinson’s disease. Prog. Brain Res. 127, 299–320 (2000).

3. Bachoud-Lévy, A. C. et al. Motor and cognitiveimprovements in patients with Huntington’s disease afterneural transplantation. Lancet 356, 1975–1979 (2000).

4. Falci, S. et al. Obliteration of a posttraumatic spinal cord cystwith solid human embryonic spinal cord grafts: first clinicalattempt. J. Neurotrauma 14, 875–884 (1997).

5. Kondziolka, D. et al. Transplantation of cultured humanneuronal cells for patients with stroke. Neurology 55,565–569 (2000).

6. Franklin, R. J. M. & ffrench-Constant, C. in MolecularBiology of Multiple Sclerosis (ed. Russell, W. C.) 231–242(Wiley, London, 1996).

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AcknowledgementsWe acknowledge the recurrent funding of the UK MedicalResearch Council in support of our own studies in this area.

Online links

DATABASESThe following terms in this article are linked online to:LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/GAP43 | NCAM | neurofilament light polypeptide | synaptophysinOMIM: http://www.ncbi.nlm.nih.gov/Omim/Huntington’s disease | Parkinson’s disease

FURTHER INFORMATIONEncyclopedia of Life Sciences: http://www.els.net/Huntington disease | Parkinson diseaseAccess to this interactive links box is free online.

the influence of environment and experience on neural grafts

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