Motor Enrichment and the Induction of Plasticity before or ...€¦ · Motor Enrichment and the Induction of Plasticity after Brain Injury 1759 Mechanisms of Preinjury Behavioral

17570364-3190/03/1100–1757/0 © 2003 Plenum Publishing Corporation

Neurochemical Research, Vol. 28, No. 11, November 2003 (© 2003), pp. 1757–1769

Motor Enrichment and the Induction of Plasticity beforeor after Brain Injury*

Jeffrey A. Kleim,1 Theresa A. Jones,2 and Timothy Schallert2,3,4

(Accepted June 6, 2003)

Voluntary exercise, treadmill activity, skills training, and forced limb use have been utilized in animalstudies to promote brain plasticity and functional change. Motor enrichment may prime the brain torespond more adaptively to injury, in part by upregulating trophic factors such as GDNF, FGF-2, orBDNF. Discontinuation of exercise in advance of brain injury may cause levels of trophic factorexpression to plummet below baseline, which may leave the brain more vulnerable to degeneration.Underfeeding and motor enrichment induce remarkably similar molecular and cellular changes thatcould underlie their beneficial effects in the aged or injured brain. Exercise begun before focal ischemicinjury increases BDNF and other defenses against cell death and can maintain or expand motor rep-resentations defined by cortical microstimulation. Interfering with BDNF synthesis causes the motorrepresentations to recede or disappear. Injury to the brain, even in sedentary rats, causes a small,gradual increase in astrocytic expression of neurotrophic factors in both local and remote brain regions.The neurotrophic factors may inoculate those areas against further damage and enable brain repairand use-dependent synaptogenesis associated with recovery of function or compensatory motorlearning. Plasticity mechanisms are particularly active during time-windows early after focal corticaldamage or exposure to dopamine neurotoxins. Motor and cognitive impairments may contribute toself-imposed behavioral impoverishment, leading to a reduced plasticity. For slow degenerative mod-els, early forced forelimb use or exercise has been shown to halt cell loss, whereas delayed rehabil-itation training is ineffective and disuse is prodegenerative. However, it is possible that, in the chronicstages after brain injury, a regimen of exercise would reactivate mechanisms of plasticity and thusenhance rehabilitation targeting residual functional deficits.

KEY WORDS: Aging; BDNF; degeneration; enrichment; exercise; experience; FGF-2; GDNF; neurotrophicfactors; Parkinson’s disease; rehabilitation; stroke.

factor expression, neurogenesis, synaptogenesis, presy-naptic and postsynaptic modulation, glucose utilization,immune system changes, and angiogenesis, to name onlya few potential mechanisms, may promote what Cotmanand Berchtold (1) have called “brain health” (2,5–29).

Exercise and Brain Health

Studies have demonstrated improvements in mem-ory, learning capacity, and sensorimotor function afterregular exercise, particularly in elderly subjects (1,2,16,30–33). It remains unclear which aspects of exercisecontribute to neuroplasticity and to what extent motor

0364-3190/03/1100–1757/0 © 2003 Plenum Publishing Corporation

* Special issue dedicated to Dr. Carl Cotman.1Canadian Centre for Behavioural Neuroscience, University ofLethbridge, Lethbridge, Alberta, Canada.

2Departments of Psychology, Neurobiology and Institute for Neuro-science, University of Texas at Austin, Austin, Texas.

3Department of Neurosurgery and Center for Human Growth andDevelopment University of Michigan, Ann Arbor, Michigan.

4Address reprint requests to: [email protected] or [email protected]

Exercise has gained considerable attention in recentyears as a potential treatment to promote or sustainbrain plasticity and has been featured prominently in theCotman laboratory (1–4). Activity-linked neurotrophic

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1758 Kleim, Jones, and Schallert

learning is required for some of the brain changes(including the skills required to effectively negotiatevoluntary movement in an activity wheel or treadmill).Exercise elevates stress (heat shock) protein chaperonesand other plasticity-promoting events that have beenobserved following very mild brain trauma or ischemiain the absence of a detectable loss of neurons(34–37,73). The metabolic demands of strenuous exer-cise and the associated activation of compensatory orbenign pathological cascades are reminiscent of whathas been observed following mild ischemia-reperfusion(38–42). This procedure can serve to precondition tis-sue so that it can tolerate more extreme attacks. On theother hand, insufficient opportunities to exhibit motorbehavior can have a suboptimal effect on structure andfunction and render the brain more vulnerable to envi-ronmental stressors, neurotoxins, ischemia, and othersources of injury.

Motor Enrichment and the Unhealthy Brain

Exercise and various motor enrichment methodshave been applied in animal models of neurological dis-orders. Cotman and Berchtold (1) have reviewed someof the major evidence from their laboratory and othersthat motor activity initiates processes that facilitate bene-ficial plasticity and protect against the erosive neuralevents of aging, stress, depression, neurodegeneration,and brain injury. Prestroke treadmill exercise has beenfound to reduce infarct size following forebrain ischemia(43,44). These effects may be related to upregulatedmechanisms of neuroprotection, neuroplasticity, orangiogenesis to support collateral blood flow. The down-regulation of processes associated with degenerativeevents, such as apoptosis, edema, or the inhibition ofneurite growth-inhibiting molecules (35,42,45,46), mayalso be affected by prestroke exercise and thus mightimprove outcome. We have been interested not onlyin how brain injury changes behavior, but also in theunique influence that behavior can have on the injuredbrain in comparison to the undamaged brain. Brain injury(e.g., ischemia or trauma models) and progressive degen-eration (e.g., models of parkinsonism) may generatechemical conditions in which experience can morereadily alter molecular, electrophysiological, or structuralevents that enhance functional outcome (47–55).

It should be noted at the outset that in most inves-tigations of exercise and motor enrichment, the standardenvironments typical of sedentary control groups areexcessively impoverished and therefore somewhat unre-alistic as models for the surroundings of nonexercising

humans. That is, even the most sedentary humans livein very complicated environments in comparison to therat models. Ideally, sedentary control groups shouldreceive at least a minimal amount of environmental andsocial enrichment, as well as periodic cognitive chal-lenges, to more closely model people who are at risk forbrain disorders (56,57).

With respect to the prophylactic effects of exerciseon subsequent brain damage, it is likely that not all exer-cise and motor enrichment regimens are adaptive andsome may even be maladaptive. However, researchershave only recently begun to explore these issues in ani-mal models. Notably, extreme forced exercise in humanscan cause a potentially adverse rise in plasma-reactiveoxygen species while compromising antioxidant scav-enging capacity (38). The neurological significance ofthis finding is currently unknown but should be inves-tigated, especially because free radicals are notoriouslylethal to neurons and have been linked to aging, stroke,traumatic brain injury, Parkinson’s disease, Alzheimer’sdisease, and a host of other neurological maladies. How-ever, it is possible that strenuous exercise before a strokewould provide prophylactic preconditioning of antioxi-dant defense systems rather than fostering ischemia-related erosive events (149).

Motor enrichment methods and voluntary exercisein running wheels have been investigated as possiblepredamage and postdamage treatments for a variety ofcentral nervous system (CNS) injuries [43,49,50,53,58–68,194]. The goals of this research have been toreduce the level of initial damage, to limit long-termsecondary degeneration, and to support neural repair orbehavioral compensation. Although preinjury motorenrichment and exercise procedures appear to have sub-stantial transoperative benefits in animal models ofstroke and Parkinson’s disease (43,63), the results ofpostinjury manipulations have been mixed. In nonse-vere, slow-degeneration models of Parkinson’s disease,immediate motor enrichment applied during the earlyphases of cellular degeneration appears to provide a neu-roprotective or growth-favoring tissue environment(50,52,53,64) In a unilateral striata hemorrhage modelassociated with chronic slow degeneration of cells, adaily routine of excercise combined with frequentsessions designed to rehabilitate the effected forelimbspecifically (starting at Day of post-surgery) signifi-cantly reduced secondary degeneration and partiallyimproved outcome in some, but not all, motor behav-iors (DeBow et al. 2003). Also, delayed skilled motortraining may be essential for ensuring adequate benefitfrom grafts of transplanted tissue in stroke and parkin-sonian models (69–71,195).

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Motor Enrichment and the Induction of Plasticity after Brain Injury 1759

Mechanisms of Preinjury Behavioral and DietaryManipulations. Exercise may upregulate multiple neu-rotrophic factors, including brain-derived neurotrophicfactor (BDNF) and insulin-like growth factor-1 (IGF-1)that could render brain tissue resistant to degenerativeevents (1,72). Housing animals in an enriched envi-ronment several weeks before brain injury causes a 50%increase in the expression of fibroblast growth factor-2(FGF-2) and attenuates functional deficits (50). More-over, forced use of one forelimb (by constraining theother forelimb) upregulates the expression of FGF-2bilaterally, and transiently increases the glial-derivedneurotrophic factor (GDNF) and BDNF expressionin the hemisphere opposite the overused forelimb(48,63,74). Preoperative, forced forelimb use confersresistance to intracranially infused, low doses of6-hydroxydopamine (6-OHDA), a neurotoxin that tar-gets nigrostriatal dopamine neurons (63).

Underfeeding, like motor enrichment manipulations,results in the induction of a number of important molec-ular and cellular events that benefit the aging or injuredbrain (33,35,75). Over a century ago, Sherrington reportedthat restricted feeding led to increased neural excitabilityand enhanced reflex activity, even in spinal animals (76).Intermittent feeding regimens that reduce body weight to80% before brain injury are known to increase motoractivity, in contrast to complete food deprivation, whichresults in the same body weight level but reduces motoractivity. Intermittent regimens, but not complete depriva-tion regimens, have been found to reduce the extent ofbrain injury and functional deficits in models of stroke,trauma, and parkinsonism (35,77–79).

There remain multiple candidate mechanisms forthe effects of under feeding. Stress (heat shock) pro-tein chaperones and BDNF are increased by restrictingfood intake preoperatively (35). This finding is espe-cially noteworthy because these proteins are highlyneuroprotective and (as noted above) are increasedwith exercise and enriched environments, which alsoenhance functional outcome when administered preop-eratively (1,3,4,20,31,34,43,50, 80,81). One possibilityis that the enhanced exploratory activity and generalalertness associated with restricted feeding regimenscontribute to the increases in the expression of plastic-ity-promoting mechanisms. However, it is unclearwhether the food restriction per se can account for thebeneficial effects of preoperative feeding regimens. Arestricted watering regimen before brain injury also hasbeneficial effects on some sensorimotor functions (82).

In contrast to the effects of intermittent fooddeprivation, preinjury exposure to high-fat diets (cafe-teria-style feeding) has been found to be detrimental

(75,77,83,84). BDNF is reduced in rats that are on adiet rich in saturated fats (84). The role of motor activityhas not been addressed experimentally.

Preoperative restricted feeding also reduces post-operative fever, whereas preoperative cafeteria-stylediets can exaggerate it (75,77). These factors may bepartly responsible for the postoperative neural andbehavioral effects. Thus, cooling the brain is neuropro-tective, whereas a fever is prodegenerative (85–90). Therole of temperature in the effects of both behavioral anddietary manipulations deserves attention. Indeed, thepotential effects of preinjury exercise on postinjury braintemperature should be examined because both may alterone or more components of cell death pathways (42),including hydroxyl radical formation (91,92).

Mechanisms of Postinjury Behavior-RelatedManipulations. After injury, there may be windowsof opportunity during which plasticity can be enhancedby motor enrichment targeting specific skilled or spon-taneous movement patterns or voluntary running inan activity wheel. The location and type of the injuryappear to dictate to some extent whether excessive motorrehabilitation training results in proplasticity, neutral, oradverse effects. The contralesional hemisphere appearsto benefit from early, intense motor enrichment, but theperilesional area may be most helped by a gradual,modest increase in motor therapy (93).

During the first few weeks after cortical injury, thereis a bihemisphere proliferation of astrocytes and anupregulation of neurotrophic factors, such as FGF-2, in asubset of astrocytes ([7,48,50,57,94–99], Fig. 1). It hasbeen argued that brain plasticity, including dendriticarborization and synaptogenesis, gets a major boost frombehavioral events and vice versa (7,47,51,57,59,100).

Intracortical microstimulation (ICMS) has beenused to examine the effects of differential motor expe-rience on the topography of movement representationswithin the motor cortex in both the intact (11,101,102)and damaged brain (58,103,104). These studies haveshown that, following focal ischemic infarct, a loss ofmovement representations extends beyond the infarctioninto intact regions of the cortex (58). The dysfunctionappears within 24 h of insult (105) and persists forweeks (106). A similar loss of movement representa-tions can be induced in the intact brain via the selec-tive inhibition of BDNF translation. Injections of BDNFantisense oligodeoxynucleotide into the forelimb motorcortex caused a significant loss of forelimb movementrepresentations within 24 h. No such loss was observedafter a similar injection of scrambled oligodeoxynu-cleotide (Fig. 2). These results suggest that the func-tional integrity of the motor cortex, as measured by the

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Fig. 2. A, Intracortical microstimulation-derived motor maps produced20 min (Map 2) and 24 h (Map 3) after injection (black circles) ofeither BDNF-oligodeoxynucleotide (ODN; top) or Scrambled-ODN(bottom). Distal movement representations (wrist and digit) are shownin green; proximal movement representations (elbow and shoulder) areshown in blue; head/neck representations are shown in yellow; andvibrissae representations are shown in pink. A significant reduction inthe total area of forelimb representations was observed in the antisense-injected animals 24 h after injection. B, Area of forelimb movementrepresentations within the motor cortex of BDNF-ODN-injectedanimals and Scrambled-ODN controls. BDNF animals had significantlysmaller forelimb representations than scrambled controls (*p � .05)24 h after injection (Map 3) but not 20 min after injection (Map 2).

presence of movement representations, is dependentupon constitutive BDNF synthesis. Recent work hasshown that 30 days of treadmill training before theinfarction reduced the loss of movement representationswithin the periinfarct cortex (Kleim, unpublished obser-vations). Exercise-induced increases in growth factorssuch as BDNF may serve both to limit neural damageand enhance functional recovery following brain trauma(1,107).

Despite the finding that exercise before brain injuryappears to be beneficial, and even neuroprotective, itmay take the wake-up call of a neurological crisis tomotivate a person to exercise. It is well established thatpeople who sustain a transient ischemic attack (TIA),even a minor one, are highly likely to experience a sec-ond ischemic event. If the TIA were detected, peoplemight be willing to engage in some form of beneficialexercise if it were prescribed. It may be important,therefore, to establish safe motor enrichment proceduresfor the intervening period between a TIA and a laterischemic event in order to improve neural and functionaloutcome. Additionally, because TIAs are not alwaysdetectable, it may also be worth investigating whetherearly detection via population-based screening would bewarranted to permit motor enrichment interventions inotherwise sedentary individuals.

Skilled movement training in intact or brain-injuredanimals enhances synaptogenesis and related indices ofneuroplasticity (49,58,62,108–117). Teaching rats to behighly acrobatic or to reach through a narrow openingto grasp small food pellets without dropping them drives

use-dependent dendritic plasticity and synaptogenesis(49,100,101,118–123). The skilled motor learning com-ponent of animal behavior in complex environmentsmay be essential for large increases in synapse form-ation, which may be one reason why these environmentscan alter behavior and structural events after damage.Postoperative dendritic arborization and synapse form-ation appear to be particularly sensitive to new motorlearning for a short period of time, because of injury-related signals (51,62,68,117,124,125). It may be thatdelayed postinjury exercise, alone or in combinationwith plasticity-promoting treatments (126), can extendor reopen this window of opportunity.

In rats that are suddenly deprived of habitual running,there occurs a decrease in BDNF expression and Trk Bmessages to levels that are even lower than those ofsedentary animals (127). It will be important to establishwhether this or other undershooting effects puts these rats

Fig. 1. Motor cortical astrocyte double-labeled for fibroblastgrowth factor 2 (blue) and glial fibrillary acidic protein (brown).Unilateral sensorimotor cortical lesions result in bilateral increasesin the density of FGF-2 immunoreactive astrocytes in the cortex.Scale bar � 20 �m.

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at risk for excessive neural damage in response to anischemic event or exposure to a dopaminergic neurotoxin.Perhaps moving animals to a complex environmentfollowing the cessation of wheel-running (as opposedto moving them to a standard, impoverished cage) mightprevent the downregulation of BDNF and, conceivably,any exaggeration of brain injury. The clinical implicationsare obvious because exercise is not typically continuous,particularly when there is a sudden illness or leg injury.

Use-Dependent Molecular and Structural Events inthe Homotopic Cortex. Synapses are uniquely vulner-able to brain injury (35), but their numbers can bounceback over time, a process that is enhanced by the interac-tion of injury- and use-dependent mechanisms. Motoractivity and skilled learning may alter synapse-savingor apoptosis-reducing molecular events in the periinjuryarea, as well as in remote brain regions, includingthe hemisphere that is not directly damaged. Some ofthese events may influence downstream mechanismsof neuroplasticity (54,55,95,128–135). After severalweeks, use-dependent enhanced arborization of den-drites, followed by pruning, dendritic spine growth andsynaptogenesis, occurs in the homotopic cortex afterischemic or electrolytic lesions of the forelimb region of

the sensorimotor cortex (49,50,61,117,136–138). Thesynapses that form there are unique in that many areperforated or have partitioned active zones (as seen inelectron micrographs; Fig. 4), and many also haveaxonal terminals that contact more than one dendrite(7,49, 98,138). These types of synapses are thought toresult in more efficacious synaptic transmission incomparison to nonperforated synapses that do notinvolve multiple dendritic contacts. Multiple synapticboutons and perforated synapses also appear in thehippocampus during long-term potentiation (139–142),which is an activity-dependent model of rapid learning,in the cortex after acrobatic training (7,49) and complexenvironment housing (143), and in the striatum afterdenervating lesions (144).

Fig. 3. Photomontage of a layer V motor-cortical pyramidal neuronvisualized using Golgi-Cox impregnation with Nissl counterstaining.This population of neurons grew new dendritic processes followingsome types of lesions of the contralateral homotopic cortex. Thisgrowth response has been linked to interactive influences of lesion-induced degeneration and behavioral change. Scale bar � 50 �m.

Fig. 4. Synapse subtypes associated with learning and restructuring afterbrain damage. A, Multiple synaptic boutons (msb) form synaptic contactswith more than one dendritic process. In this image, the bouton contacts2 dendritic spines (S1 and S2). B, Perforated synapses have multiple-partitioned postsynaptic densities (open arrows). These synapse subtypesare believed to be more efficacious than nonperforated synapses formedby single-synaptic boutons (filled arrowheads). Electron micrographs arefrom layer V of the motor cortex. Scale bar � 0.5 �m.

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There is evidence that learning involving thenonimpaired forelimb may influence the expression ofsynaptogenesis following unilateral focal damage tothe forelimb area of the sensorimotor cortex, and that thelearning capacity is given a special boost by thenew synapses. Thus the ability of the animal to learnnew skilled reaching movements with the noninjuredforelimb surpasses the motor ability of an intact animalwith the same degree of training (100).

Dendritic branching is prevented by immobilizationof the forelimb associated with the homotopic cortex(51,117,125,145). Suction lesions do not cause the sameneural events as ischemic or electrocoagulatory lesions(130,146–148); the limb corresponding to the homotopiccortex is more impaired after suction lesions (148).Moreover, aspiration of the injured tissue after electro-coagulation prevents dendritic arborization in the homo-topic cortex (149). Thus structural events after braininjury depend on motor experience and lesion type.

In human cases of hemiplegic stroke in which thereis residual function, remarkable improvements in func-tion have been reported when the nonimpaired arm isconstrained beginning long after the initial injury (150).It has been suggested that this improvement is in partdue to reversal of “learned nonuse,” which also occursin animal models (93,117,150–154). The motivation touse the impaired limb may be reduced because of earlyineptitude or fatigue in that limb and a correspondingincreased reliance on the other extremity. With the emer-gence of effective compensatory behaviors (155–165),“self-imposed” failure to engage the available but under-used motor systems becomes more likely. Delayedmotor enrichment therapies that target lost motivation,endurance, and skills have been used in stroke patientsfor many years (154,159,166). As noted above, it seemspossible that an exercise program might activate dor-mant plasticity mechanisms that would potentiate thesetherapies.

Tissue Loss Caused by Excessive Motor Activ-ity in Cortical Injury Models. Forced motor enrich-ment prolonged over the first week after surgery canexaggerate the extent of cortical ischemic or traumaticinjury (124,167–171). Core temperature elevation orincreased corticosterone cannot account for this effect(172). Indeed, forced forelimb use does not exaggeratedamage to the visual cortex, which would be expectedif a systemic event were the primary cause; however,a use-dependent rise in brain temperature locally in theperi-injury areas may interact with other local eventsassociated with injury and intense behavioral pressure(DeBows, S., McKenna, J., Kolb, B., Colbourne, F.,2003, unpublished data).

In periinjury tissue, glutamatergic activity andenergy failure may be involved in the exaggeration ofinjury caused by forced use. Glutamate is elevated inthe sensorimotor cortex and striatum in the hemisphereopposite to the limb that is overused (170,173,174) anda glutamate antagonist coadministered during the periodof forced forelimb use prevents the excess degenera-tion (170, 171,174). A recent study showed that injuredneurons in the hippocampus were highly vulnerable fora short period to a glutamate agonist at a dose that wassublethal in the intact brain (175). These neurons sur-vived in injured rats that were not given the drug. Thissecondary pharmacological challenge, like excessivebehavioral demand, was thought to exacerbate anenergy crisis characterized by dangerously depressedoxidative metabolism, thereby inducing a fatal deple-tion of energy reserves (175).

Exposing animals to an enriched environment afterbrain injury was found to prevent a secondary rise inBDNF expression bilaterally in the frontal cortex andhippocampus after a week or two (176,177). The timeframe for this effect mirrors activity-dependent increasesin dendritic spines and multiple synaptic boutons. Thisis puzzling because BDNF expression and other trophicfactors are increased for at least several weeks afterexercise in neurologically intact animals (1–4,178).Although it is conceivable that the delayed reduction inBDNF expression prepares the brain for some forms ofdelayed plasticity such as synaptogenesis, it also seemspossible that this may be one of many events that couldpromote secondary tissue loss, especially if it is exag-gerated under conditions of more intense motor behav-ior. Farrel et al. (179) found that housing animals in anenriched environment can cause delayed hippocampalcell loss in a stroke model, despite producing behavioralimprovement.

Although postoperative exposure to an enrichedenvironment without excessive motor training typicallyhas favorable effects on structural and functional out-come, the possibility that behavioral improvementsoccur despite a subtle loss of tissue, at least under someconditions, cannot be ruled out. It is particularly difficultto detect a gradual, use-dependent loss of tissue whenit extends into regions for which the selected neuro-logical test battery is not sensitive. Furthermore, manyof the behavioral tests used to assess functional outcomedo not allow the experimenter to distinguish brain repairfrom behavioral compensation (151,180).

Training can be a powerful contributor to improvedperformance, so much so that use-dependent tissue lossmight be masked in motor or cognitive tests that areinfluenced by experience (167,179,181). Indeed, peri-

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Table I. Magnitude of Sensorimotor Asymmetry: Worsens overFirst 7 Days after 6-OHDA Exposure

Pre-op Day 2 Day 4 Day 7 Day 30 Day 90

SHAM 0 0 0 0 0 06-OHDA 0 2.1 3.0 5.0 3.0 3.06-OHDA �forced motor 0 2.0 1.5 1.5 0 1.3

Note: Data are median deficit scores in a practice-independent senso-rimotor test described in references 163 and 180.

odic nonintense motor training aimed at enhancingmotor behavior can cause the performance of animalswith large lesions to exceed that of animals with muchsmaller lesions (on practice-sensitive tests). Also, fewstudies use stereological analyses to gauge the extent ofremaining tissue (as opposed to infarct size) or wait longenough to examine the brains after the initial damage.Postacute tissue loss, particularly from excessive behav-ioral demand, is typically gradual, and, without stereo-logical methods of analysis, not readily detectable formany weeks after injury (89,124,182,183). Thus dataindicating that animals subjected to postinjury trainingperform slightly better, or at least not detectably worse,on motor tests, does not adequately prove that an early,rehabilitative training regimen (including exercise) iscompletely noninjurious to the brain (151,181,184).Improved in vivo brain imaging methods and a broadarray of sensitive and meaningful neurological tests maybe needed to investigate the utility and safety of clinicalrehabilitation procedures, especially when these areintense and applied soon after brain injury(185,186,196).

Forced Use Versus Forced Rest in ParkinsonianModels. In rat and mouse models of parkinsonism,forced motor therapies during the first postoperativeweek (but not during the second week) can be highlybeneficial, at least when the dose of neurotoxin is not toosevere (52,53,64). In mice, multiple exposures to1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)cause partial bilateral gradual degeneration of nigros-triatal cells that can be rescued by early treadmilltraining (64). In the rat model (52,53), 6-OHDA wasinfused into the dopamine projection pathway at thelevel of the medial forebrain bundle, causing functionaldeficits that became progressively worse. Movementinitiation deficits peak around day 5 after neurotoxinexposure (163,181), but these are attenuated by forcingthe animals to rely excessively on the affected fore-limb early in the degeneration period. Neurochemicalmarkers (e.g., striatal dopamine content and VMAT)indicate substantial sparing of dopaminergic terminals,or perhaps sprouting of remaining terminals. Somatosen-sorimotor function also takes a few days before maximalimpairment occurs, and physical therapy attenuates thisimpairment (Table I). Activity-dependent increases inplasticity-promoting molecular and cellular processes inthe striatum and its synaptic connections may beinvolved (54,63,74,187–192).

The neurochemical and behavioral protectiveeffects of motor enrichment in the parkinsonian modelsare chronically maintained. However, the integrity ofthe nigrostriatal system may remain substantially

dependent on a minimum level of motor activity forat least several weeks and perhaps much longer (52).In rats that had been protected from the effects of6-OHDA, forced nonuse of the contralateral forelimbduring the second or third postoperative week precipi-tated behavioral and neurochemical deficits. Further-more, in rats exposed to a subthreshold dose of6-OHDA (a dose that did not cause detectable func-tional deficits and only a 20% loss of dopamine), forcednonuse of the contralateral forelimb caused enhanceddepletion of dopamine and clear behavioral deficits.Taken together with data from exercise studies on intactanimals showing a rebound downregulation of endoge-nous trophic factors (below that of intact, nonexercisedanimals) when exercise is abruptly stopped, these dataindicate that the spared, but partially compromised,dopamine neurons may be highly vulnerable to boutsof inactivity, possibly as a result of reduced trophic fac-tor expression. Even the beneficial effects of exercisecan quickly degrade unless some degree of motor activ-ity is maintained. In animals, dopamine depletion leadsto progressively reduced use of the affected limbs fordopamine-dependent behaviors (181). The extent towhich this impairment-related or self-imposed inactiv-ity contributes to the degenerative effects of neurotoxinexposure may be significant.

In addressing how these data might translate tohuman Parkinson’s disease, one would speculate that exer-cise or other motor enrichment methods might delay theonset of parkinsonian symptoms or slow the degenerativeprocess, but only when there are no substantial breaks inmotor activity. However, even in the face of knowledgethat exercise is preventive, patients who do not yet knowthey are vulnerable to Parkinson’s disease are not likelyto change their exercise routines. In contrast, advancedknowledge about one’s vulnerability might motivate peo-ple to exercise more, especially if a specific motor enrich-ment procedure can be established to be an effectiveprophylactic treatment. Obviously, early detection meth-ods that are feasible for routine physical checkups would

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be required. We suggest that people presenting with minorhemi-parkinsonian symptoms may provide researcherswith an opportunity to develop highly sensitive behavioralmethods for assessing nigrostriatal dopamine neurons andtest physical training interventions that might halt thebilateral progression of the disease. Because Parkinson’sdisease typically begins on one side of the body, a reason-able target for physical therapy might be the nigrostriatalpathway within the hemisphere associated with thepresymptomatic side of the body.

CONCLUSIONS

Activity-dependent increases in cellular and synap-tic mechanisms of plasticity may contribute to thebeneficial effects of motor enrichment procedures thatreduce degeneration and promote recovery of functionin models of brain damage and neurodegeneration.Motor fatigue or impairment, whether injury-relatedor self-imposed, can be detrimental and may reverse orprevent any gains that are made. This paper focused onneurotrophic factors and other events associated withexercise and motor interventions that improve structuraland functional outcomes in animal models.

In contrast to the behavioral and neurochemicalprotection observed in slow-degeneration parkinsonianmodels, prolonged forced-use early after cortical strokeor ablation can exaggerate the extent of injury. A saferrehabilitation regimen may be to apply brief, nonintensemotor enrichment immediately, with gradual increasesin intensity and simultaneous early extensive training ofthe nonimpaired motor systems needed to cope withchronic debilitations. However, intense excercise, ifslightly delayed, may reduce secondary remote degen-eration observed after focal brain injury.

Comprehensive training strategies that work inhumans need to be investigated carefully (193). Bach-y-Rita (158) described promising developments in motorenrichment therapies after stroke that appear to take intoaccount findings from both animal and human studies inphysical rehabilitation therapies, including the use ofhome-based training and testing. It is known that brain-damaged rats and humans fare better functionally whentested in familiar environments (77,158). Improvements inbehavioral interventions and assessment methods, alongwith advances in understanding the mechanisms ofmovement-dependent neural and glial events and theirinteraction with aging- and injury-related facilitation ofcellular processes that promote plasticity, should acceler-ate progress in the treatment of neurological disorders andmaintenance of health in the intact brain.

ACKNOWLEDGMENTS

The authors thank Gabriela Redwine for her contributions tothis work. This work was supported by National Institutes of Healthgrant NS 23979.

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