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ILAR Journal V44(2) 2003
Animal Models of Stroke and Rehabilitation

Experimental Focal Ischemic Injury: Behavior-Brain Interactions and Issues of Animal Handling and Housing
Tim Schallert, Martin T. Woodlee, and Sheila M. Fleming

Abstract

In experimental neurological models of brain injury, behavioral manipulations before and after the insult can have a major impact on molecular, anatomical, and functional outcome. Investigators using animals for preclinical research should keep in mind that people with brain injury have lived in, and will continue to live in, an environment that is far more complex than that of the typical laboratory rodent. To yield more reliable and relevant behavioral assessment, it may be appropriate in some cases to house animals in environments that allow for motor enrichment and to handle animals in ways that promote tameness. Experience can affect mechanisms of plasticity and degeneration beneficially or adversely. Behavioral interventions that have been found to modulate postinjury brain events are reviewed. The timing and interaction of biological and motor therapies and the potential contribution of experience-dependent and drug-induced trophic factor expression are discussed.

Key Words: degeneration; enrichment; exercise; experience; FGF; GABA; neurotrophic factors; stroke

Stroke and Animal Care

Animal care in basic stroke research can be a challenging issue confronting institutional animal care and use committees charged with approving experiments. Some lines of investigation may require more than one survival surgery, cocktails of several drugs or growth factors, or large numbers of animals so that multiple long-term histological time points can be examined. Moreover, postoperative (and even preoperative) experience, age, and sex have become important factors in stroke outcome. Unusual housing and handling conditions have become a major part of what is considered to be a comprehensive effort to find novel treatments for focal ischemic injury in people. Animals are typically housed in impoverished environments even though they are utilized to model brain injury in people, who live in extremely complex environments before and after the insult.

Ensuring that standard guidelines are followed is, of course, essential. However, myopic attention to the potential for exposure to bacterial or viral contamination at the expense of other welfare considerations may sometimes have a deleterious effect on experiment outcomes (Barthold 2002). For example, are the environments in which the animals live sufficiently complex? Are the animals handled extensively and appropriately? Rodents thrive in environments that are rich in odors, contain wood to gnaw on, and provide a variety of diet and motor experience. Chronic isolation with sudden, unexpected exposure to a novel testing situation is unduly stressful, making them unprepared for experiments that study recovery of function. This is clear from observations of vocalization and exploratory behavior during neurological testing in animals raised alone without extensive human contact. Taming and familiarization with injection procedures and other treatments that will be forthcoming to research animals, both before and after surgery, can make a major difference in how the animals behave. An excellent review of the issues related to experimental housing and the effects of complex experience on the brain can be found in a previous issue of ILAR Journal (Benefiel and Greenough 1998).

Research Approaches to Stroke Treatment and Recovery

In the research area of recovery from focal cerebrovascular injury, a general goal is to find effective ways to enhance neural and functional outcome. There are at least five experimental approaches that have been adopted, all designed to reduce the extent of brain damage and/or behavioral impairments in experimental models:

1. Acute neuroprotection--preventing or limiting the rapid loss of tissue, typically by pharmacological, cellular, molecular, temperature reduction, or behavioral manipulations, applied to occur during ischemia and/or soon after the brain is injured.
2. Preischemia procedures--improving functional and structural outcome by preoperative manipulations begun days, weeks, or even months before injury. Examples include induction of ischemic tolerance, food or water restriction, enhancement of social experience, motor and cognitive training, and environmentally enriched housing conditions.
3. Neuroplasticity and repair--promoting mechanisms of recovery of function. Postacute, injury-initiated events that have the potential to affect neural and functional change are targeted, including growth of neuronal dendrites and axons, synaptogenesis, glial- and neuro-genesis, and trophic factor expression. For example, motor enrichment methods may recruit endogenous neurotrophic factors and other use-sensitive processes to rewire remaining circuitry.
4. Avoiding delayed secondary degeneration--limiting subacute and chronic degeneration secondary to the primary infarct. After the initial acute damage, secondary loss of tissue can be substantial. The period of vulnerability to delayed cell death can be long-lasting (weeks or months) and is sensitive to behavioral experience. Even when acute treatments provide remarkable early neuroprotection, chronic studies frequently indicate that spared tissue may not remain viable indefinitely without help. A research target has been to improve the viability of rescued tissue.
5. Promoting late residual opportunities for deficit compensation--applying delayed therapies after apparent maximal recovery, when impairments have become stable. Rehabilitative interventions may be most effective early after the injury, in part due to transiently upregulated trophic factor expression in astrocytes; however, physical therapy also may be useful at later time points. Brain structure and function may be enhanced by environments that are more enriched than those typical of most laboratory colonies. Skilled motor training, long-term complex housing, handling experience, or the combination of exogenous neurotrophic factors together with motor experience are being studied for their possible beneficial impact.

Understanding these approaches may help investigators justify, and institutional animal care and use committees understand, many of the animal care procedures that are necessary to carry out modern stroke research adequately. This presentation of the research context in which animals sustain ischemic injury is intended to inform the reader about the rationale for long-term assessment of functional and histological outcomes and behavioral and chemical interventions.

Sparing Cells

Reducing the degree of acute tissue damage is one of the most common goals of stroke research. Typically drugs, exogenous trophic factors, marrow stromal cell implantation, or related treatments begin immediately before transient occlusion of major blood vessels such as the middle cerebral artery (MCA¹) to limit tissue loss in the peri-injury (i.e., "penumbral") area that results from the toxic effects of reperfusion (Abe 2000; Cramer and Chopp 2000; Ginsberg and Bogousslavsky 1998; Johansson 2000; Schallert et al. 2002c). Research on the details of cellular and molecular cascades leading to neuronal death is essential because this information may be used to reduce the extent of the infarct and perhaps also the extent of delayed chronic secondary degeneration.

However, to date no treatment has successfully reduced infarct size in human stroke trials, at least not detectably (Kidwell et al. 2001). Gladstone et al. (2002) have summarized the possible reasons suggested for this failure, including that the clinical trials are markedly dissimilar to preclinical animal studies in terms of time windows, outcome measures, sites of injury, and failure to target delayed degeneration of tissue adjacent to the primary infarct. We would emphasize the need not only to improve the clinical trials but also to make the animal studies more relevant and comprehensive, particularly with regard to environment, experience, and evaluation of function.

A formidable problem in developing neuroprotective treatments is that there may be many different routes to progressive cell death that may require multiple drug interventions during different but very narrow therapeutic windows, which can vary widely among the models utilized (Corbett and Nurse 1998; Lee et al. 1999; Schallert et al. 2000c). Even when the site and size of the infarct are comparable, not all ischemic injuries share identical underlying mechanisms. Therefore, it is not likely that a single treatment strategy will suffice for every type of stroke. Moreover, drug and other interventions alter neural and behavioral responses to neurological testing and motor activity, which in turn interact with housing conditions.

Drugs that appear to be neuroprotective during the first day or 2 after ischemia onset may be highly detrimental if applied during later periods (Schallert and Hernandez 1998). Gamma-amino butyric acid (GABA¹)-ergic agonists such as diazepam or other benzodiazepines, for example, can save cells from degeneration if delivered acutely, but if the drugs are not discontinued within a day or 2, they can cause remote tissue damage and prevent restoration of function (Goldstein 1998; Jones and Schallert 1992; Lodder 2001; Schallert et al. 1986). If GABAergic drugs are introduced after recovery of function, they can transiently reinstate impairments specific to the original injury in people (Lazar et al. 2002), which was reported earlier in rat studies (Schallert and Hernandez 1998; Schallert et al. 1986). N-methyl-D-aspartate (NMDA¹) antagonists also have effects that are quite time sensitive. Additionally, drugs that are beneficial for injury to one particular site may have a profoundly adverse effect on neural and behavioral outcome if delivered in exactly the same way following injury to another site (Barth et al. 1990a; Schallert and Hernandez 1998). Finally, drugs used for surgery to anesthetize animals briefly so that trophic factors or other agents can be delivered can affect cell survival (e.g., Gotts et al. 2000).

One developing strategy has been to design chemical interventions that are less specific in their neuroprotective properties so that they might render tissue less vulnerable to whatever degenerative pressures might arise. Hypothermia, gene transfer techniques that deliver trophic factors, and transplantation of marrow stromal cells are examples of treatments that appear to impart a general resistance to multiple avenues of degeneration (Abe 2000; Chen et al. 2001; Ginsberg and Bogousslavsky 1998; Johansson 2000; Krieglstein and Klumpp 2002). It is important to emphasize that although tissue may be spared by early interventions, tests that are often used to assess spared tissue function may not necessarily have been designed to evaluate the integrity of this tissue. Rather, the tests might target the region of primary infarct instead of the surrounding spared tissue. Finding a relation between function and infarct size depends critically on the location of the damage and/or of the spared tissue. Edema, particularly in hemorrhagic stroke, appears to play a key role in functional outcome without necessarily affecting the extent of damage as seen in standard histological analysis. Treatments that reduce edema may improve function without any obvious link to tissue status (Hua et al. 2002b; Wu et al. 2002). In both animal experiments and human trials, the test battery, even if sensitive to injury to particular structures, would be expected to assess spared tissue only in tests that target that tissue.

Preoperative Experience

Besides aspirin and related drugs, one of the most promising areas of prestroke intervention research involves experiments geared toward understanding the mechanisms of ischemic tolerance. Transient exposure to apparently nondamaging conditions of vascular hypoperfusion within days before an ischemic episode, which would otherwise severely damage brain tissue, can have a remarkable protective effect. Although we have found that procedures that cause ischemic tolerance cause a very transient functional impairment when sensitive behavioral tests are used, the tissue itself is not damaged detectably (Hua et al. 2002a). However, a heat shock protein (a sign of injury) is associated with ischemic tolerance and may initiate plasticity-related events that could render brain tissue less vulnerable to more severe ischemic episodes. The hope of this popular line of investigation is that understanding the mechanisms of ischemic tolerance will provide investigators with novel targets for reducing or preventing the consequences of a major ischemic attack (Ginsberg and Bogousslavsky 1998).

Additional preoperative factors that can influence postoperative outcome include diet, genetics, motor experience, and environment. These factors may reduce or increase the chances of stroke occurrence, its severity, or how efficiently the brain responds chronically to damage (Chen et al. 1996; Kolb 1995; Schallert 1989; Schallert et al. 2000c). Kolb and colleagues found that housing animals in an enriched environment before brain injury causes a 50% increase in the expression of the trophic factor fibroblast growth factor 2 (FGF-2¹) and partial amelioration of functional deficits associated with brain injury (Schallert et al. 2000c). In rats, preoperative forced use of one forelimb by constraining the opposite limb with a vest increases glial-derived neurotrophic factor (GDNF¹) in the hemisphere opposite the overused forelimb and makes the brain resistant to later exposure to neurotoxins that otherwise damage nigrostriatal neurons (Cohen et al. 2003). Additionally, patterned intermittent food restriction that reduces the body weight of animals to 80% of their normal weight for 2 wk before brain injury has sensorimotor functional enhancement and neural protective effects that may relate to the speed of onset of injury-related trophic factor upregulation (Bruce-Keller et al. 1999; Schallert 1989; Schallert and Whishaw 1978). Feeding high fat diets that cause animals to become overweight has opposite, detrimental effects (Molteni et al. 2002; Schallert 1989; Schallert and Whishaw 1978; Wu et al. 2003). Preoperative restricted feeding, which may enhance trophic factor expression, also can have a cooling effect (e.g., preventing injury-induced fever), whereas preoperative fattening can have an overheating effect (Schallert 1989; Schallert and Whishaw 1978). These factors may reasonably contribute to the transoperative effects. These studies are consistent with the considerable body of literature demonstrating the beneficial effects on degree of ischemic injury that result from cooling the brain and the adverse effects of fever (Ginsberg and Bogousslavsky 1998).

In addition to trophic factor expression and temperature, there may be other mechanisms behind the effects of restricted feeding. Preoperative manipulations may interact with recovery processes, improve baseline behavior, and/or tame the animals and familiarize them with handling, novelty, and other aspects of the neurological testing conditions, all of which would provide a decided advantage in the aftermath of severe brain injury. Restricted feeding before injury may have neural or glial carryover effects that linger sufficiently into the postoperative period to impart an influence on the brain's response to injury similar to several known postoperative manipulations that improve outcome (Schallert 1989; Schallert et al. 2000c). Intermittent restricted feeding or watering regimens enhance behavioral reactivity to sensory stimulation even in unoperated animals. It is thus reasonable that part of the beneficial effects of these manipulations is due to improvement in preinjury sensorimotor function that can extend to the postoperative period (reviewed in Schallert 1989). Moreover, when hungry or thirsty rats learn to expect food or water from people, this has an enormous impact on tameness, which improves functional outcome in multiple testing contexts. In other words, the animals become more test friendly in conditions under which untamed animals may be distracted. Testing animals in novel environments can precipitate deficits that are not apparent in familiar environments (e.g., Schallert and Whishaw 1978), but taming the animals with special handling, giving them palatable food treats, or subjecting them to restricted ingestive regimens can impart a certain degree of resistance to some neurological deficits (Schallert 1989).

Early Postacute Neuroplasticity: Use Dependency and Window of Opportunity

In the text below, we describe neural events that occur during the first several weeks after injury. We emphasize those events that appear to respond sensitively to behavioral manipulations. It is important to understand that in addition to long-term outcome testing, early behavioral interventions, including intense rehabilitation procedures such as limb immobilization or acrobatic training, are valuable tools for determining brain-behavior interactions. In traditional studies of brain repair and recovery of function, neural events and behavior are studied as a one-way relation in which brain events drive behavior. It has become increasingly clear, however, that brain events often rely heavily on behavior and sometimes simply do not occur in the absence of appropriate behavioral experience.

Influence of behavior. As noted above, in response to injury, astrocyte proliferation occurs and neurotrophic factors are upregulated in astrocytes over the first few weeks (Bury et al. 2000; Jones et al. 2003). These events may provide an opportunity for shaping brain structure, synaptic events, and function through behavioral enrichment and skills training.

Complex environment housing or acrobatic/skilled motor training are powerful behavioral interventions that influence neural events (Black et al. 1975, 1990; Freund 1996; Greenough et al. 1976; Johansson 1995, 2000; Kaas 1991; Karni et al. 1995; Kozlowski et al. 1996; Nudo et al. 1996; Pons et al. 1991; Rosenzweig 1980; Sanes et al. 1988; Schallert et al. 1980, 1997; Schwartz 1964; Whishaw and Schallert 1977; Whishaw et al. 1976, 1978, 1982; Withers and Greenough 1989). It is unclear how long after ischemic injury the brain is primed for behavior-dependent change, but experiments indicate that after several weeks the capacity for dendritic arborization, for example, is reduced substantially (Johansson 2000; Jones and Schallert 1994; Kolb 1995; Kozlowski et al. 1996; Schallert and Jones 1993; Schallert et al. 1997).

Ischemic or electrolytic lesion damage to the forelimb region of the rat sensorimotor cortex leads to partial impairment in the use of the limb contralateral to the damage as well as over-reliance on the unimpaired forelimb, particularly for weight shifting and skilled motor behaviors. As noted above, injury to the brain leaves remaining tissue prepared, for a period of time, to be reshaped automatically. Although the role of remaining tissue in the damaged hemisphere is critical, increasing attention is being paid to events in the intact hemisphere, especially in the homotopic (i.e., in the same location on the opposite side) cortex and connected regions corresponding to the nonimpaired forelimb, which is doing much of the behavioral work. Events in the intact hemisphere may require modification to enable the animal to use the corresponding limb more efficiently, allowing more time for the impaired forelimb to recover while at the same time allowing participation of the impaired limb together with the nonimpaired limb in complex movements (Schallert et al. 2002a).

Molecular and structural factors. There are a number of molecular and structural events in the intact hemisphere that might contribute to injury-initiated and behavior-modified neuroplasticity (Keyvani and Schallert 2002). Among these events are the expression of growth-correlated markers (e.g., FGF-2, growth-associated protein 43 [GAP-43¹], and synaptophysin), NMDA-dependent hyperexcitability, and reductions in the number of GABA receptors (Finklestein 1996; Kawamata et al. 1997b; Stroemer et al. 1995; Witte 1998; Witte and Stoll 1997). Dendritic arborization followed by pruning and increases in the density of dendritic spines, synaptogenesis, and perhaps neurogenesis have also been shown to occur (Bury et al. 2000; Jones and Schallert 1992; Jones et al. 1997; Parent et al. 2002; Schallert et al. 1997, 2000c). Using electron microscopy, Jones and collaborators (Jones et al. 1996, 2003) have shown that around the time when spine density peaks, which is after the maximal elaboration of dendritic arbors in the electrolytic lesion model (Kozlowski and Schallert 1998), there is an increase in special types of synapses. These synapses are characterized by axons that make synaptic contact with more than one dendrite or have discontinuous expanded regions of postsynaptic densities (perforations), which are thought to be more efficacious than single synaptic contacts (Jones 1999; Jones et al. 1999; Schallert et al. 2002b). These synapses are reminiscent of those formed in the cortex in rats living in an enriched environment (Jones et al. 2003) or during long-term potentiation (LTP¹) in the hippocampus, an activity-related model of rapid learning (Harris 1995).

Learned behavior may be required for the structural events to unfold. For example, enhanced dendritic arborization is blocked when the forelimb corresponding to the structural events is immobilized such that it cannot be used for complex locomotor function (Jones and Schallert 1994; Schallert and Jones 1993; Schallert et al. 1997; Seitz and Freund 1997; Stephan and Frackowiak 1997). If the injured tissue is aspirated after electrocoagulatory damage, the dendritic arborization in the opposite hemisphere is blocked or greatly attenuated, and functional impairment is prolonged. Therefore, it appears that signals from injured tissue contribute in a major way to the use-dependent structural changes and functional outcome (Voorhies and Jones 2002).

Plasticity. There are many other studies showing use-dependent plasticity during the first weeks after injury. Nudo et al. (1996, 2003) have examined the functional properties of the motor cortex in squirrel monkeys using microstimulation mapping techniques before and after focal ischemic injury to the region of the cortical area controlling hand movements. There was a loss of "hand control territory" that gradually extended into healthy cortical tissue. Retraining of hand and wrist food-retrieving skills beginning 5 days after the injury prevented the extension of tissue loss, an effect shown also in rats (Kleim et al. 1998, 2002). Castro-Alamancos et al. (1992, 1995) used reinforcing electrical stimulation contingent on specific movements to improve functional outcome and reorganize brain tissue closely adjacent to focal ischemic injury to the motor cortex, as indicated by cortical mapping techniques.

In the peri-injury zone, LTP-like neuronal activity or epileptoid bursting may drive some of the effects of motor interventions on plasticity and behavior (Carmichael and Chesselet 2002; Eysel 1997; Johansson 2000; Witte 1998). Indeed, brief seizures produced by electroconvulsive shock or chemoconvulsant drugs during the first few days after injury enhance the rate of recovery of function (Feeney et al. 1987; Hernandez and Schallert, 1988). The peri-injury zone may extend a few millimeters outside the region of damaged tissue and 0.5 to 1 mm outside the penumbral tissue in which neural activity is reduced (Eysel 1997). During the first several days after focal heat-induced injury to the sensorimotor cortex, in vitro examination of field potentials and single cell electrophysiology indicated that the region outside the penumbra had an increased level of NMDA-mediated excitatory postsynaptic potentials and reduced GABA-mediated currents. These in vitro effects were not present in vivo, however, suggesting that metabolic, vascular, or other deficiencies contributed to the penumbral suppression. Normalization of these events occurred after the first week. A recent study by Strong et al. (2002) suggests that this suppression could be associated with injury-triggered cortical spreading depressions (i.e., "waves" of depressed electrical activity in the cortex), the discontinuation of which may contribute to recovery.

GABA receptor regulation. After focal photothrombotic injury, the intermediate peripenumbral zone is hyperexcitable for several weeks, and inhibitory GABA_A receptors are downregulated there (Witte 1998; Witte and Stoll 1997). Moreover, in the focal heat-injury model, fast GABA_A- and slow GABA_B-mediated inhibitory postsynaptic potentials are greatly reduced in vitro (Eysel 1997), which could lead to an increase in the activation of NMDA receptors (Luhmann and Prince 1990). Consistent with these findings, diazepam administered peripherally or GABAergic agonists infused locally into the sensorimotor cortex during the first week after more medially located focal lesions severely impairs recovery of function (even chronically, long after discontinuation of the drug), whereas low doses of GABAergic antagonists can improve recovery (Hernandez and Schallert 1988; Schallert and Hernandez 1998; Schallert et al. 1986). Eysel (1997) and Witte and Stoll (1997) suggest that mild LTP-like hyperexcitability of perilesion neurons may sometimes favor functional reorganization, whereas neuronal inhibition may impede it, and that early physical therapy or impoverished environments may mirror or interact with the excitation or inhibition, respectively (see also Johansson 2000). The role of injury-induced or activity-dependent neurotrophic factor expression in the perilesion region in modulating these electrophysiological events remains to be determined, although neurotrophic factors applied in vitro can enhance synaptic transmission by affecting GABA_A receptors (Tanaka et al. 1996, 1997).

Brain Injury, Motor Enrichment, and FGF-2

As noted above, many neurotrophic factors are upregulated in astrocytes after ischemic or other types of brain injury. Trophic factors are enhanced by motor therapies (Bury et al. 2000; Gómez-Pinilla et al. 1977) or noradrenergic agonists such as amphetamine (Flores and Stewart 2000) that, when combined with physical rehabilitation or environmental enrichment, may promote learning of motor strategies to compensate for deficits in function (Feeney and Sutton 1987; Feeney et al. 1987; Goldstein, 1998; Karhunen et al. 2003). Because adjacent and remotely located tissue degenerates slowly after focal brain injury for weeks or months after the primary damage, it is possible that one or several of these trophic factors could contribute to survival, maintenance, and plasticity of neural, glial, or vascular cells (Bury et al. 2000; Kolb 1995; Logan et al. 1992; Mattson and Scheff 1994; Nieto-Sampedro and Cotman 1985; Riva et al. 1992; Schallert et al. 2002b,c; Speliotes et al. 1996; Takami et al. 1992; Thoenen 1995). Among the most explored of these factors is FGF-2.

FGF-2 immunoreactivity can be seen in the nuclei of astroglia and neurons in many brain regions (Mattson and Scheff 1994; Speliotes et al. 1996). Immediately after injury, FGF-2 mRNA expression is observable most prominently in the nuclei and cell bodies of reactive astrocytes surrounding the injury (Bury et al. 2000; Finklestein 1996; Finklestein et al. 1988; Frautschy et al. 1991; Humm et al. 1997; Humpel et al. 1994; Schallert et al. 2000c). FGF-2 mRNA precedes FGF-2 protein expression (Speliotes et al. 1996).

After injury, glial, endothelial, and neural cells express high-affinity FGF-2 receptors (Wanaka et al. 1990), and FGF-2 receptor binding in neurons is enhanced for several weeks (Kato et al. 1992). Binding of FGF-2 to one of these high-affinity receptors appears to cause an intracellular signal transduction cascade leading to gene expression and protein synthesis (Dionne et al. 1990; Keegan et al. 1991; Lee et al. 1989; Partanen et al. 1991). FGF-2 is a potent mitogen, even at low concentrations, and therefore may cause cell proliferation, differentiation, and migration of fibroblasts, endothelial cells, glial cells (particularly astrocytes), neuronal precursors, myoblasts, and a number of other cell types (Burgess and Maciag 1989; Gritti et al. 1996; McDermott et al. 1997; Menon and Landerholm 1994; Morrison et al. 1986, 1988; Thomas 1987; Thomas and Gimenezgallego 1986; Walicke 1988).

Excitatory amino acids or other injury-related or behavior-modulated signals (e.g., increased free radicals, nitric oxide, or heat shock protein induction) are likely to influence the expression of FGF-2 (Kawamata et al. 1997b; Mattson and Scheff 1994; Sharp et al. 1998). In addition, polysialic acid-neural cell adhesion molecule levels are increased along with cellular mitosis in the forebrain subependyma 1 wk after frontal cortex damage (Schallert et al. 2000c; Szele and Chesselet 1996), as are L-1 antigen and other molecules involved in cell proliferation, process outgrowth, and migration (Giordana et al. 1994; Khoja et al. 1995). In the dorsolateral corner of the forebrain subependyma, FGF-2 expression (Humm et al. 1997) and cytochrome oxidase activity (Valla et al. 1999) are also increased 1 wk after electrolytic or suction lesions of the forelimb area of sensorimotor cortex.

Rowntree and Kolb (1997), using immunostaining with FGF-2 antisera, found that astrocytes expressing FGF-2 were visible in the region surrounding a focal suction ablation of the sensorimotor cortex. There was a temporal and spatial increase in FGF-2 immunoreactivity between days 2 and 7 after injury, which gradually declined (although it was still easily detectable) by day 21. This overexpression of astrocytic FGF-2 may be linked with neuronal outgrowth that occurs later after injury (Nieto-Sampedro and Cotman 1985). Rowntree and Kolb (1997) propose that the delay in sprouting may be due partly to the time it takes for locally expressed FGF-2 to be transported to neuronal cell bodies retrogradely (Grothe and Wewetzer 1996).

The spatial and time-dependent characteristics of FGF-2 expression are likely to be influenced by motor experience and differ from one lesion model to another, as indicated by research on entorhinal cortex lesions in the laboratory of Gómez-Pinilla et al. (1977, 1992) and research on cerebral infarction by Speliotes et al. (1996). Injury that induces spreading depression or seizures in the period immediately after the injury might be expected to have characteristic FGF-2 onset because these events may contribute to the initiation of FGF-2 and FGF-2 mRNA expression (Follesa et al. 1994; Lippoldt et al. 1993; Witte and Stoll 1997). Thus, it is necessary to characterize the sequence of specific postinjury events carefully for the particular model being adopted, especially when motor interventions are used.

Rowntree and Kolb (1997) showed that when FGF-2-neutralizing antibodies were infused via gelfoam placed directly into the lesion site, the number of FGF-2-positive (but not glial fibrillary acidic protein-positive) astrocytes was decreased substantially. Dendritic arborization and spine density in surviving neurons within the same peri-injury area were dramatically reduced, and recovery of function in the contralateral limb was disrupted markedly. Control agents, including saline or biotinylated anti-goat immunoglobulin G developed in rabbit, had virtually no effect on FGF-2 expression, dendritic morphology, or sensorimotor outcome. It was suggested that FGF-2 antibodies block the expression of FGF-2 in astrocytes by occupying an otherwise active site on the FGF-2 molecule, which would prevent the molecule from binding to FGF receptors on cells (Rowntree and Kolb 1997). Because FGF-2 promotes neuronal survival and neurite extension (Anderson et al. 1988; Grothe et al. 1989; Otto et al. 1989; Sievers et al. 1987; Walicke 1988), this factor may facilitate neuronal integrity, neuritic outgrowth (or regrowth), and recovery of function after injury.

Exogenous FGF-2 as After-Injury Treatment

Exogenous delivery of FGF-2 promotes survival of neurons and recovery of function after brain damage or transplantation procedures in animals (Brecknell et al. 1996; Cummings et al. 1992; Mayer et al. 1993; Sabel et al. 1997). Significant neuroprotection was also found after fluid percussion injury, which is designed to simulate a blow to the head (Dietrich et al. 1996; McDermott et al. 1997), as well as after fimbria-fornix transection (Anderson et al. 1988; Cummings et al. 1992; Gómez-Pinilla et al. 1992; Miyamoto et al. 1993; Otto et al. 1989), axon-sparing striatal damage (Frim et al. 1993), neurotoxic damage to nigrostriatal dopaminergic neurons (a model of Parkinson's disease; Otto and Unsicker 1990), vascular injury (Yamada et al. 1991), and kainic acid induced neuronal damage (Liu et al. 1993).

Pretreatment with exogenous FGF-2 just before unilateral middle cerebral artery occlusion (so that it is in the brain at the time of injury) prevents or attenuates the usual expansion of the infarct into the penumbral tissue (Finklestein 1996). FGF-2 delivered intracisternally starting 24 hr after unilateral middle cerebral artery occlusion (at a time when maximal infarct would have occurred but before the onset of delayed gradual degeneration of cells), and twice weekly for several weeks thereafter, enhanced recovery of limb use function without affecting the size of the infarct detectably (Kawamata et al. 1996).

In collaboration with Finklestein's group, we showed that a comparable pattern of delayed intracisternally delivered FGF-2 led to upregulated expression of a growth-associated marker (GAP-43) and promoted modest use of the impaired forelimb for simple placing and landing functions for vertical-lateral exploratory behavior. The treatment previously appeared to improve bilimb (i.e., simultaneous) use and interlimb coordination, thereby reducing preferential reliance on only the good limb for these movements (Kawamata et al. 1997a).

FGF-2 may alter the expression of other neurotrophic factors. For example, FGF-2 application leads to increases in nerve growth factor (NGF¹) in astrocytes in vitro (Yoshida and Gage 1991) and in vivo (Yoshida and Gage 1992). It is well established that NGF enhances dendritic arborization and improves recovery of motor function after sensorimotor cortical injury (Kolb 1995; Kolb et al. 1997). FGF-2 may even interact with NGF to promote regeneration. It appears reasonable that the interaction between FGF-2 and NGF might be modulated by motor experience.

Seizure activity increases the mRNA of several neurotrophic factors, including FGF-2 (Ernfors et al. 1991; Follesa et al. 1994; Gall and Isackson 1989). This finding may be significant in light of studies showing that mild doses of convulsant drugs or mild electroconvulsant stimulation of the amygdala can increase motor behavior and promote recovery of function after injury. Mirroring these findings, anticonvulsant GABAergic agonists can disrupt recovery of function and exaggerate subcortical degeneration associated with anteromedial cortical injury (Jones and Schallert, 1992; Schallert and Hernandez 1998, for review).

Forced nonuse of the affected forelimb in rats appears to reduce neurotrophic factor expression and dendritic arborization in the peri-injury region (Schallert et al. 2002b). The extent to which expression of neurotrophic factors other than FGF-2 is inhibited by motor disuse after brain injury is unexplored, although, as noted above, GDNF is increased by forced use of the forelimb in the corresponding hemisphere (Cohen et al. 2003). Moreover, forced nonuse can exaggerate the degenerative effects of neurotoxins (Tillerson et al. 2002).

Several growth factors are associated with neurotransmitter release in the intact adult and developing brain, and the potential exists for these factors to be modified by decreasing or increasing sensory and motor activity (Lindholm 1997, for review). Indeed, neurotrophin production is thought to be influenced by the balance of excitatory (e.g., glutamatergic) and inhibitory (e.g., GABAergic) neuronal activity (Lindholm 1997).

In vitro, FGF-2 promotes neurite outgrowth and glutamate causes dendritic retraction; however, balancing the doses of each can lead to specific synapse selection that models use-dependent plasticity (Finklestein 1996; Kozlowski et al. 1994; Mattson et al. 1993). Without sufficient FGF-2, glutamate can compromise or even kill the neuron; and without sufficient glutamate, FGF-2 can produce excessive outgrowth (Cotman et al. 1989; Mattson et al. 1993). Cotman et al. (1989) have suggested that throughout the life span, growth factors like FGF-2 and activity-related neurotransmitters like glutamate interact in a mutually antagonistic way to produce, select, and maintain dendritic or axonal processes and synapses. According to Cotman and colleagues, these interactions are involved in the normal development of much of the nervous system, and in plasticity after brain injury and degenerative disorders. Complex housing environments may influence these interactions (Benefiel and Greenough 1998). The dynamic nature of trophic factors and excitatory transmitters also may be relevant to the erosive process of aging, wherein there is a decline in the capacity for trophic factors to be expressed relative to glutamatergic activity (Tropepe et al. 1997).

FGF-2 is primarily an axon-stimulating protein. After permanent MCA occlusion (MCAO¹), the dendrite-promoting protein, osteogenic protein 1 (OP-1¹), has been shown to produce a small but significantly detectable improvement in limb use asymmetries for weight shifting exploration along vertical walls, which lasts up to 90 days (Schallert et al. 2000b). These results are comparable to those obtained with FGF-2 in the identical stroke model (Kawamata et al. 1997a). Neither FGF-2 nor OP-1 appears to exert a large enough effect on independent use of the impaired forelimb to be clinically promising, although with motor therapy specifically targeting the impairment, these agents conceivably could be detectably effective in well-designed clinical trials that match the preclinical studies.

Delayed Degeneration of Tissue: Use Dependency and Window of Vulnerability

Slowing or stopping the relentless and progressive delayed degeneration of tissue in brain areas surrounding and remote from the site of injury has become an important focus of stroke research. Although degeneration slows down beyond the first week after ischemic injury, it can continue for weeks or months after the primary damage (Conti et al. 1998; Du et al. 1996; Kozlowski et al. 1996). Indeed, it appears that even tissue that is spared initially (e.g., by hypothermia, glutamate antagonists, or ischemia preconditioning) may eventually degenerate at later time points (Colbourne et al. 2000; Dietrich et al. 1993).

A major segment of current research in brain injury is devoted to preventing this secondary loss of tissue spared by early interventions. Extending the period of hypothermia (e.g., to 48 hr) has been shown to greatly attenuate delayed loss of neurons and to improve chronic functional outcome in stroke models (Colbourne et al. 1999, 2000; Corbett et al. 2000). Note, however, that rescuing neurons from delayed degenerative processes is not always beneficial in a functional sense, particularly if inhibitory input to these regions is not also spared so that, in effect, the brain is left with renegade tissue that is hyperactive in contexts in which it normally would be quiescent (Schallert and Hernandez 1998). This seemingly paradoxical situation is not so surprising given that a large number of neurological symptoms in animals and people are related to activity in remote brain regions that is excessively disinhibited.

Delayed exaggerated degeneration of tissue, continuing for several months after brain injury, occurs when intense use of the impaired forelimb is imposed after focal sensorimotor cortex injury (Kozlowski et al. 1996; Schallert et al. 2000a; Schallert and Hernandez 1998). By 60 days the size of the injury is typically doubled. Immobilization of the nonimpaired forelimb for the first 7 days after injury, but not during the second 7 days, leads to exaggerated degeneration of adjacent cortical and subjacent striatal tissue. Tissue remaining after the original insult apparently is susceptible to excessive behavioral demand and can be fatally injured by it. However, although stereological analysis can detect modest use-dependent tissue loss by 2 to 3 wk after the injury, for unknown reasons the tissue continues to degenerate up to 60 days postoperatively and includes a secondary loss of cells in substantia nigra pars reticulata. This effect, which is attenuated by intermittent exposure to halothane or NMDA antagonists (Gotts et al. 2000; Humm et al. 1998, 1999), is not due to systemic events such as increased corticosterone levels because immobilization of the contralateral (impaired) limb, which produces a comparable small increase in corticosterone levels during limb immobilization, does not exaggerate the injury detectably (although it does reduce the extent of dendritic arborization in the peri-injury layer V pyramidal neurons and has a transient effect on functional outcome; Schallert et al. 2000c). Moreover, Colbourne and his colleagues at the University of Calgary, Calgary, Alberta, Canada (unpublished data, 2002) have found that forcing overuse of the impaired forelimb after unilateral sensorimotor cortex lesions, but not after visual cortex lesions, causes delayed exaggeration of injury comparable to that found in the Kozlowski et al. (1996) study. This finding indicates that use-dependent exaggeration of injury is not caused by systemic events.

In MCAO models in which the infarct is restricted to the neocortex (Belayev et al. 1996), forced overuse of the affected forelimb increases the size of the infarct (Bland et al. 2000, 2001; Risedal et al. 1999; Schallert et al. 2000a). However, overuse of an injury-impaired forelimb does not always lead to exaggeration of injury. Infarcts caused by MCAO that extend deeply into striatal tissue are not exaggerated. Also, in 6-hydroxydopamine or MPTP parkinsonian models of slow degeneration of nigrostriatal dopamine neurons, forced overuse of the forelimb or treadmill exercise greatly attenuates the extent of degeneration, sparing key markers of dopamine neuron integrity and function (Schallert et al. 2000a; Tillerson et al. 2001, 2002, 2003), whereas forcing nonuse of the impaired forelimb causes exaggerated degeneration and functional impairment after subclinical doses of neurotoxin (Tillerson et al. 2002). This "use it or lose it" pattern is in contrast to what is seen in cortical lesions and underscores the complexity with which behavioral interventions can interact with neural events to promote recovery, dependent not only on the time course of recovery events but also on the spatial pattern of brain damage seen in different lesion models.

Delayed Motor Therapy

It is well established that if the sensorimotor cortex is subtotally damaged, considerable function can be restored in the impaired forelimb. However, if sensitive tests are used, residual impairment can usually be detected (Barth et al. 1990b; Black et al. 1975; Bucy 1944; Denny-Brown 1950; Fulton and Kennard 1934; Gless and Cole 1950; Gowland 1987; Kolb 1995; Lashley 1924; Lieberman 1986; Passingham et al. 1983; Penfield 1954; Schallert et al. 1997, 2000b; Travis and Woolsey 1956; Twitchell 1951; Whishaw et al. 1991).

Taub et al. (1993) have shown that residual impairment of the affected limb in humans is partially amenable to motor therapy because it is associated with "learned nonuse," a phenomenon that can also be seen to some extent in animal models (Denny-Brown 1950; Schallert et al. 1997, 2002a,c; Winstein and Pohl 1995; Taub 1993). Delayed therapies that target motor learning and motivation have been successful in stroke patients that evidence partial recovery of function (Ostendorf and Wolf 1981; see also Odin and Franz 1917, cited in Lashley 1924). Animals appear to adopt alternative motor strategies to compensate for dysfunction caused by injury or drugs (Bach-y-Rita 1990, 1993; Day and Schallert 1996; Gentile et al. 1978; LeVere 1988; Rose et al. 1987; Schallert 1988, 1989, 1995; Schallert and Whishaw 1984, 1985; Schallert et al. 1992, 1996, 1997). Although these learned strategies can be dramatically effective for some tasks, the animals may fail to achieve their maximum potential for function because the compensatory strategies become so successful. Synaptogenesis in the intact cortex may mediate, or at least contribute to, many of these strategies. Behavioral tests that detect the ways in which these strategies are used to compensate have been devised so that the residual deficits are revealed and true brain repair can be evaluated and potentially promoted (Schallert et al. 2002a,c).

In humans, once it is clear how they compensate, moderate rehabilitative pressure can be applied that focuses preferentially on the impaired extremity. Long-standing deficits have been ameliorated by repetitive extremity-specific skills training or by immobilizing the unaffected limb as has been done experimentally in rats and primates (Freund 1996; Liepert et al. 2000; Taub 1980; Taub et al. 1993, 1996). Even several months after a stroke, immobilizing the unaffected arm to encourage physical rehabilitation of the affected arm has been reported to improve the function of the affected arm or digits. However, the degree to which the improvement might be mediated, at least in part, by alternative strategies will require careful kinematic analysis.

In later periods after stroke, the brain may no longer be primed with trophic factors or other plasticity-promoting factors characteristic of the early postinjury period. Therefore, it has been argued that delivery of exogenous trophic factors, together with skills training aimed specifically at the primary residual deficit, may provide optimal rehabilitation in long-term stroke survivors. In animal models of stroke, it is thus necessary to use appropriate behavioral tests that not only detect residual deficits reliably but also do not detect improvement in the absence of training that targets the deficits (Schallert and Whishaw 1984; Schallert et al. 1986, 2000b, 2002c; Zhang et al. 2002).

Conclusions

Housing and handling factors, as well as behavioral manipulations and functional outcome test selection, are key considerations in animal modeling of brain injury and recovery of function and in preclinical investigations of potential treatments. Time-dependent glial and neural events associated with brain repair and recovery of function may both drive and be driven by behavior. Pre- and postoperative behavioral manipulations may influence acute and chronic mechanisms of plasticity and degeneration.

There appears to be a window of opportunity during which the brain is particularly ready for change, due in part to upregulation of endogenous neurotrophic factor expression in astrocytes. Enriched motor housing before ischemic injury appears to enhance the capacity of astrocytes in the brain to express neurotrophic factors. Both brain injury and nonintense postoperative behavioral demand may be needed for optimal rewiring of the brain. Exogenously delivered trophic factors may slightly improve outcome. However, in later periods after injury, when mechanisms of plasticity are no longer primed, the effects of trophic factor delivery may be much greater, provided that limb-specific skills training is coadministered. Animals with brain injury self-regulate disuse of the impaired forelimb, which means that endogenous trophic factor treatment might be without effect on the impairment unless more normal use of the limb is simultaneously targeted by therapy.

Forced total nonuse of the affected forelimb after stroke (by immobilization of the impaired forelimb) can stunt neural growth and retard functional recovery, suggesting that complete motor quiescence during the first week or so after injury may be detrimental. However, extreme forced overuse of the impaired forelimb can promote delayed severe degeneration and functional deficits, depending on the site and type of injury. In stroke models, the extent of the primary infarct and the timing of the motor training can be significant factors in determining whether rehabilitative pressure has a beneficial or adverse effect on outcome. Use-dependent extracellular glutamate and NMDA receptor activation may interact with vascular, metabolic, or other factors associated with excessive movement to degrade perilesion tissue, which appears to be vulnerable during the first week or so after injury.

Finally, we suggest that delayed rehabilitation that prevents the use of compensatory strategies specifically aimed at the true impairment, perhaps together with delivery of neurotrophic factors at levels comparable to that observed early after the injury, may be effective long after a stroke when recovery of function stabilizes. We also conclude that, as suggested by Cenci et al. (2002), rodents make excellent models for stroke and other neurological disorders, provided that they receive appropriate housing and behavioral experience and that investigators use appropriate outcome measures.

Acknowledgments

The authors thank Jitsen Chang, Ted Lin, Marnie Preston, and Gabriela Redwine for their contributions to this work. This work was supported by National Institutes of Health grant NS 23979.

¹Abbreviations used in this article: FGF-2, fibroblast growth factor 2; GABA, gamma-amino butyric acid; GAP-43, growth-associated protein 43; GDNF, glial-derived neurotrophic factor; LTP, long-term potentiation; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; MPTP, 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; OP-1, osteogenic protein 1.

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