Background and Purpose-Behavioral experience can drive brain plasticity, but we lack sufficient knowledge to optimize its therapeutic use after stroke. Methods-We outline recent findings from rodent models of cortical stroke of how experiences interact with postinjury events to influence synaptic connectivity and functional outcome. We focus on upper extremity function. Results-After unilateral cortical infarcts, behavioral experiences shape neuronal structure and activity in both hemispheres. Key Words: learned nonuse Ⅲ motor cortex Ⅲ motor rehabilitation Ⅲ synaptic plasticity B ehavioral experience can cause dendrites to grow and regress, synapses to change in efficacy, vasculature and glia to be modified, and, sometimes, neurons to be added or lost. 1 It is at work continuously and across the lifespan. It is safe to assume that it will be a factor in stroke recovery. However, what pragmatic use can we make of this? Currently, experience, in the form of physical therapy and rehabilitation, is the major tool available for treatment in the chronic poststroke period, but we lack the knowledge required to optimize its use alone or in combination with other treatments. Animal research is beginning to reveal how behavioral experience interacts with degenerative and regenerative cascades after stroke onset. This research suggests that the nature and timing of behavioral experiences can have a major influence on brain reorganization with good, bad, and mixed consequences for functional outcome. Shaping Postinjury ExperienceBrain damage can impair and enhance experience-dependent plasticity depending on the region and time window after the injury. 1,2 We have found that, in rats with unilateral ischemic sensorimotor cortical lesions, the contralesional motor cortex, in concert with transcallosal degenerative changes, becomes more sensitive to behavioral experiences of the ipsilesional "unaffected" forelimb ( Figure). 3 After these lesions, rats spontaneously begin to rely more on the unaffected forelimb and this drives the growth of synapses and dendrites in the contralesional cortex. More synapses also have ultrastructural characteristics of enhanced efficacy. These effects occur more robustly than those resulting from similar asymmetrical forelimb experience in intact animals. Thus, this is an example of injury-induced enhancement of experiencedependent plasticity.The facilitation of plasticity in the contralesional cortex may enhance an animal's ability to learn compensatory ways of using the unaffected forelimb. Consistent with this, even in the presence of significant impairments in the "unaffected" limb, some types of skill acquisition with this limb are enhanced, an effect that is lesion size-and time-sensitive. 3,4 However, there is a cost for the impaired limb. When rats were trained to use the unaffected limb for skilled reaching in the weeks after injury, it reduced neuronal activation (as assayed by FosB/⌬FosB expression) in the remaining periinfarct motor cortex, a region that is important for recovery of ...

Background In animal stroke models, peri-infarct cortical stimulation (CS) combined with rehabilitative reach training (RT) enhances motor functional outcome and cortical reorganization, compared with RT alone. It was unknown whether the effects of CS+RT: 1) persist long after treatment, 2) can be enhanced by forcing greater use of the paretic limb and 3) vary with treatment onset time. Objective To test the endurance, time-sensitivity, and the potential for augmentation by forced forelimb use of CS+RT treatment effects following ischemic stroke. Methods Adult rats that were proficient in skilled reaching received unilateral ischemic motor cortical lesions. RT was delivered for 3 weeks alone or concurrently with 100Hz cathodal epidural CS, delivered at 50% of movement thresholds. In study 1, this treatment was initiated at 14 days postinfarct, with some subgroups receiving an overlapping period of continuous constraint of the nonparetic forelimb to force use of the paretic limb. The function of the paretic limb was assessed weekly for 9–10 mo post-treatment. In study 2, rats underwent CS, RT and the combination during the chronic post-infarct period. Results Early onset CS+RT resulted in greater functional improvements than RT alone. The CS-related gains persisted for 9–10 mo post-treatment and were not significantly influenced by forced-use of the paretic limb. When treatment onset was delayed until 3 mo post-infarct, RT alone improved function, but CS+RT was no more effective than RT alone. Conclusion CS can enhance the persistence, as well as the magnitude of RT-driven functional improvements, but its effectiveness in doing so may vary with time post-infarct.

Unilateral damage to sensorimotor cortical (SMC) regions can profoundly impair skilled reaching function in the contralesional forelimb. Such damage also results in impairments and compensatory changes in the less-affected/ipsilesional forelimb, but these effects remain poorly understood. Furthermore, anesthetization of the ipsilesional hand in humans with cerebral infarcts has been reported to produce transient functional improvements in the paretic hand [14,48]. One aim of this study was to sensitively assay the bilateral effects of unilateral ischemic SMC damage on performance of a unimanual skilled reaching task (the single pellet retrieval task) that rats had acquired pre-operatively with each forelimb. The second aim was to determine whether partially recovered contralesional reaching function is influenced by anesthetization of the ipsilesional forelimb. Unilateral SMC lesions were found to result in transient ipsilesional impairments in reaching success and significant ipsilesional abnormalities in reaching movements compared with sham-operates. There were major contralesional reaching impairments which improved during a 4 week training period, but movements remained significantly abnormal. Anesthetization of the ipsilesional forelimb with lidocaine at this time attenuated the contralesional movement abnormalities. These findings indicate that unilateral ischemic SMC lesions impair skilled reaching behavior in both forelimbs. Furthermore, after partial recovery in the contralesional forelimb, additional improvements can be induced by transient anesthetization of the ipsilesional forelimb. This is consistent with the effects of unilateral anesthetization in humans which have been attributed to the modulation of competitive interhemispheric interactions. The present findings suggest that such interactions are also likely to influence skilled reaching function in rats.

Reaching tasks are popular tools for investigating the neural mechanisms of motor skill learning and recovery from brain damage in rodents, but there is considerable unexplained variability across studies using these tasks. We investigated whether breeder, batch effects, experimenter, time of year, weight and other factors contribute to differences in the acquisition and performance of a skilled reaching task, the single pellet retrieval task, in adult male Long-Evans hooded rats. First, we retrospectively analyzed task acquisition and performance in rats from different breeding colonies that were used in several studies spanning a three year period in our laboratory. Second, we compared reaching variables in age-matched rats from different breeders that were trained together as a batch by the same experimenters. All rats had received daily training on the reaching task until they reached a criterion of successful reaches per attempt. We found significant breeder-dependent differences in learning rate and final performance level. This was found even when age-matched rats from different breeders were trained together by the same experimenters. There was also significant batch-to-batch variability within rats from the same breeder trained by the same experimenter. Other factors, including weight, paw preference and the experimenter, were not as strong or consistent in their contributions to differences across studies. The breeder and batch effects found within the same rat strain may reflect genetic and environmental influences on the neural substrates of motor skill learning. This is an important consideration when comparing baseline performance across studies and for controlling variability within studies.