SPACE PROVIDED. The goal of the proposed project is to investigate how the aged brain responds to skilled motor training, both before and after stroke-like brain injury. This will be accomplished by first determining differences in behavior and neural plasticity in intact young and aged mice, and then by determining how behavior and neural plasticity change following motor cortex stroke and behavioral rehabilitation in young and aged mice. The hypothesis that the aged brain retains plasticity in response to skilled motor training, both before and after brain injury, but that the time course of learning and plasticity will differ from that of young animals, will be tested the following specific aims: (1) examine the rate of learning a skilled reaching task in intact young and aged mice, (2) examine training-induced structural and functional plasticity in the motor cortex of intact young and aged mice, (3) determine the rate of behavioral recovery following unilateral ischemic stroke and motor rehabilitation in young and aged mice, and (4) determine the ability of the injured hemisphere to recover neural function following ischemia and rehabilitation in young and aged mice. Mice will be trained and assessed on two skilled reaching tasks: the pasta matrix reaching task and the single seed retrieval task. Functional and structural plasticity in the motor cortex will be assessed using intracortical microstimulation (ICMS) to derive motor maps of the forelimb area of motor cortex and immunohistochemical analyses of activity and plasticity-associated proteins, specifically FosB/AFosB, PSD95, and MAP2. In studies of plasticity and functional recovery following motor cortex lesions, intracortical injections of endothelin-1, a vasoconstricting peptide, will be used to create unilateral ischemic lesions of the forelimb area of motor cortex contralateral to the preferred reaching limb. It is hypothesized that aged mice, as compared to young mice, will be slower to learn the skilled reaching task, and will take longer to recover to pre-lesion performance levels after ischemia and motor rehabilitation. It is predicted that aged mice will be more resistant to training-induced plasticity of the motor cortex, and that this plasticity will be stunted even more following ischemia. However, it is expected that the aged brain will retain the ability to recover from ischemia if given an extended period of rehabilitation. The overall goal of the proposed project is to better understand the plasticity of the aged brain in response to skilled motor training, both before and after brain injury. Aged mice will be a valuable tool for studying the effect of stroke on the aged brain, allowing adaptation of rehabilitative therapies to better suit the unique demands of the aged brain, thereby providing a more clinically relevant model of stroke than young mice.
