Stroke remains a leading cause of morbidity and mortality in the US. Our recent work has shown that neuronal regeneration in the hippocampus after cerebral ischemia due to an increased proliferation and differentiation of neural stem cells located in the dentate gyrus. Recovery of cognitive function has been documented in both humans and experimental animals. This suggests that hippocampal neural stem cells may be involved in the structural repair of the dentate gyrus and functional recovery. The goal of this study is to determine if neural stem cells play a role in maintaining the structural integrity of the dentate gyrus and in mediating the functional recovery of rats receiving a focal ischemic insult. This proposal will also determine if an enriched environment increases the survival of newly born neurons induced by the ischemic injury, and if the environmental enhancement of functional recovery after stroke is dependent on the neuroplasticity mediated through neural stem cells. The long term objective of this studies are to enhance stroke-related brain plasticity as a potential rehabilitation therapy. It is hypothesized that: (a). Disruption of neurogenesis in the granule cell layer by depleting the progenitor pool prior to cerebral ischemia will result in the loss of structural integrity of the dentate gyrus, and reduced functional recovery of ischemia-induced impairments of spatial learning and memory. (b). An enriched environment will enhance the survival of dividing progenitor cells and increase the frequency of neuronal differentiation among their surviving progeny after ischemia. (C). When the postoperative animals are housed in an enriched environment, enhanced stem cell plasticity also mediates their improved cognitive function. Experiments will determine whether the depletion of dentate gyrus progenitor cells by radiosurgery affects the structure of dentate gyrus and the functional recovery after focal ischemia. The total number of granule cell neurons in the granule cell layer will be measured and the performance of behavioral tests will be compared in both stem cell-depleted and control groups after ischemia. Experiments are also designed to test if an enriched environment will enhance the survival of ischemia-induced new born neurons and increase the frequency of neuronal differentiation among the surviving progeny by housing postoperative animals in an enriched environment. The final set of experiments will determine if hippocampal neural stem cells also mediates improved cognitive function of ischemic animals placed in an enriched environment after surgery.
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