Enhancing Recovery after Neonatal Stroke

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DESCRIPTION (provided by applicant): Recent studies suggest that behavioral interventions enhance functional recovery after stroke. We developed experimental models in which to study the impact of behavioral intervention on recovery after neonatal stroke, to enable us to learn more about underlying mechanisms of post-injury plasticity in the immature brain. In a well-characterized neonatal rodent stroke model, elicited by unilateral carotid ligation followed by moderate hypoxia exposure in seven-day-old (P7) rats, we documented that spatial learning is impaired. We recently also demonstrated bilateral decreases in hippocampal dendritic length, branching and spine density after neonatal stroke. We evaluated the impact of the behavioral intervention, neonatal "Handling" on the post-stroke cognitive deficit. Handling (brief daily separation from the dam) is extensively studied; its effects include increased synaptogenesis, increased Brain-Derived Neurotrophic Factor (BDNF) production, and improved learning rates. We demonstrated that, after neonatal stroke, treatment with daily Handling resulted in improved spatial learning in adulthood. A limitation of Handling is its between-litter design. The recently described "Neonatal Novelty" paradigm replicates many of Handling's effects in a within-litter design. Preliminary studies of post-hypoxic-ischemic Novelty suggest it also leads to improved cognitive outcome in adulthood. In this proposal, we will begin to identify the neural mechanisms that underlie the beneficial effect of behavioral intervention (Neonatal Novelty) after neonatal stroke. In the P7 rat stroke model, we will determine whether treatment with a 2-week Novelty protocol results in increased synapse formation (Aim 1), and changes in BDNF, trkB and ERK1/2 in the post-ischemic period (Aim 2). Animals will be lesioned on P7; 2.5 mo. later we will evaluate 3 measures of synapse formation: (i) dendritic morphology, (ii) synaptophysin, (iii) NCAM. We predict that behavioral intervention will reverse post-stroke synaptic deficits. In Aim 2 we will evaluate changes in hippocampal and cortical BDNF, its receptor trkB and the downstream MAP kinase ERK1/2, during post-stroke Neonatal Novelty exposure. We hypothesize that both Neonatal Novelty and stroke will stimulate BDNF production and that the stroke-induced increase in BDNF and its downstream signaling will be amplified by the behavioral intervention. Together these experiments will provide insights into the mechanisms that mediate and modulate functional recovery after neonatal stroke.