Vascular Contributions to Enriched Rehabilitation in Hypertension

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Project Summary/Abstract This project is designed to address a gap in vascular contributions to cognitive impairment/dementia (VCID) research by determining the role and vascular mechanisms by which rehabilitation impacts post-stroke cognitive impairment, a principal VCID, in hypertension, the leading comorbid disease in patients with VCID and stroke. The central hypothesis is that enriched rehabilitation prevents profound progressive post-stroke cognitive impairment and improves functional outcomes in hypertensive animals via restoration of mature brain-derived neurotrophic factor (BDNF)-dependent vasotrophic coupling. In order to test this hypothesis, the proposal contains two specific aims to determine (1) the impact of ER on functional recovery after ischemic brain injury in hypertension and (2) the role of the BDNF system in the vascular contributions of ER-mediated recovery after ischemic brain injury in hypertension. Male and female spontaneously hypertensive rats (SHRs) will undergo either middle cerebral artery occlusion (MCAO) or sham procedure and be exposed to either standard housing conditions or a rehabilitation intervention with a combination of environmental enrichment and reach training for 5 weeks and 4 weeks of follow up. Cognitive and sensorimotor functional outcomes will be assessed by behavioral tests (novel object recognition, y-maze, Catwalk, and single-pellet reach task) for short- and long- term memory/learning in addition to kinematic analysis of paw movements and gait. A variety of molecular methods, including immunohistochemistry, will be used to identify potential mediators of the angiogenic and neurotrophic components of the recovery response to ER following MCAO. BDNF is one promising mechanistic target in VCID research. An endothelial cell-specific shRNA silencing approach will be used to examine the role of BDNF in the recovery response to ER. The applicant will complete the experiments outlined in this proposal under the guidance of her sponsor, Dr. Adviye Ergul, in the Department of Pathology & Laboratory Medicine at the Medical University of South Carolina. The applicant plans to utilize the technical skills and professional development she gains during the fellowship training to transition to a junior faculty position with a focus on translational VCID research. The long-term career goal of the applicant is to ultimately develop and maintain an independent research program that will contribute to our fundamental knowledge of the critical role of the vasculature in rehabilitation interventions in order to reduce the burden of cardio/cerebrovascular diseases.