The proposed studies are intended to further our understanding of the cellular events underlying neural plasticity and treatment strategies that can promote the recovery of function after brain damage. Specifically, we will determine whether exercise and the norepinephrine-selective antidepressant reboxetine, used in the treatment of post-stroke depression can enhance neurite outgrowth and synapse replacement after brain injury. The rationale for the study is based on previous reports from our laboratories and those of others that show: 1) neural plasticity plays a critical role in the recovery of function after brain injury; 2) exercise and reboxetine stimulate neurotrophin (BDNF) and intracellular signaling pathways that regulate cell survival and plasticity in the nervous system; 3) the increase in hippocampal BDNF following reboxetine treatment is enhanced and accelerated by exercise; and 4) exercise-induced increases in hippocampal BDNF expression are dependent upon noradrenergic activation. The specific hypotheses to be tested are: 1) that exercise and reboxetine act in a convergent manner to facilitate synapse replacement after brain injury by activation of intracellular signaling pathways that promote neurite outgrowth, svnaptogenesis and cell survival, and 2) a key mediator in the convergent effect of exercise and reboxetine treatment is BDNF. The experimental design integrates the research expertise on neural plasticity from Dr. McNeill's laboratory with that of Dr. Russo-Neustadt who has examined the effect of antidepressant treatment and exercise on the induction of neurotrophin (BDNF) and intracellular signaling pathways that regulate cell survival and plasticity in rat models of depression. While both labs have ample background data to support the major aspects of the project independently, we lack pilot data for the effect of reboxetine treatment and exercise on the anatomical and molecular changes that underlie neural plasticity after brain injury. We wish to use this R21 application to develop the necessary pilot data to support our overarching hypotheses and to form a solid base of preliminary data to justify the submission of a R01 application in the future. Data from these studies are fundamental for broadening our understanding of the capacity of the brain to compensate for damage, and central to the development of new treatment strategies that can translate the basic principles of neuroplasticity into effective interventions in the treatment of brain injury.
