Recent studies in our labs have implicated a role for glial cells (astrocytes and microglia) in exercise- induced synaptogenesis and synaptic repair. The primary goal of this application is to investigate the role of astrocytes, microglia and peripheral monocytes in regulating exercise induced synaptogenesis and behavioral recovery in Parkinson's disease. Studies in this application will explore region specific metabolic changes mediated by exercise, using imaging tools and molecular biology approaches to determine the mechanistic roles of glial cells, metabolism and immune processes associated with exercise induced neuroplasticity and potential disease modification. Specific Aim 1 will test the hypothesis that exercise induced astrocytic activation and elevated lactate metabolism regulates synaptogenesis and behavioral recovery in an animal model of PD. Specific Aim 2 will test the hypothesis that activation of anti-inflammatory resident microglia and infiltrating peripheral mononuclear cells regulate synaptogenesis in the striatum and Prefrontal cortex of exercised 6-OHDA mice. We will further test the hypothesis that anti- vs. pro-inflammatory serum immune soluble factors (cytokines and BDNF) are associated with exercise benefits in PD.