Functional Adaptation of Neural Circuits After Exercise and Basal Ganglia Injury

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DESCRIPTION (provided by applicant): Evidence suggests that the type of exercise and the way it is performed results in the recruitment of different motor circuits in the brain. A systematic investigation on the relationship between exercise training (ET) and functional brain reorganization is lacking. The current proposal focuses on the compensatory cerebral responses elicited by ET in a rat model of basal ganglia injury. Specifically, we address in what circuits of the brain does functional reorganization occur, and what is the relationship between motor improvement, histologic/biochemical changes and changes in neural function in the lesioned and nonlesioned brain. Functional brain mapping during a locomotor challenge is used to examine the role exercise plays in the basal ganglia-thalamic-cortical (BGTC) and the cerebellar-thalamic-cortical (CbTC) circuits, as well as in accessory sensorimotor areas. A novel, implantable, minipump developed by our team is used for timed injection of the cerebral blood flow (CBF) tracer [14C]-iodoantipyrine by remote activation in the freely moving animal. Regional CBF-related tissue radioactivity is quantified by autoradiography and analyzed in the three-dimensionally reconstructed brain. Region-of-interest analysis and statistical parametric mapping (SPM) provide information on regional cerebral changes, while effective connectivity analyses addresses changes at the level of specific brain circuits. Regional measurements of vascular endothelial growth factor and vascular density allow the examination of the role played by angiogenesis in response to ET, while measurement of GAP-43 will provide an assessment of exercise-related neural sprouting and synaptic plasticity. Motor skill assessment will track neurologic recovery, while tyrosine hydroxylase immunohistochemistry and cell counts will provide a measure of lesion extent. At the end of the project, we will know to what extent specific parameters of ET (complexity, intensity, duration, forced or voluntary engagement, and ET cessation) determine regional changes in brain function, and what the impact is of basal ganglia injury on such changes. In addition, we will know to what extent ET restores functionality of damaged circuits, and the relative importance of the recruitment of alternate motor and nonmotor circuits. Together, these studies have a wide-ranging impact for our understanding of experience-based functional reorganization in the healthy and injured brain. The proposal is responsive to a greater need to understand neural plasticity at the level of circuits in the brain (NIH Blueprint for Neuroscience Research), to optimize specific neurorehabilitation strategies (NCMRR mission), and to improve our understanding of Parkinson's disease (NINDS Parkinson's Research Agenda).