Targeted Circuit Manipulation for Ameliorating Huntington's Disease Pathogenesis

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PROJECT SUMMARY/ABSTRACT The Diversity Supplement candidate will be trained in all aspects of manipulating the firing activity within the cortico-striatal microcircuit by chemogenetic inhibition of pyramidal neurons, testing efficacy of inhibition by electrophysiological recordings in vivo, and assessing in behavioral tests if these manipulations before the onset of symptoms will slow HD disease progression. The training includes stereotaxic injections of AAV, acute extracellular recordings and computational electrophysiological data analysis, and conducting behavioral test batteries and analyzing the collected data. The experimental approach will allow the candidate to assess the efficacy of novel inhibitory luminopsins within this well-defined experimental paradigm while building a solid conceptual and experimental foundation for his future activities in biomedical research. The training experiences the candidate will gain are critical for his understanding and interpretation of state-of- the-art neuroscience experiments. The training plan takes into consideration that the candidate is at the very beginning of his research training and ensures that the candidate will have an exceedingly strong background for entering the next phase of research training towards meeting his career goals. His training will have ranged from hands-on experience in executing in vivo experiments for controlling neural activity and behavior to evaluating and interpreting the collected data. Therefore, this training in in vivo electrophysiology and behavior testing will not only significantly contribute to the parent grant but will specifically provide him the experience required to pursue his long-term interest in pursuing a career as a physician-scientist. The proposed training outlined in the application is ideal given the candidate’s career stage and future plans and is tailored to having the greatest impact within th ehsortest possible time. An established training strategy will foster the candidate’s ability to swiftly reach a level where he can independently approach new projects and will be an asset to any research lab where he continues his training. The proposed supplement activities will increase the parent award’s overall impact within the original scope of award while at the same time advancing the training and career development of the candidate.