Circuit Analysis by Rapid Silencing of Specific Interneuron Populations In Vivo

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DESCRIPTION (provided by applicant): This project is the initial phase of a systematic research program for the functional dissection of a neural circuit. The experimental approach employs some of the latest transgenic techniques to rapidly and reversibly inactivate distinct classes of interneurons and analyzes the impact of this intervention on both signaling in the neural circuit and behavior. This strategy should yield a deeper and more comprehensive understanding of how a circuit's architecture shapes neural computations. The proposed experiments focus specifically on analysis of neural circuit function in the cerebellum, a brain structure that plays a central role in motor learning and the coordination of movements. The first Aim of the project is to generate transgenic animals that can be used to rapidly and reversibly inactivate a class of cerebellar interneurons called Golgi cells in a restricted region of the cerebellum, without perturbing any other neurons in the brain. The second Aim of the project is to use the mice generated in the first Aim to analyze the contribution of the Golgi cells to the neural computations supporting the generation of movements with appropriate amplitude and timing. These experiments represent the first step in a systematic analysis of how the different classes of neurons in the cerebellum and other neural circuits support the computational functions supporting perception and action. Many diseases of the nervous system involve the malfunction of neural networks caused by the degeneration of specific classes of neurons. This proposed research develops an experimental approach for analyzing how the function of neural networks is disrupted by the loss of specific populations of neurons. The results will aid in the development of rational therapeutic interventions for pathological states of the nervous system resulting from the degeneration of specific classes of neurons.