Deconstructing the roles of basal ganglia and cerebellum-related thalamic inputs to motor cortex during control of dexterous behavior

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PROJECT SUMMARY Neural dynamics in motor cortex are necessary for dexterous behavior, but the mechanisms that generate these activity patterns are unclear. The long-term goal of our research is to understand how cortical dynamics are constructed to control movement, so that therapies could be developed to identify and repair aberrant activity patterns associated with motor disorders. My laboratory recently showed that these cortical dynamics arise from a collaboration between the intrinsic properties of cortex and inputs from the rest of the brain, but how distinct input streams are received and processed by the cortex remains poorly understood. To characterize these operations, we must understand the identity of the contributing inputs and their relationship to cortical dynamics. The objective of this proposal is to directly test the role of two major inputs, from ventral anterior (VA) and ventral lateral (VL) thalamic nuclei, to primary motor cortex. VA and VL have distinguishable input/output features: VA receives more input from basal ganglia, VL receives more input from cerebellum, VA and VL project to distinct cortical targets, and their intrinsic physiological properties differ. The central hypothesis to be tested here is that the VA-to-cortex pathway modulates, while the VL-to-cortex pathway drives, cortical dynamics and control of movement. To test the roles of VA and VL in the construction of cortical dynamics and behavior, we produced and validated genetic tools in the mouse that allow selective monitoring and manipulation of specific thalamic nuclei. With these tools, we will assess the relationship between a cortically dependent prehension task and the activity patterns of VA and VL neurons. We will then determine how activity in VL and VA drive or modulate cortical activity. Efforts to model the production of cortical commands have focused almost exclusively on firing patterns of cortex, leaving aside the influence of external inputs, leading to a cortico-centric view of pattern generation. With the data we collect, we will generate a more realistic computational model for pattern generation that considers the role of both intrinsic cortical dynamics and external inputs. Thus completion of these aims will advance understanding of how the cortical dynamics underlying prehension are constructed through interactions with the basal ganglia and cerebellum. The proposed research is innovative because it will use a new genetic toolbox for exploring thalamus, will produce an in-depth assessment of thalamocortical dynamics during a new complex prehension task, will advance the use of causal perturbations for testing interactions between brain regions, and will generate a more holistic model for pattern generation for dexterous behavior. The proposed work is significant because understanding the relationships among cortex, cerebellum, and basal ganglia can elucidate how their damage or disease leads to motor disorders and support the development of therapies designed to replace lost or corrupted signals.