The cerebellum is essential for the production of smooth and accurate movements. While much is known about the neurophysiology of cerebellar neurons, our understanding of the mechanistic relationship between cerebellar output and movement is limited. Two prominent hypotheses attempt to explain the function of cerebellar output in motor control: that it operates as a motor command, or as a forward model for state estimation. The motor command hypothesis predicts that cerebellar output contributes to movement directly, while the forward model hypothesis suggests that cerebellar output encodes a prediction that is utilized by downstream motor centers. Previous manipulations of cerebellar output lacked cell-type specificity and used reversible lesions that lasted much longer than a single movement, preventing any causal test of whether cerebellar output functions as a motor command or forward model. To address these limitations, this proposal utilizes a kinematic closed-loop (kCL) system for optogenetics, in which stimulation is triggered by the real-time kinematics of skilled reach behavior in mice. Combining this system with cell-type specific opsin expression in the Interposed Nucleus (IN), the cerebellar nucleus most involved in reaching movements, will allow for short- term, reversible manipulation of cerebellar output at specific kinematic locations of a single reaching movement, differentiating fundamental hypotheses of cerebellar contributions to motor control.
Cerebellar lesions result in widespread impairments in movement and cognitive function. This proposal will expand our understanding of how the cerebellum functionally contributes to movement, paving the way for potential therapies to mitigate cerebellar deficits.
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