Reaching movements are fundamental to human interactions with the environment. Cerebellar damage impairs reach precision and accuracy, but the mechanistic contribution of cerebellum to reach control is unclear. Recent work has illuminated principles of cerebellar feedforward control, where Purkinje cells learn predictive contingencies, termed forward models, but our understanding of control signals issued from the cerebellar nuclei, particularly to improve reach precision, is poor. The proposed studies leverage our discoveries made in the previous grant cycle, identifying and characterizing internal motor copy pathways, to test mechanisms of cerebellar predictive control. Outcomes of these studies will reconcile diverse hypotheses of cerebellar motor control and identify circuit mechanisms by which feedforward motor control is produced. We have identified strong endpoint-aligned neural activity in the cerebellar interposed nucleus of reaching mice and showed, using closed-loop optogenetics that this activity exerts a causal pull on the limb, sculpting reach endpoint. In the proposed studies we will explore this code to test its role in real-time control, learning and sequencing.
In aim 1 we will identify the cell-types that produce this activity and its role in shaping reach kinematics on a trial- by-trial basis to improve precision.
In aim 2, we explore whether reach adaptation changes neural patterns in the cerebellar nuclei associated with endpoint control. Finally, in Aim 3 we leverage findings from the previous grant cycle where we characterized anatomical and physiological properties of a feedback pathway from cerebellar output neurons back to the cerebellar cortex ending as mossy fibers. We will examine the contribution of this internal feedback pathway in reach control, testing the hypothesis that this fast feedback regulates time-varying neural and behavioral sequencing. The outcomes of these studies will advance our long term goal of understanding the circuit mechanisms of feedforward motor control in mammals, which is critical for precise movement and hypothesized to be impaired in movement disorders that involve the cerebellum.
Cerebellar ataxias are debilitating neurological disorders. The next generation of therapies for neurological disorders will likely include manipulations of specific pathways within neural circuits, making it essential to understand how specific neural pathways contribute to precise motor behavior and function. The proposed studies will provide insight into how cerebellar circuits are causally involved in refining movements and test specific neural pathways in fine tuning control, potentially offering therapeutic targets for intervention in patients with cerebellar dysfunction or movement disorders.
