Project Grant R37NS131839

FUNCTIONAL ROLES OF INHIBITORY CEREBELLAR OUTPUTS - PROJECT SUMMARY/ABSTRACT: THE PRECISION AND ACCURACY OF VERTEBRATE MOVEMENT IS MEDIATED BY THE CEREBELLUM. CEREBELLAR DAMAGE RESULTS IN A SIGNATURE MOTOR PHENOTYPE CALLED DYSMETRIA, CHARACTERIZED BY PROMINENT ENDPOINT ERRORS IN MOVEMENTS SUCH AS REACHES. THESE ENDPOINT DEFICITS HAVE BEEN ATTRIBUTED TO THE ABSENCE OF ANTICIPATORY BRAKING SIGNALS FROM THE CEREBELLAR INTERPOSED NUCLEUS THAT ACCURATELY SLOW THE LIMB TO TARGET. OUR PREVIOUS WORK IN MICE HAS SHOWN A CAUSAL ROLE FOR ACTIVITY IN THE INTERPOSED NUCLEUS THAT SCALES THE RATE OF REACH DECELERATION RELATIVE TO PEAK REACH VELOCITY, PRODUCING STABLE ENDPOINTS DESPITE REACH-BY-REACH KINEMATIC VARIABILITY. WE HYPOTHESIZE THAT THIS ACTIVITY IS LEARNED AND UNDER ADAPTIVE CONTROL FROM PURKINJE NEURONS AND THE INFERIOR OLIVE (IO): REACHES THAT END OFF TARGET WILL ALTER THE FREQUENCY OF TEACHING SIGNALS FROM THE IO, REWEIGHT CONTEXTUAL SIGNALS TO PURKINJE CELLS, AND RECALIBRATE INTERPOSED DECELERATION SIGNALS SUCH THAT FUTURE REACHING ATTEMPTS LAND ON TARGET. DESPITE THIS DEVELOPING FRAMEWORK, THE INTERPOSED NUCLEUS HOUSES MULTIPLE PROJECTION NEURON TYPES, INCLUDING INHIBITORY NEURONS THAT PROJECT DENSELY TO THE IO, TERMED NUCLEOOLIVARY NEURONS (NO). THIS PROPOSAL USES OUR UNIQUE BEHAVIORAL PARADIGM OF CLOSED-LOOP CIRCUIT MANIPULATIONS TO ADVANCE THE CEREBELLAR LEARNING HYPOTHESIS BY ASKING HOW THE CEREBELLUM TUNES ITS OWN TEACHING SIGNALS VIA THIS INHIBITORY OUTPUT PATHWAY AND ACTUATES CONTROL WITH THESE NEURONS. TOGETHER THESE PROJECTIONS RAISE THE INTRIGUING POSSIBILITY THAT THE CEREBELLUM TEACHES ITS TEACHERS. 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.