Multiple forms of activity dependent, synaptic plasticity have been described in the cerebellar cortex. Hypothesized to play a central role in motor learning, the overall goal of this proposal is to address key questions concerning cerebellar synaptic plasticity in the intact animal. The experimental approach is based on optical imaging of activity in the mouse cerebellar cortex to evaluate the spatial and temporal aspects of the long-term changes. Theoretical models and behavioral data require that parallel fiber (PF) activity precede climbing fiber (CF) input for PF-Purkinje cell (PC) long-term depression (LTD) to support learning. Therefore, Specific Aim 1 investigates the optimal timing and stimulation parameters for evoking PF-PC LTD in vivo.
Specific Aim 1 also characterizes the signaling requirements, examines whether granular layer and mossy fiber stimulation generates PF-PC LTD, and tests the hypothesis that PF-PC LTD should modify the responses evoked in the cerebellar cortex by peripheral inputs. Long-term potentiation (LTP) has been described at the PF-PC synapse in vitro.
Specific Aim 2 tests in vivo whether LTP occurs at the PF-PC synapse, characterizing the stimulation parameters, stimulation at different stages in the circuitry, signaling requirements and spatial characteristics.
Specific Aim 2 also examines how PF-PC LTP modifies the responses evoked by peripheral inputs. Central to theories of the cerebellum's role in motor learning is the reversibility of both LTD and LTP. Reversibility has only been demonstrated in vitro with little information on reversibility in vivo.
Specific Aim 3 tests whether induction of LTP can reverse PF-PC LTD and conversely whether induction of LTD can reverse PF-PC LTP. Recent evidence suggests that the synaptic connections between the PFs and the molecular layer inhibitory interneurons are modifiable. Using an optical imaging methodology that allows monitoring the off-beam inhibition evoked by PF stimulation, Specific Aim 4 investigates the induction properties, spatial characteristics, and signaling mechanisms of these long-term changes in the molecular layer inhibitory network. Understanding the role of cerebellar synaptic plasticity will require studying LTD and LTP in the awake, behaving animal. Therefore, Specific Aim 5 first characterizes LTD and LTP in the awake animal.
Then Specific Aim 5 also tests the hypothesis that LTD and LTP contribute to the changes in cerebellar cortical activity that occur with adaptation to a mechanical perturbation of a forelimb reaching movement. The goal is to directly link the changes in the cerebellar cortex occurring during motor learning to synaptic plasticity at the PF-PC synapses.
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