Testing the cellular mechanisms that underlie cerebellar synaptic plasticity and motor learning

Abstract The cerebellum is a compelling model for studying how cellular activity can shape animal behavior, one of the key goals of neuroscience research. Molecular, circuit, and behavioral studies have tested cerebellar function at these respective levels; however, due to technical limitations for measuring synaptic responses in vivo, it has been challenging to connect synaptic plasticity mechanisms with cerebellum-dependent motor learning. This proposal is designed to test the role of synaptic plasticity onto cerebellar Purkinje cells in motor learning, using cerebellar-dependent delay eyelid conditioning behavior to assess plasticity mechanisms at the parallel fiber- Purkinje cell synapse, as well as the molecular signaling cascades involved in the expression of this form of plasticity. Thus, these experiments will directly test the hypothesis that long-term synaptic depression of parallel fiber inputs onto Purkinje cells is involved in cerebellar motor learning. I will use a powerful combination of established optogenetic and in vitro electrophysiology techniques to measure synaptic plasticity in tissue from animals trained on the delay eyelid conditioning task. Additionally, I will test a novel biosensor, SPOTlight, for its potential to identify Purkinje cells that have undergone postsynaptic long-term depression. Overall, this research will test a learning mechanism at the molecular, circuit, and behavioral levels to address a foundational question of how cerebellar function enables learning.