The goal of this project is to understand the algorithm by which the cerebellum guides learning. The cerebellum is a brain structure responsible for motor learning. Because of its well defined circuit architecture, the cerebellum provides an opportunity for detailed analysis of neural mechanisms supporting learning. Contrary to classical theory that posits a single mechanism for all cerebellum-dependent learning, recent studies indicate that different mechanisms support different aspects of learning. In this proposal, we will take advantage of new developments in molecular and optogenetic techniques to test the contribution of different molecular and cellular mechanisms supporting vestibulo-ocular reflex (VOR) learning. The VOR is a reflex that helps to stabilize images on the retina. Normal learning of the VOR occurs when the reflex needs to be recalibrated due to changes in muscle strength or other aging processes. Because VOR learning can be induced to either increase or decrease in amplitude, we can use this paradigm to probe the mechanisms that preferentially supports these different aspects of learning. To address this question, we will first examine VOR gain increases and decrease in a mouse model with enhanced pf-LTD. pf-LTD is the plasticity mechanism proposed in classical models to be responsible for cerebellum-dependent learning. We will test whether enhanced pf-LTD leads to enhanced learning and whether the effect is common to both learning. Will also conduct unit recording of neural activity during learning to examine how pf-LTD changes the neural circuit in support of learning. Next, we will test the contribution of Purkinje cell simple spike activity as another possible mechanism supporting VOR learning. We will do this by pairing head rotation with direct stimulation Purkinje cell using optogenetics, a technique that uses light-activated molecules to control neuronal excitability. This genetically-targetable approach allows for specific manipulation of only Purkinje cell activity to determine whether it is sufficient to replace normal visual stimuli to induce VOR learning. Lastly, we will use a specially designed pharmacological agent to dissociate between different roles the Purkinje cells might play for the induction of learning. PUBLIC HEALTH RELEVANCE: By having a more thorough understanding of the diversity of learning mechanisms, we can begin to tailor and design rational therapy to better engage each mechanism to help patients with cerebellum-related dysfunction. The insights gained from studies on motor learning can be generalized to non-motor functions of the cerebellum.