Trace L. Stay - US grants

? DESCRIPTION (provided by applicant): There is mounting evidence that the cerebellum might play a major role in sensory function, even though it is better known for controlling motor behavior. To support this hypothesis, one prediction is that the cerebellum exerts a powerful influence over how sensory signals are processed. This prediction raises a critical question - what neural mechanisms in the cerebellum control ongoing sensory computations? To address this problem I postulated that Purkinje cells receive and encode key signals that are necessary for normal sensation. Based on multiple computations making up a well-defined sensory process, I further postulated that Purkinje cells could influence vestibular perception in both development and adulthood. But in order to fully test this I had to devise a mouse model that would enable me to induce tractable changes in sensory behavior after manipulating the flow of information in the cerebellum. For this, we developed a conditional genetic strategy to manipulate synaptic neurotransmission in particular circuits. Our approach uses the Cre/loxP genetic approach to selectively block the expression of the vesicular GABA transporter VGAT in Purkinje cells. By doing so, I can now delineate the mechanisms for how the Purkinje cells control motion selectivity. I have compelling preliminary data from my mice showing that altering cerebellar activity obstructs vestibular sensory computations in vivo. I propose to expand on this work by testing the hypothesis that Purkinje cell communication to target neurons controls self-motion sensation by dissociating sensory flow into circuits for tilt and translation. In Aim 1, I wll determine Purkinje cell output is required for initial establishment of internal representations of inertial versus gravitational acceleration during development. In Aim 2, I will determine whether GABAergic signals from Purkinje cells are necessary for dissociating tilt and translation during ongoing adult behavior. The completion of my aims will define the mechanistic actions of how the cerebellum impacts vestibular sensation and provide a more complete wiring diagram for how sensory signals are transformed into behavioral outputs.

PROJECT SUMMARY The vestibular system is essential for many functions, including maintaining balance and orchestrating reflexes. For instance, the vestibulo-ocular reflex (VOR) is necessary for stabilizing eye fixation with head movement. However, the role that individual cell types play in orchestrating the VOR motor response is not fully determined. Previous research has been limited by serial single-unit recordings, which cannot capture the dynamics of simultaneous activity across synapses, and limited behavioral testing sets, which result in confounding co- variation between predictor variables. Three related questions of VOR function are how vestibular information is integrated with other input pathways (e.g. visual and efference copy inputs), how neural processing changes over the course of VOR adaptation (specifically, to gain or phase), and what mechanistic means are used to create VOR learning. The goal of this proposal is to answer these three questions in mice, using large-scale in vivo electrophysiology during innovative probe conditions, carefully designed training sets that dissociate learned timing from learned gain responses, and precise genetic interrogation to conditionally manipulate molecular signaling at a key point in the VOR circuit. Neural responses will be analyzed with unbiased computational models, to fully establish signal transformations between circuit nodes. Determining the signal content in the cerebellum and brainstem vestibulo-ocular neurons will help answer a decades-long debate about the nature of plasticity during in vivo learning (depression vs potentiation). Resolving the differences in filtering that occur over adaptation will illuminate learning motifs of the circuit. Assessing the relative contribution of presynaptic plasticity to VOR learning will better define specific molecular pathways that could be targeted for specific therapeutic effects. These experiments will be performed in an ideal research setting at Stanford University, with specially-prepared equipment and access to leading experts in vestibular research and neuroscience more generally. The overall outcomes of this study will contribute significantly to the goal of defining normal and disordered processes in vestibular function.