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.
The cerebellum performs sensory-motor computations that are critical for controlling coordination, balance, posture, and learning. My goal in this proposal is to test how cerebellar function impacts the ability to generate an internal estimate of orientation relative to gravity, a computational mechanism that allows the brain to actively engage with the real world. Addressing this problem has major implications for human health because obstructing the operation of internal neural representations may underlie motor and non-motor diseases.
| White, Joshua J; Lin, Tao; Brown, Amanda M et al. (2016) An optimized surgical approach for obtaining stable extracellular single-unit recordings from the cerebellum of head-fixed behaving mice. J Neurosci Methods 262:21-31 |
