Cerebellar computations for sensing self-motion

 描述（由申请人提供）：越来越多的证据表明，小脑可能在感觉功能中发挥重要作用，尽管它更好地控制运动行为。为了支持这一假设，一个预测是小脑对感觉信号的处理方式施加了强大的影响。这一预测提出了一个关键问题--小脑中的什么神经机制控制着正在进行的感觉计算？为了解决这个问题，我假设浦肯野细胞接收并编码正常感觉所必需的关键信号。基于构成一个定义明确的感觉过程的多重计算，我进一步假设浦肯野细胞可以影响发育和成年期的前庭感知。但为了充分验证这一点，我必须设计一个小鼠模型，使我能够在操纵小脑中的信息流后诱导感官行为发生易处理的变化。为此，我们开发了一种条件遗传策略来操纵特定回路中的突触神经传递。我们的方法使用Cre/loxP遗传方法来选择性地阻断浦肯野细胞中囊泡GABA转运蛋白VGAT的表达。通过这样做，我现在可以描绘浦肯野细胞如何控制运动选择性的机制。我从我的老鼠身上得到了令人信服的初步数据，表明改变小脑活动会阻碍活体前庭感觉计算。我建议扩大这项工作的假设，浦肯野细胞通信的目标神经元控制自我运动的感觉，通过分离的感觉流到电路的倾斜和翻译。在目的1中，我将确定浦肯野细胞输出是初始建立内部表征所必需的。 惯性加速度与重力加速度的对比在目标2，我将确定是否GABA能信号浦肯野细胞是必要的解离倾斜和翻译在进行中的成年行为。我的目标的完成将定义小脑如何影响前庭感觉的机械作用，并为感觉信号如何转化为行为输出提供更完整的布线图。

 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.