Signal transformations in the vestibulo-ocular circuit

项目摘要 前庭系统对许多功能至关重要，包括保持平衡和协调反射。 例如，前庭眼反射（VOR）是头部运动时稳定眼睛注视所必需的。 然而，单个细胞类型在协调VOR运动反应中发挥的作用尚未完全确定。 以前的研究受到连续单单位记录的限制，无法捕捉到 突触之间的同时活动，以及有限的行为测试集，这导致了混淆的共同- 预测变量之间的差异。VOR功能的三个相关问题是前庭信息如何 与其他输入途径（例如视觉和传出复制输入）相结合，神经处理如何改变 在VOR适应过程中（特别是增益或相位），以及使用什么机械手段来 创建VOR学习。这项提案的目标是在小鼠中回答这三个问题，使用大规模的 体内电生理学在创新的探针条件下，精心设计的训练集， 从习得性增益反应的定时，以及精确的遗传询问，以有条件地操纵分子 在VOR电路中的关键点发出信号。神经反应将通过无偏计算分析 模型，以完全建立电路节点之间的信号转换。确定信号中的信号内容 小脑和脑干前庭眼神经元将有助于回答长达数十年的争论的性质， 在体内学习过程中的可塑性（抑郁与增强）。解决过滤中出现的差异 过自适应将照亮电路的学习基元。评估突触前神经元的相对贡献 VOR学习的可塑性将更好地定义特定的分子途径，这些分子途径可以针对特定的 治疗效果这些实验将在斯坦福大学的理想研究环境中进行， 专门准备的设备，以及前庭研究和神经科学领域的顶尖专家更多 一般来说。这项研究的总体结果将大大有助于定义正常和 前庭功能紊乱

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.