Molecular and sensory foundations of vestibular reflex circuit assembly in the larval zebrafish

项目摘要：神经发育疾病的行为障碍通常是由异常引起的 神经电路组件。然而，规定电路组织、功能和功能的发展逻辑 归根结底，由于大多数电路的复杂性，行为仍未解决。凝视稳定行为的研究 斑马鱼幼体是了解组装功能神经回路的机制的理想模型。 垂直凝视稳定利用简单的架构：所有脊椎动物都使用三个细胞种群 (外周感觉神经元、中央前庭投射神经元和眼外运动神经元) 将鼻子朝上或鼻子向下的头部运动转变为补偿性的眼球旋转。在脊椎动物中， 斑马鱼特别容易驯养，因为它的遗传可及性、透明度和快速的外部发展。 之前，我发现凝视稳定电路是按地形组织的，而这个地形 在明显的时间进程中发展。我的目标是利用这个组织来了解这些贡献 运动和感觉伴侣群体对神经回路发育的影响。使用遗传功能丧失工具，我 已经证明，运动伙伴对于凝视稳定电路的开发是不可或缺的。 这项拟议的研究的目的有两个：1)确定感觉的发育贡献 伴侣群体凝视稳定电路的拓扑结构、功能和行为(F99)，以及2) 阐明特定分子支配功能电路组件(K00)的机制。在目标1中 (F99)，我将训练在发育过程中扰动外周前庭感觉神经元的亚群。跟随 外周扰动，我将使用经过验证的光遗传诱发行为范式来分析 功能电路拓扑图和组装。这些数据将提供对发育信号类型的洞察 (例如，活性依赖的、营养的或形态发生的)，组装凝视稳定电路。更广泛地说， 交付成果将说明感觉对神经回路组装的贡献。在目标2(K00)中，我将选择一个 博士后实验室利用现代技术研究功能神经回路组装的遗传学基础 排序和计算方法。我将把这些分子的洞察力与解剖学、功能性、 以及正确电路组装的行为读数。完成这一目标将训练我阐明如何 基因定义的发育程序决定了电路的组织、功能和行为。 总的来说，我的培训将加强我对以下机制的整体理解 管理典型的神经电路组件和功能。我将在我自己的实验室中使用这种方法来说明 神经发育疾病中行为功能障碍的机制。

PROJECT SUMMARY: Behavioral dysfunction in neurodevelopmental diseases often arises from aberrant neural circuit assembly. However, the developmental logic that dictates circuit organization, function, and ultimately behavior remains unresolved due to the complexity of most circuits. Gaze stabilization behavior in the larval zebrafish is an ideal model to understand the mechanisms that assemble functional neural circuits. Vertical gaze stabilization leverages simple architecture: all vertebrates use three cellular populations (peripheral sensory neurons, central vestibular projection neurons, and extraocular motor neurons) to transform nose-up or nose-down head movements into compensatory eye rotations. Among vertebrates, the zebrafish is particularly tractable for its genetic accessibility, transparency, and rapid external development. Previously, I discovered that the gaze stabilization circuit is topographically organized, and that this topography develops in a distinct temporal progression. I aim to leverage this organization to understand the contributions of motor and sensory partner populations to neural circuit development. With a genetic loss-of-function tool, I have already demonstrated that that motor partners are dispensable for gaze stabilization circuit development. The goal of the proposed research is twofold: 1) To define the developmental contributions of sensory partner populations to gaze stabilization circuit topography, function, and behavior (F99), and 2) To illuminate mechanisms by which specific molecules dictate functional circuit assembly (K00). In Aim 1 (F99), I will train to perturb subsets of peripheral vestibular sensory neurons during development. Following peripheral perturbations, I will use a validated optogenetically-evoked behavioral paradigm to assay changes in functional circuit topography and assembly. These data will provide insight into types of developmental signals (e.g., activity-dependent, trophic, or morphogenic) that assemble the gaze stabilization circuit. More broadly, the deliverables will speak to sensory contributions to neural circuit assembly. In Aim 2 (K00), I will select a postdoctoral lab to investigate the genetic foundations of functional neural circuit assembly using modern sequencing and computational approaches. I will integrate these molecular insights with anatomical, functional, and behavioral readouts of proper circuit assembly. Completion of this aim will train me to elucidate how genetically-defined developmental programs determine circuit organization, function, and behavior. Collectively, my training will strengthen my holistic approach to understanding mechanisms that govern typical neural circuit assembly and function. I will use this approach in my own lab to illuminate mechanisms of behavioral dysfunction in neurodevelopmental diseases.