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

斑马鱼幼虫前庭反射回路组件的分子和感觉基础

• 批准号: 10541342
• 负责人: Dena Goldblatt
• 金额: $ 4.14万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541342
• 关键词: Ablation; Afferent Neurons; Age; Anatomy; Architecture; Behavior; Behavioral; Behavioral Mechanisms; Behavioral Paradigm; Biological Assay; Brain Stem; Cells; Computer Models; Data; Development; Developmental Process; Disease; Equilibrium; Eye; Eye Movements; Foundations; Functional disorder; Future; Gene Transfer Techniques; Genetic; Genetic Transcription; Goals; Head Movements; Impaired health; Interneurons; Knowledge; Learning; Link; Logic; Measures; Mission; Modeling; Modernization; Molecular; Molecular Profiling; Motor; Motor Neurons; Nature; Neurodevelopmental Disorder; Neuroglia; Neurons; Neurosciences; Nose; Pathology; Peripheral; Phase; Population; Postdoctoral Fellow; Principal Investigator; Process; Public Health; Research; Research Project Grants; Role; Rotation; Sensory; Shapes; Signal Transduction; Specificity; Stereotyping; Synapses; System; Techniques; Training; Transgenic Organisms; United States National Institutes of Health; Ursidae Family; Vertebrates; Work; Zebrafish; axon guidance; base; gaze; holistic approach; in vivo; insight; loss of function; nervous system disorder; neural circuit; optogenetics; programs; tool; two-photon; vestibular reflex

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.

项目摘要：神经发育疾病的行为功能障碍通常是由于异常引起的 神经电路组件。但是，决定电路组织，功能和 最终，由于大多数电路的复杂性，行为仍未解决。凝视稳定行为 幼虫斑马鱼是了解组装功能性神经回路的机制的理想模型。 垂直凝视稳定利用简单的结构：所有脊椎动物都使用三个蜂窝种群 （周围感觉神经元，中央前庭投射神经元和眼外运动神经元） 将鼻子向上或向下的头部移动转变为补偿性眼旋。在脊椎动物中， 斑马鱼的遗传可及性，透明度和快速外部发育尤其可容纳。 以前，我发现凝视稳定电路是地形组织的，并且该地形 在不同的时间进程中发展。我的目的是利用该组织了解贡献 运动和感官伴侣人群的神经回路发展。使用遗传功能丧失工具，I 已经证明，运动伙伴对于凝视稳定电路的发展是可分配的。 拟议研究的目标是双重的：1）定义感官的发展贡献 伴侣人群凝视稳定电路的地形，功能和行为（F99），以及2） 照明特定分子决定功能电路组装的机制（K00）。在目标1中 （f99），我将在发育过程中训练前庭感觉神经元的扰动子集。下列的 外围扰动，我将使用经过验证的光遗传学诱发的行为范式来测定变化 功能电路的地形和组装。这些数据将提供有关发展信号类型的洞察力 （例如，依赖活性，营养或形态发生的），组装凝视稳定电路。更广泛地 可交付成果将与对神经电路组件的感觉贡献有关。在AIM 2（k00）中，我将选择一个 博士后实验室研究功能神经回路组件的遗传基础 测序和计算方法。我将将这些分子见解与解剖学，功能性， 和适当电路组件的行为读数。这个目标的完成将训练我阐明如何 遗传定义的发展计划决定了电路组织，功能和行为。 总的来说，我的培训将加强我的整体方法来理解机制 控制典型的神经回路组件和功能。我将在自己的实验室中使用这种方法来照亮 神经发育疾病中行为功能障碍的机制。