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: 10662257
• 负责人: Dena Goldblatt
• 金额: $ 4.23万
• 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/10662257
• 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; Vertebrates; Work; Zebrafish; axon guidance; candidate identification; gaze; holistic approach; in vivo; insight; loss of function; nervous system disorder; neural circuit; oculomotor; 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：神经发育疾病中的行为功能障碍通常由异常行为引起 神经回路组装。然而，决定电路组织、功能和功能的发展逻辑 由于大多数电路的复杂性，最终的行为仍未得到解决。凝视稳定行为 斑马鱼幼虫是理解功能神经回路组装机制的理想模型。 垂直凝视稳定性利用简单的架构：所有脊椎动物都使用三种细胞群 （外周感觉神经元、中央前庭投射神经元和眼外运动神经元） 将鼻子向上或鼻子向下的头部运动转化为补偿性眼球旋转。在脊椎动物中， 斑马鱼因其遗传可及性、透明度和快速的外部发育而特别容易驯服。 之前，我发现凝视稳定回路是按地形组织的，并且这种地形 以明显的时间进程发展。我的目标是利用这个组织来了解贡献 运动和感觉伙伴群体对神经回路发育的影响。借助遗传功能丧失工具，我 已经证明，运动伙伴对于凝视稳定电路的开发是可有可无的。 拟议研究的目标有两个：1）定义感官的发展贡献 伴侣群体凝视稳定回路的地形、功能和行为 (F99)，以及 2) 阐明特定分子决定功能电路组装 (K00) 的机制。目标 1 (F99)，我将训练在发育过程中扰乱外周前庭感觉神经元的子集。下列的 外周扰动，我将使用经过验证的光遗传学诱发行为范例来分析 功能电路拓扑和组装。这些数据将提供对发育信号类型的深入了解 （例如，活动依赖性、营养性或形态发生）组装凝视稳定回路。更广泛地说， 交付成果将讨论感官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性神经回路组装的遗传基础 排序和计算方法。我会将这些分子见解与解剖学、功能学、 以及正确电路组装的行为读数。完成这个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，我的培训将加强我理解机制的整体方法 控制典型的神经回路组装和功能。我将在我自己的实验室中使用这种方法来阐明 神经发育疾病中行为功能障碍的机制。