Functional development of interneurons that mediate the vestibulo-ocular reflex

介导前庭眼反射的中间神经元的功能发育

• 批准号: 10058259
• 负责人: David Schoppik
• 金额: $ 59.77万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058259
• 关键词: Ablation; Acute; Adopted; Afferent Neurons; Anatomy; Behavior; Cell surface; Cells; Chronic; Cues; Data; Development; Disease; Electrophysiology (science); Equilibrium; Esthesia; Excision; Eye; Fishes; Functional disorder; Gene Expression Profile; Genetic; Goals; Hair Cells; Impaired health; Impairment; Interneurons; Knowledge; Lasers; Lateral; Ligands; Light; Link; Logic; Mediating; Mission; Modeling; Molecular; Motor Neurons; Mutation; Neurons; Optics; Pathology; Process; Property; Public Health; RNA; Reflex action; Research; Role; Sensory; Siblings; Source; Specific qualifier value; Specificity; System; Testing; Time; To specify; Transcript; United States National Institutes of Health; Work; Zebrafish; developmental disease; experimental study; in vivo; innovation; mutant; nerve supply; neural circuit; organ growth; receptor; sensor; single-cell RNA sequencing; tool; vestibular reflex; vestibulo-ocular reflex

Project Summary / Abstract The vestibular system is critical for maintaining balance reflexes, vital behaviors that are disturbed both in ag- ing and in several developmental disorders. While we know much about how the vestibular system functions we know considerably less about how it develops. To form functional circuits, neurons must adopt the correct identities and connect to appropriate partners. Many molecular mechanisms underlying these processes have been proposed but how these mechanisms work in the context of a specific system to generate behavior is not yet clear. We propose an innovative approach: to use the vestibulo-ocular reflex system of the larval zebrafish as a simple and tractable model to determine the origin of cues that specify vestibular interneuron identity. The vestibulo-ocular reflex circuit is a simple 3-neuron arc comprised of sensory neurons, interneurons, and motoneurons. Proper behavior requires that the right sensors (e.g. for upward tilts) be linked to the proper mo- toneurons (e.g. those that move the eyes down). Our lab has developed tools to determine interneuron identity anatomically and electrophysiologically. We can remove possible sources of identity cues (motoneurons and sensory neurons) either chronically, through genetic means, or acutely, through laser-mediated photoablation. Finally, we can collect and process neurons across development to profile their patterns of gene expression. This application proposes three Aims: To determine whether cues for interneuron identity arise from either (1) the motor neurons, (2) the sensory neurons, or (3) from local interactions between interneurons themselves. Completion of these experiments stands to make a significant contribution: to reveal the principles responsible for balance circuit development. As such, the work is a major step towards the long-term goal of using such an understanding to shed light on the mechanisms underlying vestibular and neurodevelopmental dysfunction.

项目总结/摘要 前庭系统对于维持平衡反射至关重要，平衡反射是一种重要的行为， 以及几种发育障碍。虽然我们对前庭系统的功能了解很多 我们对它是如何发展的知之甚少。为了形成功能回路，神经元必须采用正确的 身份并连接到适当的合作伙伴。这些过程背后的许多分子机制 但这些机制如何在特定系统的上下文中工作以产生行为， 还很清楚我们提出了一个创新的方法：利用斑马鱼幼鱼的前庭-眼反射系统 作为一个简单和易于处理的模型，以确定来源的线索，指定前庭中间神经元的身份。 前庭-眼反射回路是由感觉神经元、中间神经元和感觉神经元组成的简单的3-神经元弧。 运动神经元正确的行为要求正确的传感器（例如向上倾斜）与正确的运动相关联。 toneurons（例如，那些移动眼睛）。我们的实验室已经开发了确定中间神经元身份的工具 解剖学和电生理学上。我们可以去除身份线索的可能来源（运动神经元和 感觉神经元），或者通过遗传手段慢性地，或者通过激光介导的光消融急性地。 最后，我们可以收集和处理整个发育过程中的神经元，以分析它们的基因表达模式。 本申请提出了三个目的：确定中间神经元身份的线索是否来自（1） 运动神经元，（2）感觉神经元，或（3）中间神经元本身之间的局部相互作用。 这些实验的完成将做出重大贡献：揭示了 平衡电路的发展。因此，这项工作是朝着使用这种 了解揭示前庭和神经发育功能障碍的机制。