Functional development of interneurons that mediate the vestibulo-ocular reflex

项目摘要/摘要 前庭系统对维持平衡反射至关重要，这种重要行为在老年人和老年人中都受到干扰。 ING和几种发育障碍。虽然我们对前庭系统是如何运作的了解很多 我们对它是如何发展的知之甚少。为了形成功能电路，神经元必须采用正确的 身份，并联系到适当的合作伙伴。这些过程背后的许多分子机制 但这些机制是如何在特定系统的上下文中工作以生成行为的 但很清楚。我们提出了一个创新的方法：利用斑马鱼幼体的前庭-眼睛反射系统 作为一种简单易处理的模型来确定指定前庭神经元间身份的线索的来源。 前庭-眼反射回路是一个简单的由3个神经元组成的弧形，由感觉神经元、中间神经元和 运动神经元。正确的行为要求正确的传感器(例如，向上倾斜)连接到正确的运动模式- 色调神经元(例如，那些向下移动眼睛的神经元)。我们的实验室已经开发出工具来确定神经元间的身份 从解剖学和电生理学上讲。我们可以删除可能的身份线索来源(运动神经元和 感觉神经元)，要么是慢性的，通过遗传手段，要么是急性的，通过激光介导的光消融。 最后，我们可以收集和处理发育过程中的神经元，以描绘它们的基因表达模式。 这项申请提出了三个目标：确定神经元间同一性的线索是否来自(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：揭示负责的原则 用于平衡电路开发。因此，这项工作是朝着使用这种技术的长期目标迈出的重要一步 了解前庭和神经发育障碍的潜在机制。

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.