Understanding the Role of a Novel Cell Type in Triggering Voluntary Saccades

项目摘要/摘要 眼睛位置的快速变化被用来将眼睛重新定向到感兴趣的点。照亮了 这些运动的启动机制可以提供对眼球运动障碍的洞察 典型的特征是不自主的运动，如扫视干扰。这些无意识的动作 通过改变视网膜中心凹的焦点而使视力模糊。详细的功能研究，主要是在非人类 灵长类动物的研究结果表明，当单个人的眼球运动 神经元或神经元群超过一个阈值。然而，缺乏支持这种模式的直接证据。 这项建议的目标是提供我们最近获得的一种细胞类型的结构和功能分析 发现其活动表明其在眼跳启动中起作用；这些细胞显示出钙的持续上升 在扫视前几秒钟。我们发现，在聚焦激光消融后，眼跳率出现了中断 包含这些神经元的种群。为了找到这些细胞，我们利用了小体积、遗传和 斑马鱼幼体大脑的光学可及性，以成像整个大脑中单个细胞的钙活动 大多数后脑同时跟踪自发的眼球运动。我们发现的细胞是 唯一含有扫视前活动的后脑神经元。根据这些结果，我们假设这些 细胞参与启动自发眼跳的神经回路。 我提出两个目的来阐明眼球跳动前活动在触发快速眼动中的作用。在 指导K99阶段，我将表征快相中具有眼跳前活动的神经元的活动 使用全脑钙成像和电生理学进行视动刺激和眼跳的研究。我会改进的 这些神经元在刺激过程中通过可逆地沉默和激活其活动而发挥的行为作用(AIM 1；K99)。最后，我将评估这种神经元类型如何与动眼神经回路中的其他细胞类型相互作用 描述这类细胞的形态特征(目标2；R00)。总体而言，这些实验将解决 在我们对水平眼动是如何产生的理解中，有一些悬而未决的问题。培训计划 本建议书中描述的详细说明了获得成功所需的必要技能的重点战略 从实习生过渡到独立调查员。我的主要导师，威尔康奈尔大学的埃姆雷·阿克赛博士 医学院和我的模范导师团队都是经过精心挑选的，以提供必要的 实现这一目标的经验和技术专长。指导律师，重复的数据演示， 参加研讨会、会议和专业课程都将被用来建立必要的 沟通和领导能力对成功的科学事业至关重要。在过渡到独立的 阶段，我将使用这些技能建立一个实验室，使用跨学科的工具来研究神经基础 运动启动的时间。

Project Summary/Abstract Rapid changes in eye position are used to reorient the eyes towards points of interest. Illuminating the mechanisms underlying the initiation of these movements can provide insight into oculomotor disorders typically characterized by involuntary movements such as saccadic intrusions. These involuntary movements obscure vision by changing the focus of the retinal fovea. Detailed functional studies, primarily in non-human primates, have resulted in models that propose that rapid eye movements occur when the activity of single neurons or neuronal populations rises above a threshold. However, direct evidence for this model is absent. The goal of this proposal is to provide structural and functional analysis of a cell type we have recently discovered whose activity suggests a role in saccade initiation; these cells show a consistent rise in calcium multiple seconds before saccades. We uncovered a disruption in saccade rate following focal laser ablations of populations containing these neurons. To find these cells, we took advantage of the small size, genetic and optical accessibility of the larval zebrafish brain to image calcium activity from single cells throughout the majority of the hindbrain while simultaneously tracking spontaneous eye movements. The cells we found were the only hindbrain neurons containing pre-saccadic activity. Based on these results, we hypothesize that these cells contribute to the neural circuit initiating spontaneous saccades. I propose two aims to elucidate role of pre-saccadic activity in triggering rapid eye movements. In the mentored K99 stage, I will characterize the activity of neurons with pre-saccadic activity during the fast phase of optokinetic stimulation and saccades using whole-brain calcium imaging and electrophysiology. I will refine the behavioral role of these neurons by reversibly silencing and activating their activity during stimulation (Aim 1; K99). Finally, I will assess how this neuron type interacts with other cell types in the oculomotor circuit and characterize the morphology of this cell class (Aim 2; R00). Collectively, these experiments will address unanswered questions in our understanding of how horizontal eye movements are generated. The training plan described in this proposal details a focused strategy for acquiring the necessary skills I need to successfully transition from a trainee to independent investigator. My principal mentor, Dr. Emre Aksay at Weill Cornell Medical College, and my exemplary team of co-mentors have been carefully chosen to provide the necessary experience and technical expertise to achieve this goal. Mentor counsel, recurring data presentations, attendance of seminars, conferences and professional courses will all be utilized to build the necessary communication and leadership skills vital to a successful scientific career. After transitioning to the independent phase, I will use these skills to establish a laboratory that uses interdisciplinary tools to study the neural basis of movement initiation.