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

了解新型细胞类型在触发自愿眼跳中的作用

• 批准号: 10832719
• 负责人: Alexandro D Ramirez
• 金额: $ 24.9万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10832719
• 关键词: Ablation; Address; Affect; Anatomy; Animals; Automobile Driving; Behavior; Behavioral; Brain; Calcium; Cell Communication; Cells; Cellular Morphology; Communication; Counseling; Data; Disease; Dyes; Electron Microscopy; Electrophysiology (science); Electroporation; Eye; Eye Movements; Foundations; Functional disorder; Generations; Genetic; Goals; Human; Image; Influentials; Involuntary Movements; Laboratories; Lasers; Leadership; Location; Mediating; Membrane; Mentors; Midbrain structure; Modeling; Modernization; Molecular Biology; Morphology; Motor; Movement; Neurons; Neurosciences; Optics; Optokinetic nystagmus; Pathology; Pathway interactions; Phase; Population; Positioning Attribute; Prosencephalon; Ramp; Reading; Recurrence; Research; Research Personnel; Retina; Role; Saccades; Signal Transduction; Solid; Structure; Synapses; System; Technical Expertise; Testing; Training; Vision; Work; Zebrafish; awake; career; cell type; experience; experimental study; eye velocity; fovea centralis; hindbrain; improved; insight; interest; mathematical model; medical schools; neural; neural circuit; neural network; nonhuman primate; novel; oculomotor; optogenetics; postsynaptic; public health relevance; rapid eye movement; response; skills; symposium; temporal measurement; therapy development; time interval; tool; two-photon; voltage

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.

项目总结/摘要 眼睛位置的快速变化用于将眼睛重新定向到感兴趣的点。照亮 引发这些运动的潜在机制可以提供对眼功能障碍的深入了解 典型地以诸如扫视侵入的无意识运动为特征。这些无意识的动作 通过改变视网膜中央凹的焦点使视力模糊。详细的功能研究，主要是在非人类 灵长类动物，已经导致了模型，提出快速眼球运动发生时，单一的活动， 神经元或神经元群上升到阈值以上。然而，这种模式的直接证据是缺乏的。 这项提案的目标是提供一种细胞类型的结构和功能分析，我们最近 发现其活动表明在扫视启动中的作用;这些细胞显示钙离子的持续升高 在扫视前几秒。我们发现，在局部激光消融后， 包含这些神经元的群体。为了找到这些细胞，我们利用了小尺寸，遗传和 光可及性的幼虫斑马鱼脑图像钙活动从单细胞在整个 大部分的后脑，同时跟踪自发眼球运动。我们发现的细胞 是唯一含有前扫视活动的后脑神经元。基于这些结果，我们假设这些 细胞对启动自发扫视的神经回路起作用。 我提出了两个目标，以阐明在触发快速眼球运动的前扫视活动的作用。在 在K99阶段，我将描述快速阶段具有前扫视活动的神经元的活动 使用全脑钙成像和电生理学的视动刺激和扫视。我要熬炼 这些神经元在刺激过程中通过可逆性沉默和激活其活性而发挥的行为作用（目的 1; K99）。最后，我将评估这种神经元类型如何与眼回路中的其他细胞类型相互作用， 表征该细胞类别的形态（目标2; R 00）。总的来说，这些实验将解决 在我们对水平眼球运动是如何产生的理解中，有一些悬而未决的问题。培训计划 本提案中所描述的详细说明了一个重点战略，以获得成功所需的必要技能， 从实习生到独立调查员的转变。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，和我的共同导师的模范团队已经精心挑选，以提供必要的 技术和经验，以实现这一目标。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。在过渡到独立后， 在这一阶段，我将利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 运动的开始。