Understanding the Developmental Mechanisms that Ensure Robustness in Neuronal Patterning

了解确保神经元模式稳健性的发育机制

• 批准号: 10251027
• 负责人: Pavak Kirit Shah
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251027
• 关键词: 3-Dimensional; Ablation; Adult; Advisory Committees; Alleles; Award; Behavior; Brain; Caenorhabditis elegans; Calcium; Cells; Cellular biology; Cilia; Communities; Complement; Development; Developmental Process; Dorsal; Embryo; Embryonic Development; Embryonic Nervous System; Ensure; Environment; Equilibrium; Feedback; Financial compensation; Fluorescence Microscopy; Future; Generations; Genetic; Glutamates; Goals; Growth; Head; Head Movements; Human Development; Image; Individual; Institutes; Interleukin-1; Knowledge; Label; Laboratories; Lasers; Learning; Measurement; Measures; Mechanics; Memory; Mental disorders; Mentors; Mentorship; Methods; Modeling; Motor; Motor Neurons; Motor output; Movement; Muscle; Nature; Nematoda; Nervous System Physiology; Nervous system structure; Neurodevelopmental Disorder; Neuromuscular Junction; Neurons; Optics; Output; Paper; Pattern; Phase; Physical Stimulation; Play; Postdoctoral Fellow; Process; Property; Publishing; Quantitative Microscopy; Reagent; Regulation; Reporter; Resolution; Sensory; Source; Specificity; Speed; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Time; Tissues; Training; Training Support; Universities; Vertebrates; Work; analysis pipeline; automated image analysis; base; career; career development; cholinergic; design; experience; flexibility; human disease; improved; in vivo; insight; interest; medical schools; motor behavior; mutant; neuronal circuitry; neuronal patterning; optogenetics; preservation; relating to nervous system; response; sensory feedback; sensory input; transgene expression

Abstract: Establishing a balance between the activities of competing neuronal circuits is essential to the coordination of behaviors. We propose to investigate the developmental strategies that ensure the establishment of this balance in the nervous system. Studies of the vertebrate embryonic nervous system have shown that correlated activity patterns the structure and output nascent circuits through mechanisms akin to learning. The scale and complexity of vertebrate brains has made it challenging to identify the rules which govern this learning or the mechanisms which drive optimization of the circuit toward a balanced output. The small size and invariance of the Caenorhabditis elegans nervous system make it possible to study these processes with specificity not possible in vertebrates. Using the development of one of the first functional circuits in the C. elegans embryo as a model, I will study how functional balance is established in the developing nervous system and identify the developmental mechanisms that ensure the robustness of this balance. To accomplish this goal, I propose the following specific aims: 1) To identify the models of IL1 neuron function in the patterning of embryonic head movement. 2) To automate and improve an approach for controlling transgene expression with single cell resolution by infrared laser-induced heatshock. And 3) To determine the mechanisms by which the IL1 circuit establishes and maintains a balanced output to produce coordinated movements. To enable this, I have developed a real-time cell tracking system which automates the identification of targeted cells during embryonic development and can control the conduct of single cell optical perturbations such as laser ablation as described in a recently published paper in Developmental Cell or, as will be developed in Aim 2, single cell heatshock. I have also developed an automated image analysis pipeline which allows me to track and measure movement patterns in the early embryo with which I have identified the neuronal origins of patterned head movement and, using genetic mutants of neuronal function, shown that this patterning is defined by neuronal input. I believe that this work will provide important insights into the patterning of the embryonic nervous system with implications for our understanding of the circuit-level origins of some neurodevelopmental disorders. In order to expand my training as a biologist and complement my broad technical training and expertise, I will carry out the mentored phase of this award as a postdoctoral Research Associate in the laboratory of Dr. Zhirong Bao, an expert on C. elegans embryonic development, and under the mentorship of a well-accomplished advisory committee comprised of experienced biologists and neuroscientists. I have designed a structured plan to further my scientific training and support my career development to prepare for an independent career. The Sloan Kettering Institute and the tri- institutional community at Weill Cornell Medical College and The Rockefeller University provide an unparalleled intellectual environment to support my scientific growth and progress towards independence.

摘要：在竞争神经元电路的活动之间建立平衡对 行为的协调。我们建议调查确保 在神经系统中建立这种平衡。脊椎动物胚胎神经系统的研究具有 表明相关的活动模式通过类似的机制结构和输出新生电路 学习。脊椎动物大脑的规模和复杂性使确定规则的规则具有挑战性 控制这一学习或将电路优化到平衡输出的机制。这 秀丽隐杆线虫神经系统的小尺寸和不变性使研究这些 在脊椎动物中不可能具有特异性的过程。使用第一个功能之一的开发 秀丽隐杆线虫胚胎中的电路作为模型，我将研究如何建立功能平衡 开发神经系统并确定确保这一点鲁棒性的发展机制 平衡。为了实现这一目标，我提出以下特定目的：1）确定IL1神经元的模型 在胚胎头运动的模式下起作用。 2）自动化并改善一种方法 通过红外激光诱导的热轴通过单细胞分辨率控制转基因表达。和3）到 确定IL1电路建立并保持平衡输出以产生的机制 协调的动作。为了实现这一目标，我已经开发了一个实时单元跟踪系统，该系统可自动 在胚胎发育过程中鉴定靶细胞，并可以控制单细胞的传导 光学扰动，例如激光消融，如最近发表的发育论文中所述 单元格或将在AIM 2中开发的单细胞热轴。我还开发了自动图像 分析管道使我能够在早期胚胎中跟踪和测量运动模式 已经鉴定出图案化头部运动的神经元起源，并使用神经元的遗传突变体 函数，表明该图案是由神经元输入定义的。我相信这项工作将提供重要的 洞悉胚胎神经系统的模式，对我们对 某些神经发育障碍的电路级起源。为了扩大我作为生物学家和 补充我广泛的技术培训和专业知识，我将作为一个奖项的指导阶段作为一个 秀丽隐杆线虫胚胎专家Zhirong Bao博士实验室的博士后研究助理 在经验丰富的咨询委员会的指导下，由经验丰富的咨询委员会的指导 生物学家和神经科学家。我设计了一个结构化计划，以进一步进一步的科学培训和支持 我的职业发展为独立职业做准备。斯隆·凯特林学院和三 威尔·康奈尔医学院和洛克菲勒大学的机构社区提供了无与伦比的 智力环境支持我的科学成长并向独立发展。