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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

基本信息

批准号：
10004225
负责人：
Pavak Kirit Shah
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2022-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004225
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 mutant neuronal circuitry neuronal patterning optogenetics preservation relating to nervous system response sensory feedback sensory input transgene expression

项目摘要

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：在相互竞争的神经回路活动之间建立平衡对大脑的健康至关重要