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Mechanisms of neural circuit formation in C. elegans

线虫神经回路形成机制

基本信息

批准号：
9768244
负责人：
Dong Yan
金额：
$ 29.56万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768244
关键词：
Address Adult Affect Animal Model Apoptosis Apoptotic Axon Birth Brain Caenorhabditis elegans Calcium Signaling Caspase Cell Death Cells Clinical Research Data Defect Dendrites Development Disease Dissection Dorsal Down Syndrome Electron Microscopy Electrophysiology (science)F-Actin Fragile X Syndrome Future Gap Junctions Generations Genetic Head Movements Individual Knowledge Left Microfilaments Microtubules Mitochondria Modeling Molecular Motor Neurons Muscle Nervous system structure Neurites Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurons Outcome Pathologic Pathway interactions Physiological Play Prader-Willi Syndrome Process Proteins Regulation Role Signal Transduction Specific qualifier value Synapses Synaptic plasticity System Time Transgenic Organisms autism spectrum disorder axon growth axon regeneration base chronic painful condition experience genetic analysis in vivo in vivo imaging injury and repair innovation migration mitochondrial dysfunction neural circuit neurodevelopment neuromechanism neuron development neuronal circuitry new therapeutic target novel public health relevance relating to nervous system synaptogenesis tool

项目摘要

DESCRIPTION (provided by applicant): Neural circuit formation is a critical step of brain development, and disruption of neural circuit formation causes many birth conditions. The formation of a functional circuit requires the intricate orchestration of multiple steps, including fate determination, migration, axon/dendrite differentiation, axon growth, and synapse formation and elimination. However it is still unclear how individual neurons are assembled into the functional circuits during development. Here, we propose to use the development of a defined neuronal circuit in Caenorhabditis elegans-the RME circuit- to study molecular mechanisms of neural circuit formation. RME circuit development utilizes all the critical steps of mammalian cortex development and involves neuron- neuron, neuron-glia, and neuron-muscle interactions. This system has enabled us to analyze neural circuit formation from the birth of neurons to the maturation of functional circuits. In this proposal we focus on address two important questions: how do glial cells instruct neuronal polarity through gap junctions, and what is the local regulatory mechanism of the cell death pathway in synapse elimination. In our preliminary studies we uncovered a previous unknown function of glial cells during neuronal development in which glial cells form gap junctions with nearby neurons to regulate microtubule polarity and neuronal polarity. We propose studies of the molecular mechanism underlying this observation. The final step of the circuit formation is refinement of synaptic connections through synapse elimination. We found that local activation of the cell death pathway is required for synapse elimination, and this local activation needs the presence of mitochondria. In this application we outline a strategy to address the long time questions in the field: how the apoptotic pathway is locally activated without causing cell death, and what are the downstream targets of caspases in neuronal development. Completion of this proposal will lead to the discovery of novel mechanisms of neural circuit formation, establish the development of RME circuit as a powerful model to study neural circuit formation, and generate new tools for further studies. Given that many neural disorders are associated with defects in neural circuit formation, it is hopeful that this project will help to understand brain development under both physiological and pathological conditions.