Neuromodulator signaling and activity in the C. elegans egg-laying circuit

线虫产卵回路中的神经调节信号和活动

基本信息

批准号：
10398019
负责人：
Kevin Michael Collins
金额：
$ 43.8万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2024-01-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10398019
关键词：
Acetylcholine Affect Animal Model Animals Area Behavior Biological Assay Biology Brain Brain Diseases Caenorhabditis elegans Candidate Disease Gene Carbon Dioxide Cells Coupled Defect Diglycerides Disease Drosophila genus Embryo Environment Equilibrium Escherichia coli Event Feedback Food G alpha q Protein G-Protein-Coupled Receptors GTP-Binding Proteins Genes Genetic Goals Human Human Biology Image Individual Knock-out Lac Operon Length Measures Mechanics Mediating Medical Methods Modeling Mood Disorders Motor Neurons Muscle Muscle Cells Muscle Contraction Mutation Neuromodulator Neurons Neuropeptide Receptor Neuropeptides Neurotransmitter Receptor Neurotransmitters Organism Parkinson Disease Pathway interactions Pattern Pattern Formation Periodicity Phase Role Sensory Serotonin Signal Transduction Source Stretching Synapses System Testing Transgenes Uterus Work cell type cholinergic egg imaging approach insight mutant mutation screening neural circuit neural model optogenetics overexpression postsynaptic presynaptic receptor response rho serotonin receptor small molecule success

项目摘要

Project Summary The long-term goal of this project is to delineate at an unprecedented level of precision how all the neurotransmitter signaling events within a model neural circuit together produce its dynamic pattern of activity. Neural circuits are a basic unit of brain function, and altered signaling within neural circuits can disrupt circuit function to produce mood disorders and other human brain diseases. To date, our understanding of such diseases remains vague because we understand only a few individual features within each of the many different neural circuits that have been studied. Therefore, our approach is to analyze all the signaling events within one simple neural circuit, anticipating that this will yield new insights into how neural circuits in general work. This approach is inspired by past successes in other areas of biology in which deep analysis of a simple model in a genetically tractable organism (e.g. the lac operon in E. coli or pattern formation in the Drosophila embryo) led to conceptual breakthroughs that generalized to human biology. Thus, we are intensely studying the simple egg-laying circuit of C. elegans, an experimental system in which we have developed a powerful combination of genetic, optogenetic, chemogenetic, and Ca2+ imaging approaches that together can provide unprecedented mechanistic insights into circuit function. Our analysis has already discovered two instances in which a small-molecule neurotransmitter signals alongside co-released neuropeptides, and also that ongoing circuit activity responds to homeostatic feedback from the postsynaptic cells. These features are likely conserved in other neural circuits. In the next period of this project we aim to understand how the egg-laying circuit turns itself on. This circuit alternates between ~20 minute inactive phases and ~2.5 minute periods of rhythmic activity. Our recent work shows that the two HSN command neurons release a combination of serotonin and neuropeptides encoded by the nlp-3 gene to activate the circuit. These neuromodulators signal through a set of at least five receptors to alter the postsynaptic muscle response to acetylcholine released from presynaptic motor neurons. Aim 1. We will determine how the HSN neurons “decide” when to release serotonin and NLP-3 neuropeptides to activate the circuit. Aim 2. We will determine how a diverse set of receptors for serotonin and NLP-3 neuropeptides alter activity of various specific cells of the circuit to make the circuit active. Aim 3. We will identify the cells and signals that act with HSN-released serotonin and NLP-3 neuropeptides to help activate the circuit and ultimately trigger egg-laying muscle contraction.

项目概要该项目的长期目标是以前所未有的精确度描述所有模型神经回路内的神经递质信号事件共同产生其动态活动模式。神经回路是大脑功能的基本单位，神经回路内的信号传导可能会破坏回路迄今为止，我们对此类疾病的了解还不够。疾病仍然模糊不清，因为我们只了解众多疾病中的每一种的几个单独特征因此，我们的方法是分析所有的信号事件。在一个简单的神经回路中，预计这将产生关于神经回路一般如何运作的新见解这种方法的灵感来自于过去在生物学其他领域的成功，其中对简单的深入分析。遗传上易处理的生物体中的模型（例如大肠杆菌中的紫胶操纵子或果蝇中的模式形成）胚胎）导致了推广到人类生物学的概念突破，因此，我们正在深入研究。线虫的简单产卵回路，这是一个实验系统，我们在其中开发了强大的遗传、光遗传学、化学遗传学和 Ca2+ 成像方法的组合可以提供我们的分析已经发现了两个实例。一种小分子神经递质与共同释放的神经肽一起发出信号，并且正在进行电路活动可能会对突触后细胞的稳态反馈做出反应。在这个项目的下一个阶段，我们的目标是了解产卵的过程。电路自行开启。该电路在约 20 分钟的非活动阶段和约 2.5 分钟的非活动阶段之间交替。我们最近的工作表明，两个 HSN 指挥神经元释放出一种组合。由 nlp-3 基因编码的血清素和神经肽可激活这些神经调节信号。通过一组至少五个受体来改变突触后肌肉对乙酰胆碱释放的反应突触前运动神经元。目标 1. 我们将确定 HSN 神经元如何“决定”何时释放血清素和 NLP-3 神经肽来激活电路。目标 2. 我们将确定一组不同的血清素和 NLP-3 神经肽受体如何改变电路的各种特定单元使电路活跃。目标 3. 我们将鉴定与 HSN 释放的血清素和 NLP-3 神经肽作用的细胞和信号，以帮助激活回路并最终引发产卵肌肉收缩。