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

• 批准号: 10599389
• 负责人: Kevin Michael Collins
• 金额: $ 8.57万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599389
• 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

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.

项目摘要 该项目的长期目标是在前所未有的精确级别上划定如何所有这些 神经递质中的神经递质信号传导事件共同产生其动态活性模式。 神经回路是大脑功能的基本单位，神经回路内的信号变化会破坏电路 发挥情绪障碍和其他人脑疾病的功能。迄今为止，我们对这种理解 疾病仍保持投票，因为我们只了解许多人中的每个特征 已经研究了不同的神经回路。因此，我们的方法是分析所有信号事件 在一个简单的神经电路中，预计这将产生有关神经回路的新见解 工作。这种方法的灵感来自于其他生物学领域的成功，其中对简单的深入分析 一般可拖动的生物（例如，大肠杆菌中的lac Operaon或果蝇中的模式形成）中的模型 胚胎）导致了概念上的突破，这些突破概念化为人类生物学。那我们正在聪明地学习 秀丽隐杆线虫的简单卵电路，这是一个实验系统，我们在其中开发了一个强大的鸡蛋。 遗传，光遗传学，化学遗传学和Ca2+成像方法的结合在一起，可以提供 对电路函数的空前机械洞察。我们的分析已经发现了两个实例 小分子神经递质信号与共同发行的神经肽以及正在进行的 电路活动对来自突触后细胞的体内平衡反馈的反应。这些功能可能是 在其他神经回路中保守。在此项目的下一个阶段，我们旨在了解卵子的方式 电路自身打开。该电路替代范围在约20分钟之间，不活跃的阶段和约2.5分钟的时间 节奏活动。我们最近的工作表明，两个HSN命令神经元发布了 NLP-3基因编码的5-羟色胺和神经肽激活电路。这些神经调节剂信号 通过一组至少五个受体改变对乙酰胆碱的反应 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5-羟色胺和NLP-3神经肽 激活电路。 AIM 2。我们将确定5-羟色胺和NLP-3神经肽的受体如何改变活性 电路的各种特定电池使电路活跃。 AIM 3。我们将确定用HSN释放的5-羟色胺和NLP-3神经肽作用的细胞和信号 有助于激活电路并最终触发卵子的肌肉收缩。