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: 10535094
• 负责人: Kevin Michael Collins
• 金额: $ 7.19万
• 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/10535094
• 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以前所未有的精确度描绘所有 模型神经回路内的神经递质信号事件一起产生其动态活动模式。 神经回路是大脑功能的基本单位，神经回路中的信号改变会破坏回路。 产生情绪障碍和其他人类大脑疾病的功能。到目前为止，我们对这种情况的了解 疾病仍然是模糊的，因为我们只了解许多疾病中的每一种疾病的少数个别特征。 不同的神经回路。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，预计这将产生新的见解，了解神经回路一般如何 工作这种方法的灵感来自于过去在生物学其他领域的成功，在这些领域中，对一个简单的 在遗传上易处理的生物体中的模型（例如E.大肠杆菌或模式形成在果蝇 胚胎）导致了概念上的突破，推广到人类生物学。因此，我们正在认真研究 简单的产卵回路。elegans，一个实验系统，我们已经开发出一个强大的 遗传学、光遗传学、化学遗传学和Ca 2+成像方法的组合， 对电路功能的前所未有的机械见解。我们的分析已经发现了两个例子， 一种小分子神经递质与共同释放的神经肽一起发出信号， 回路活动响应来自突触后细胞的稳态反馈。这些特征很可能 在其他神经回路中是保守的。在这个项目的下一个阶段，我们的目标是了解如何产卵 该电路在~20分钟的非活动阶段和~2.5分钟的间歇期之间交替。 节律活动我们最近的工作表明，两个HSN命令神经元释放一种组合， 5-羟色胺和由NLP-3基因编码的神经肽来激活回路。这些神经调质发出信号 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 激活电路 目标二。我们将确定一组不同的5-羟色胺和NLP-3神经肽受体如何改变神经元的活性。 电路的各种特定单元以使电路有效。 目标3.我们将识别与HSN释放的血清素和NLP-3神经肽作用的细胞和信号， 帮助激活电路并最终触发产卵肌肉收缩。