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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：
9813142
负责人：
Kevin Michael Collins
金额：
$ 45.2万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813142
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.

项目总结