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: 8915782
• 负责人: Kevin Michael Collins
• 金额: $ 36.36万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915782
• 关键词: Acetylcholine; Affect; Animal Model; Animals; Behavior; Biogenic Amines; Brain; Brain Diseases; Caenorhabditis elegans; Calcium; Cells; Cholinergic Receptors; Complex; Coupled; Defect; Disease; Event; Feedback; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gap Junctions; Genetic; Goals; Health; Human; Image; Imaging technology; Individual; Investigation; Knock-out; Length; Mediating; Medical; Mental Depression; Modeling; Monitor; Mood Disorders; Motor Neurons; Muscle; Muscle Cells; Neuroendocrine Cell; Neuromodulator; Neurons; Neuropeptides; Neurotransmitters; Nicotinic Receptors; Obesity; Organism; Parkinson Disease; Pattern; Phase; Proteins; Role; Serotonin; Signal Transduction; Signaling Molecule; Synapses; System; Systems Analysis; Testing; Time; Tyramine; Uterus; Vulva; Work; cell type; driving behavior; egg; fast-acting neurotransmitter; knock-down; mutant; neural circuit; optogenetics; postsynaptic; promoter; receptor; response; sensor; serotonin receptor; tool

DESCRIPTION (provided by applicant): Altered signaling by neuromodulators, such as biogenic amines or neuropeptides, underlies human brain diseases including mood disorders and Parkinson's disease, yet our understanding of exactly how neuromodulators produce proper functioning of neural circuit's remains vague. How do neuromodulators collaborate with fast-acting neurotransmitters to create patterns of activity in neural circuits that underlie complex behaviors? Our goal is to understand for the first time precisely how neuromodulators function in a model neural circuit. The egg-laying circuit of C. elegans contains just three types of neurons and one set of postsynaptic muscles. This circuit involves just one fast-acting neurotransmitter, acetylcholine, plus a set of neuromodulators: the biogenic amines serotonin and tyramine, and several neuropeptides. The circuit generates a two-state behavior that alternates between a ~2.5 minute active phase in which rhythmic egg-laying contractions occur, and a ~20 minute inactive phase. Over the past 16 years, we have developed a battery of C. elegans mutants that show increased or decreased egg laying due to defects in specific signaling molecules in the circuit. We have also developed cell-specific promoters that allow us to express any protein we want in any individual cell type of the egg-laying system. We have now developed new tools to optogenetically manipulate activity of the individual cell types and to use the genetically-encoded Ca2+ sensor GCaMP to quantitatively analyze activity of each cell type within freely-behaving animals. These new tools have brought us to a tipping point at which we are ready to delineate how each cell and each neurotransmitter in the circuit act to together produce the activity pattern of the circuit. We expect a newly meaningful understanding of neuromodulators will be revealed now that we can finally analyze their function in the context of detailed investigation of a circuit they modulate. We will generate this understanding through three aims, each focused on dissecting the function one of the three neuron types in the circuit: Aim 1. We will determine how serotonin and the neuropeptide NLP-3, co-released from the HSN motor neuron, signal onto other cells in the circuit to initiate the active phase of egg laying. Aim 2. W will determine how acetylcholine, released from the VC motor neurons within the active phase, acutely triggers egg-laying contractions only when serotonin and NLP-3 have activated the circuit. Aim 3. We will determine how the uv1 neuroendocrine cells release tyramine to lengthen the inactive phase of egg laying and to space out egg-laying events during the active phase.

描述(申请人提供)：神经调节剂的信号变化，如生物胺或神经肽，是包括情绪障碍和帕金森病在内的人类大脑疾病的基础，但我们对神经调节剂如何产生神经回路的正确功能的确切理解仍然含糊不清。神经调节剂如何与快速作用的神经递质合作，在构成复杂行为的神经回路中创造活动模式？我们的目标是首次准确了解神经调节剂如何在模型神经回路中发挥作用。线虫的产卵回路只包含三种类型的神经元和一组突触后肌肉。这个回路只涉及一种快速作用的神经递质--乙酰胆碱，外加一组神经调节剂：生物胺5-羟色胺和酪胺，以及几种神经肽。该电路产生两种状态的行为，在发生有节奏的产卵收缩的~2.5分钟活动阶段和~20分钟的非活动阶段之间交替。在过去的16年里，我们已经开发了一组线虫突变体，这些突变体显示由于电路中特定信号分子的缺陷而增加或减少产卵。我们还开发了细胞特异性启动子，允许我们在产卵系统的任何单个细胞类型中表达任何我们想要的蛋白质。我们现在已经开发了新的工具来光遗传操作单个细胞类型的活动，并使用遗传编码的钙传感器GCaMP来定量分析自由行为动物中每种细胞类型的活动。这些新工具将我们带到了一个临界点，在这个临界点上，我们准备好描绘出电路中的每个细胞和每个神经递质是如何共同作用来产生电路的活动模式的。我们期待着对神经调节剂的新的有意义的理解将被揭示，现在我们终于可以在详细研究它们调节的电路的背景下分析它们的功能。我们将通过三个目标来产生这种理解，每个目标都专注于剖析电路中三种神经元类型之一的功能：目标1。我们将确定从HSN运动神经元共同释放的5-羟色胺和神经肽NLP-3如何向电路中的其他细胞发出信号，以启动产卵活跃期。目的2.W将确定只有当5-羟色胺和NLP-3激活该回路时，从活动期的VC运动神经元释放的乙酰胆碱如何强烈地触发产卵收缩。目的3.我们将确定uv1神经内分泌细胞如何释放酪胺，以延长产卵的非活动期，并在活动期划分产卵事件。