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（由申请人提供）：神经调节剂（例如生物胺或神经肽）的信号改变是人类脑疾病（包括情绪障碍和帕金森氏病）的基础，但我们对神经调节剂如何确切地产生神经回路的正确功能的理解。神经调节剂如何与快速作用的神经递质合作，以创建构成复杂行为的神经回路中的活动模式？我们的目标是首次了解神经调节剂在模型神经回路中的功能。秀丽隐杆线虫的卵子电路仅包含三种类型的神经元和一组突触后肌肉。该电路仅涉及一个快速作用的神经递质，乙酰胆碱，以及一组神经调节剂：生物胺5-羟色胺和酪胺，以及几种神经肽。该电路产生了两态行为，在有节奏的卵子收缩的一个约2.5分钟的活动相位上交替，并且〜20分钟的不活动相。在过去的16年中，我们已经开发了一组秀丽隐杆线虫突变体，这些突变体显示出由于电路中特定的信号分子缺陷而导致的卵产生增加或减少。我们还开发了细胞特异性启动子，使我们能够在任何单个细胞类型的卵形系统中表达所需的任何蛋白质。现在，我们已经开发了新的工具来光遗传学操纵单个细胞类型的活性，并使用遗传编码的CA2+传感器GCAMP来定量分析自由塑造动物中每种细胞类型的活性。这些新工具将我们带到了一个临界点，我们准备描绘电路中每个细胞和每个神经递质如何共同产生电路的活性模式。我们希望，现在将揭示对神经调节剂的新有意义的理解，我们最终可以在调节其调节电路的详细研究中分析其功能。我们将通过三个目标产生这种理解，每个目标都集中在电路中的三种神经元类型之一：AIM 1。我们将确定如何从HSN运动神经元共同发出的5-羟色胺和神经肽NLP-3如何信号到电路中的其他细胞上，以启动产卵的活性相。 AIM2。W才能确定仅当血清素和NLP-3激活电路时，乙酰胆碱是如何从活性相中从VC运动阶段释放的乙酰胆碱。 AIM 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不活跃相，并在活性阶段散发出卵子的事件。