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：
8814527
负责人：
Kevin Michael Collins
金额：
$ 33.51万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8814527
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 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 public health relevance receptor response sensor serotonin receptor tool

项目摘要

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）改变的信号传导是包括情绪障碍和帕金森氏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常功能的确切理解仍然模糊。神经调节剂如何与快速作用的神经递质协作，在构成复杂行为的神经回路中创建活动模式？我们的目标是首次准确地了解神经调节器如何在模型神经回路中发挥作用。线虫的产卵回路仅包含三种类型的神经元和一组突触后肌。该回路仅涉及一种快速作用的神经递质乙酰胆碱，加上一组神经调节剂：生物胺血清素和酪胺以及几种神经肽。该电路产生两种状态行为，在约 2.5 分钟的活跃阶段和约 20 分钟的非活跃阶段之间交替，其中发生有节奏的产卵收缩。在过去的 16 年里，我们开发了一系列秀丽隐杆线虫突变体，由于回路中特定信号分子的缺陷，这些突变体表现出产卵量增加或减少。我们还开发了细胞特异性启动子，使我们能够在产卵系统的任何单个细胞类型中表达我们想要的任何蛋白质。我们现在已经开发出新的工具来光遗传学操纵单个细胞类型的活性，并使用基因编码的 Ca2+ 传感器 GCaMP 来定量分析自由行为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转折点，我们已经准备好描绘回路中的每个细胞和每个神经递质如何共同产生回路的活动模式。我们期望对神经调节剂有新的有意义的理解，现在我们终于可以在对其调节的电路进行详细研究的背景下分析它们的功能。我们将通过三个目标来达成这一理解，每个目标都侧重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血清素和神经肽 NLP-3 如何发出信号到回路中的其他细胞上以启动产卵的活跃阶段。目标 2. W 将确定仅当血清素和 NLP-3 激活回路时，活跃期 VC 运动神经元释放的乙酰胆碱如何急剧触发产卵收缩。目标 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间隔开产卵事件。