Cellular and circuit mechanisms that modulate serotonin signaling in C. elegans

调节线虫血清素信号传导的细胞和电路机制

• 批准号: 9112796
• 负责人: Kara E Zang
• 金额: $ 3.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112796
• 关键词: Absence Epilepsy; Address; Adverse effects; Affect; Aggressive behavior; Animal Behavior; Animals; Anxiety Disorders; Behavior; Biological Assay; Brain; CRISPR/Cas technology; Caenorhabditis elegans; Calcium; Cell physiology; Cells; Coupled; Coupling; Desire for food; Development; Exhibits; G-Protein-Coupled Receptors; Generalized Anxiety Disorder; Generations; Genetic; Genetic Models; Genetic study; Homologous Gene; Human; Image; Knock-in; Life; Ligands; Link; Major Depressive Disorder; Measurement; Measures; Mental Depression; Mental disorders; Modeling; Molecular; Molecular Genetics; Mood Disorders; Moods; Motor Neurons; Muscle; Mutation; Nematoda; Neuromodulator; Neurons; Neuropeptide Receptor; Neuropeptides; Neurotransmitter Receptor; Neurotransmitters; Panic Disorder; Parkinson Disease; Patients; Physiological; Physiological Processes; Play; RNA Interference; Reporter; Reproductive Behavior; Reproductive system; Role; Serotonergic System; Serotonin; Signal Pathway; Signal Transduction; Site; Stimulus; Study models; Suppressor Mutations; System; T-Type Calcium Channels; Techniques; Thalamic structure; Therapeutic; Time; Tissues; Transgenes; Tremor; Vertebrates; calcium indicator; cell type; cholinergic; driving behavior; effective therapy; egg; gain of function mutation; genetic analysis; genome editing; improved; in vivo; mood regulation; mutant; nervous system disorder; neural circuit; neuronal excitability; novel; novel therapeutics; optogenetics; promoter; public health relevance; receptor; receptor coupling; research study; response; sensory gating; serotonergic regulation; serotonin receptor; targeted treatment

 DESCRIPTION (provided by applicant): Serotonin is an important neuromodulator involved in many physiological processes, such as mood, appetite, and aggression. Altered serotonin levels have been linked to several neurological disorders, such as major depressive disorder, panic disorder, and generalized anxiety disorder. The mechanism of serotonin signaling is not well understood, resulting in a continued demand for improved therapeutics. The therapeutics that do exist are not always effective and often cause off-target side effects. Understanding the mechanism of serotonin signaling is the first step to creating more effective treatments for patients. The nematode worm C. elegans is a powerful model for studying serotonin signaling. It has a short generation time and well-understood genetics, and its reproductive behavior, egg laying, is driven by serotonin. The egg-laying circuit is comprised of only three cell types, and egg laying is an easy-to-assay behavior. Animals carrying mutations that affect serotonin signaling become bloated with unlaid eggs, making them easily identifiable. One such mutation is egl-6(gf). egl-6 encodes a neuropeptide receptor that is expressed by the pair of serotonergic motor neurons, the HSNs, that drive egg laying. EGL-6 inhibits serotonin release from the HSNs, and animals with a gain-of- function mutation (egl-6(gf)) do not release enough serotonin, causing the animals to become bloated with unlaid eggs. To discover novel regulators of serotonin signaling, a screen for suppressors of egl-6(gf) was performed. The screen yielded a mutation in cca-1. This means that egl-6(gf) animals are bloated with unlaid eggs, but egl-6(gf) cca-1 mutant double mutants exhibit wild-type egg-laying behavior. cca-1 encodes a T-type calcium channel. T-type calcium channels regulate neuronal excitability, or how easily neurons respond to stimuli. In humans, mutations in T-type calcium channels have been linked to several pathological states including absence epilepsy. Because cca-1 mutation potently suppresses egl-6(gf), it was hypothesized that CCA-1 would be expressed by the HSNS alongside EGL-6. However, it is not. The first aim of this proposal is to determine in what cells CCA-1 acts. The second aim is to understand how cca-1 mutation changes the functional connections of the cells in the serotonergic egg-laying circuit. The finding that a mutation in a T type calcium channel can profoundly affect a serotonin-driven behavior was novel and unexpected. The proposed studies will establish a link between serotoninergic circuits and T-type calcium channels. By identifying the cells that are affected by cca-1 mutation, determining how they are functionally coupled to serotonin neurons, and determining how mutation of a T-type channel alters that coupling, these studies will elucidate mechanisms required for the effects of serotonin on a neural circuit to regulate behavior. These studies will advance our understanding of how this neuromodulator system, which is targeted by many therapeutics, can be modulated and manipulated.

 描述（由申请人提供）：血清素是一种重要的神经调节剂，参与许多生理过程，例如情绪、食欲和攻击性。血清素水平的改变与多种神经系统疾病有关，例如重度抑郁症、恐慌症和广泛性焦虑症。血清素信号传导机制尚不清楚，导致对改进疗法的持续需求。现有的治疗方法并不总是有效，并且常常会导致脱靶副作用。了解血清素信号传导机制是为患者创造更有效治疗方法的第一步。线虫秀丽隐杆线虫是研究血清素信号传导的强大模型。它的世代时间短，遗传学易于理解，其繁殖行为（产卵）是由血清素驱动的。产卵回路仅由三种细胞类型组成，产卵是一种易于分析的行为。携带影响血清素信号传导突变的动物会因为未产下的卵而变得臃肿，使它们很容易被识别。一种这样的突变是egl-6(gf)。 egl-6 编码一种神经肽受体，由驱动产蛋的一对血清素能运动神经元（HSN）表达。 EGL-6 抑制 HSN 释放血清素，具有功能获得性突变 (egl-6(gf)) 的动物不能释放足够的血清素，导致动物因未下蛋而变得肿胀。为了发现新型血清素信号调节剂，对egl-6(gf) 抑制剂进行了筛选。筛选产生了 cca-1 突变。这意味着egl-6（gf）动物因未产卵而肿胀，但egl-6（gf）cca-1突变体双突变体表现出野生型产卵行为。 cca-1 编码 T 型钙通道。 T 型钙通道调节神经元兴奋性，或神经元对刺激做出反应的难易程度。在人类中，T 型钙通道的突变与包括失神癫痫在内的多种病理状态有关。由于 cca-1 突变有效抑制egl-6(gf)，因此推测 CCA-1 将与 EGL-6 一起由 HSNS 表达。然而，事实并非如此。该提案的首要目标是确定 CCA-1 在哪些细胞中发挥作用。第二个目标是了解 cca-1 突变如何改变血清素产卵回路中细胞的功能连接。发现 T 发生突变 型钙通道可以深刻影响血清素驱动的行为，这是新颖且出乎意料的。拟议的研究将建立血清素能回路和 T 型钙通道之间的联系。通过识别受 cca-1 突变影响的细胞，确定它们如何在功能上与血清素神经元耦合，并确定 T 型通道的突变如何改变这种耦合，这些研究将阐明血清素对神经回路影响以调节行为所需的机制。这些研究将增进我们对如何调节和操纵这种许多治疗方法所针对的神经调节系统的理解。