Cellular and Circuit Mechanisms of Neuropeptide Signaling

神经肽信号转导的细胞和电路机制

• 批准号: 10406828
• 负责人: Jennifer L Garrison
• 金额: $ 50.87万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406828
• 关键词: Address; Affect; Anatomy; Animals; Anxiety; Arousal; Behavior; Behavior Control; Behavioral; Biochemical; Biological Models; Brain; Communication; Disease; Emotional; Enzymes; Etiology; Functional disorder; Funding; Goals; Health; Homeostasis; Human; Lead; Literature; Logic; Medical; Mental Depression; Mental disorders; Metabolic Diseases; Methods; Monitor; Moods; Motivation; National Institute of General Medical Sciences; Nervous system structure; Neuraxis; Neuropeptides; Obesity; Output; Pain; Pain Disorder; Peptides; Physiological Processes; Physiology; Research; Role; Schizophrenia; Signal Transduction; Signaling Molecule; Sleep; Sleep Disorders; Stress; Synapses; addiction; autism spectrum disorder; behavior influence; cell type; clinically relevant; druggable target; imaging genetics; insight; mouse model; neural circuit; neuropsychiatry; neuroregulation; neurotransmission; new therapeutic target; novel; receptor; uptake

Project Summary The overall goal of NIGMS-funded research in my lab is to understand the cellular and circuit mechanisms by which neuropeptide signaling influences the neural circuits that control behavior. Neuropeptides are the most common signaling molecule in the central nervous system and among the best markers for cell types in the brain. These endogenous peptides transmit messages within the brain and across the body to control vital physiologic processes like energy homeostasis, as well as motivational and emotional states including sleep, arousal, pain, stress, and mood. Dysregulation of peptidergic signaling is implicated in medical conditions ranging from obesity to psychiatric disorders. A vast scientific literature has investigated the role of neuropeptides in physiology and behavior over decades, yet even for many well-studied circuits, their functional significance is still an open question. Because they are not restricted spatially by the anatomical wiring diagram nor temporally by rapid re-uptake or degradation, delineating the precise connectivity of neuropeptide circuits in whole animals has proved challenging. My lab seeks to address this gap by developing novel methods to monitor and selectively manipulate neuropeptide signaling in living animals, and to identify the fundamental enzymes that regulate neuropeptide communication. We employ advanced imaging, genetic, and biochemical approaches to investigate these questions using both worm and mouse model systems from the subcellular level all the way to behavioral output. Our goal is to understand the biochemical logic of circuit neuromodulation by neuropeptides with the same clarity that we understand fast neurotransmission at synapses. This research will provide fundamental new insight into longstanding questions about the spatial and temporal organization of neuropeptide signaling and lead to an understanding of how long-term changes are affected in the nervous system that result in different behaviors. As neuropeptides and their receptors are druggable targets implicated in a wide-range of diseases, we anticipate that mechanistic insight into their signaling is likely to have broad clinical relevance for diseases characterized by behavioral dysfunction.

项目概要 我的实验室由 NIGMS 资助的研究的总体目标是通过以下方式了解细胞和电路机制： 哪种神经肽信号传导影响控制行为的神经回路。神经肽是最 中枢神经系统中常见的信号分子，也是细胞类型的最佳标记之一 脑。这些内源性肽在大脑内和全身传递信息以控制重要生命体 能量稳态等生理过程，以及包括睡眠在内的动机和情绪状态， 觉醒、疼痛、压力和情绪。肽能信号传导失调与医疗状况有关 从肥胖到精神疾病。大量科学文献研究了 几十年来，神经肽在生理学和行为中发挥着重要作用，但即使对于许多经过充分研究的电路来说，它们的 功能意义仍然是一个悬而未决的问题。因为它们在空间上不受解剖学的限制 接线图也不是暂时通过快速重新摄取或降解来描绘的精确连接 事实证明，研究整个动物的神经肽回路具有挑战性。我的实验室致力于通过开发来解决这一差距 监测和选择性操纵活体动物神经肽信号传导并识别的新方法 调节神经肽通讯的基本酶。我们采用先进的成像、遗传、 和生化方法使用蠕虫和小鼠模型系统来研究这些问题 亚细胞水平一直到行为输出。我们的目标是理解电路的生化逻辑 神经肽的神经调节与我们理解快速神经传递的清晰度相同 突触。这项研究将为解决有关空间和空间的长期问题提供根本性的新见解。 神经肽信号传导的时间组织，并导致了解长期变化是如何发生的 神经系统受到影响，导致不同的行为。由于神经肽及其受体 与多种疾病有关的可药物靶标，我们预计对其的机制了解 信号传导可能与以行为功能障碍为特征的疾病具有广泛的临床相关性。