Cellular and Circuit Mechanisms of Neuropeptide Signaling

神经肽信号转导的细胞和电路机制

基本信息

批准号：
10615215
负责人：
Jennifer L Garrison
金额：
$ 48.5万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
依托单位国家：
美国
项目类别：
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/10615215
关键词：
Address Affect Anatomy Animals Anxiety Arousal Behavior Behavior Control Behavioral Biochemical Biological Models Brain Central Nervous System Communication Disease Emotional Enzymes Etiology Functional disorder Funding Genetic Goals Health Homeostasis Human Image Literature Logic Medical Mental Depression Mental disorders Metabolic Diseases Methods Monitor Moods Motivation National Institute of General Medical Sciences Nervous System 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 insight mouse model neural circuit neuropsychiatry neuroregulation neurotransmission new therapeutic target novel receptor reuptake transmission process

项目摘要

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.

项目摘要在我的实验室中，由NIGMS资助的研究的总体目标是通过哪些神经肽信号传导影响控制行为的神经回路。神经肽是最大的中枢神经系统中的常见信号分子，以及对细胞类型的最佳标记之一脑。这些内源性肽在大脑内和整个体内传播消息以控制重要能量稳态，以及动机和情感状态等生理过程，包括睡眠，唤醒，疼痛，压力和情绪。肽能信号的失调与医疗条件有关从肥胖到精神疾病不等。大量的科学文献调查了数十年来的生理和行为中的神经肽，即使对于许多研究的电路，他们功能意义仍然是一个悬而未决的问题。因为它们不受解剖学的空间限制接线图或通过快速重新摄取或退化的时间进行接线图，描述事实证明，全动物中的神经肽回路具有挑战性。我的实验室试图通过发展来解决这一差距在活动物中监测和选择性操纵神经肽信号的新方法，并确定调节神经肽通信的基本酶。我们采用先进的成像，遗传，以及使用蠕虫和鼠标模型系统研究这些问题的生化方法亚细胞级一直到行为输出。我们的目标是了解电路的生化逻辑神经肽的神经调节具有与我们了解快速神经递质的相同清晰度突触。这项研究将为有关空间和长期问题的基本新见解提供基本的新见解。神经肽信号传导的时间组织，并导致对长期变化的理解在神经系统中受到影响，导致行为不同。由于神经肽及其受体是可吸毒目标涉及各种疾病，我们预计机械性的洞察力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。