Inhibitory feedback mechanisms that couple circadian clock neurons in mammals

耦合哺乳动物生物钟神经元的抑制反馈机制

• 批准号: 9278316
• 负责人: Jennifer Anne Evans
• 金额: $ 28.44万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278316
• 关键词: Address; Argipressin; Behavior; Behavior Control; Binding; Biological; Biological Assay; Biological Models; Brain; Cardiac Myocytes; Circadian Rhythms; Coupling; Data; Disease; Ensure; Epilepsy; Event; Feedback; Foundations; Functional disorder; Genetic; Goals; Head; Health; Immunologic Deficiency Syndromes; Impaired cognition; In Vitro; Light; Link; Mammals; Maps; Mediating; Modeling; Morphology; Nerve Degeneration; Neurons; Neuropeptides; Optical reporter; Parkinson Disease; Pathologic; Pattern; Pharmacology; Physiology; Population; Preparation; Process; Research; Risk; Role; Schizophrenia; Signal Pathway; Signal Transduction; Sleep Disorders; Slice; Somatostatin; Subgroup; System; Testing; Time; Tissues; Vasoactive Intestinal Peptide; Vertebral column; Viral; Work; bioluminescence imaging; cancer risk; cardiovascular risk factor; circadian pacemaker; disorder risk; experimental study; genetic manipulation; human disease; in vivo; innovation; insight; knock-down; mouse model; nervous system disorder; neural circuit; novel; novel strategies; novel therapeutics; obesity risk; prevent; programs; public health relevance; receptor; relating to nervous system; response; suprachiasmatic nucleus; tool; virtual

 DESCRIPTION (provided by applicant): Neuron ensembles display coordinated activity patterns that arise from feedback connections among the constituent neurons; however, the mechanisms that synchronize neural activity in time and space remain poorly understood. This is a fundamental gap in our understanding because neuronal synchronization is critical for normal brain function and its dysfunction is implicated in numerous neurological disorders (e.g., epilepsy, Parkinson's disease, schizophrenia). An excellent model system for studying the principles and mechanisms underlying neuronal synchronization is the suprachiasmatic nucleus (SCN). The SCN is a network of neuronal oscillators that programs circadian rhythms of behavior and physiology in mammals to ensure biological events occur at the appropriate time of day. As a population, SCN neurons display coordinated activity patterns that are integral to circadian clock function; however, the signaling mechanisms that regulate this process remain ill defined. One major obstacle barring progress on this front is the challenge of investigating neuronal interactions while the SCN network is in a functional state. To address this important issue, we have developed a novel analytical assay that quantifies the dynamic process by which SCN neurons interact using an ex vivo slice preparation. In the proposed studies, we will employ this analytical assay together with specific pharmacological tools and innovative genetic manipulations to investigate how different subclasses of SCN neurons interact to control circadian behavior. First, we will test the hypothesis that feedback within the SCN network is necessary for neuronal synchronization in vitro. Second, we will define the intracellular signaling mechanisms that mediate this feedback. Last, we will evaluate whether feedback in the SCN network is required for circadian rhythms in vivo. By defining the functional role of novel signaling pathways that modulate SCN function in vitro and in vivo, our work will significantly advance understanding of the circuit mechanisms that bind SCN neurons into a synchronized network. Greater insight into SCN circuitry is expected to help develop novel therapies to prevent and alleviate the adverse health consequences of disrupted clock function, such as sleep disorders.

 描述（由申请人提供）：神经元集合显示出由组成神经元之间的反馈连接引起的协调活动模式;然而，在时间和空间上同步神经活动的机制仍然知之甚少。这是我们理解中的一个根本性差距，因为神经元同步对于正常的脑功能至关重要，并且其功能障碍涉及许多神经系统疾病（例如，癫痫、帕金森病、精神分裂症）。视交叉上核（SCN）是研究神经元同步化原理和机制的一个极好的模型系统。SCN是神经元振荡器的网络，其编程哺乳动物的行为和生理的昼夜节律，以确保生物事件在一天中的适当时间发生。作为一个群体，SCN神经元显示出协调的活动模式，这是生物钟功能不可或缺的;然而，调节这一过程的信号传导机制仍然不明确。阻碍这方面进展的一个主要障碍是在SCN网络处于功能状态时研究神经元相互作用的挑战。为了解决这个重要的问题，我们已经开发了一种新的分析方法，量化SCN神经元使用离体切片制备相互作用的动态过程。在拟议的研究中，我们将采用这种分析方法以及特定的药理学工具和创新的遗传操作来研究SCN神经元的不同亚类如何相互作用以控制昼夜节律行为。首先，我们将测试的假设，SCN网络内的反馈是必要的神经元在体外同步。其次，我们将定义细胞内信号传导 调节这种反馈的机制。最后，我们将评估SCN网络中的反馈是否需要体内的昼夜节律。通过定义在体外和体内调节SCN功能的新型信号通路的功能作用，我们的工作将显著推进对将SCN神经元结合到同步网络中的电路机制的理解。对SCN电路的更深入了解有望帮助开发新的疗法，以预防和减轻生物钟功能中断对健康的不良影响，如睡眠障碍。