CRCNS: The balance between robustness and sensitivity in circadian synchrony

CRCNS：昼夜同步的鲁棒性和敏感性之间的平衡

• 批准号: 9047972
• 负责人: Erik Herzog
• 金额: $ 19.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047972
• 关键词: Advocacy; Aminobutyric Acids; Area; Bees; Behavior; Biological Models; Biological Rhythm; Biology; Brain; Cells; Chemistry; Chronobiology; Circadian Rhythms; Collaborations; Computer Simulation; Computer software; Coupled; Coupling; Data; Development; Dose; Education; Education and Outreach; Educational process of instructing; Environment; Equilibrium; General Population; Generations; Genetic; High School Faculty; Hormones; Individual; International; Japan; Learning Module; Light; Maintenance; Mathematics; Measures; Metabolism; Modeling; Mus; Neurosciences; Neurotransmitters; Participant; Periodicity; Phase; Physics; Physiology; Research; Role; Running; Schools; Scientist; Signal Transduction; Sleep; Slice; Societies; Stimulus; Students; System; Testing; Time; Training; Travel; Vasoactive Intestinal Peptide; circadian pacemaker; day length; flexibility; gamma-Aminobutyric Acid; in vitro Model; in vivo; novel; outreach; programs; receptor; research study; shift work; suprachiasmatic nucleus; tool

 DESCRIPTION (provided by applicant): Overview The suprachiasmatic nucleus (SCN) serves as a circadian pacemaker that drives daily rhythms in vertebrate behavior and physiology. It generates robust, self-sustained oscillations that entrain to the local day-night cycle including hormone secretion, metabolism and sleep-wake. In addition, the SCN must adapt to slow seasonal changes in day length and, with travel across time zones, rapid shifts in the 24-h environment. It is an important and fundamental question how the oscillatory systems balance robust rhythmicity with flexible synchronization. Intellectual Merit: We hypothesize that opposing actions of two coupling agents contribute to the robust, yet sensitive, cycling of the network of SCN cells. Vasoactive intestinal peptide (VIP) and γ-aminobutyric acid (GABA) are key neurotransmitters involved in the generation and maintenance of SCN rhythms. Genetic and pharmacological experiments revealed central roles for VIP and its canonical receptor (VPAC2R) and GABA and GABAA receptors in synchronization among circadian cells. We will test the hypothesis that GABA signaling makes SCN timekeeping less precise but more amenable to phase shifting by external stimuli, such as light. We will combine theoretical and experimental tools to study the synergistic actions of VIP and GABA for synchronization among cells and entrainment to the environment. The SCN provides an outstanding model system of coupled oscillators that can be studied in vivo, reduced and simplified to a slice or individual cells in vitro, and modeled in silico. Although it is comprisedof thousands of heterogeneous cells, the SCN offers a unique opportunity to understand the balance between reliable rhythmicity and adaptable synchrony. We have three specific research aims: 1. Data-driven modeling of two competing coupling mechanisms. 2. Experimental studies of GABA blockade and enhancement in wild-type and VIP-deficient mice. 3. Theoretical and experimental optimization of adjustment to shift work via dosing strategies of benzodiazopines. Broader impacts The proposed research includes the development of novel software (the "Entrainometer") for analysis of rhythm synchronization to a periodic input. This software will be freely available and useful to a wide range of scientists wanting to reliably measure features of entrainment. The proposal also includes significant outreach, education, and research opportunities. Both Drs. Herzog and Herzel are deeply committed to training young scientists. Dr. Herzog founded the St. Louis Chapter of the Society for Neuroscience through which he runs major outreach activities including NeuroDay (1500 visitors), HealthFest (1500 visitors) and the St. Louis Area Brain Bee (40 competitors, 200 participants). He also runs a 1-week summer course for high school teachers that includes material on circadian rhythms. Both Drs. Herzog and Herzel have taught in and directed the International Chronobiology Summer School for many years (including 2014 in Sapporo, Japan). As the 2014 Program Chair for the Society for Research on Biological Rhythms, Dr. Herzog promoted advocacy to the general public (e.g., a discussion of school start times) and chronobiology education (e.g. how to use chronobiology to excite students about physics, chemistry, math and biology). He continues to share his enthusiasm for rhythms research as the 2014-1016 Chair of Fundraising for SRBR. As part of this collaboration, the PIs will develop "Modeling Circadian Clocks," a teaching module, for use by undergraduate and graduate educators around the world.

 描述(由申请人提供)： 概述 视交叉上核(SCN)起着昼夜节律的作用，驱动脊椎动物行为和生理的日常节律。它产生强大的、自我维持的振荡，导致当地的昼夜循环，包括激素分泌、新陈代谢和睡眠-觉醒。此外，SCN必须适应白天长度的缓慢季节性变化，以及跨时区旅行的24小时环境中的快速变化。振荡系统如何在稳健的节奏性和灵活的同步之间取得平衡是一个重要而基本的问题。 智力价值： 我们假设，两个偶联剂的相反作用有助于SCN细胞网络的强大而敏感的循环。血管活性肠肽和γ-氨基丁酸是参与中枢神经系统节律产生和维持的关键神经递质。遗传学和药理学实验揭示了VIP及其典型受体(VPAC2R)以及GABA和GABAA受体在昼夜节律细胞之间的同步性中的中心作用。我们将测试这样一个假设，即GABA信号使SCN计时不那么精确，但更容易受到外部刺激(如光)的相移。 我们将结合理论和实验工具来研究VIP和GABA在细胞间同步和携带到环境中的协同作用。SCN提供了一个出色的耦合振荡器模型系统，可以在体内研究，在体外简化和简化为切片或单个细胞，并在电子计算机中建模。尽管它由数千个不同种类的细胞组成，但SCN提供了一个独特的机会来理解可靠的节律性和适应性同步性之间的平衡。我们有三个具体的研究目标： 1.两种相互竞争的耦合机制的数据驱动建模。 2.GABA对野生型和VIP缺陷小鼠的阻断和增强作用的实验研究 3.苯并二氮杂环己烷给药策略对工作调整的理论和实验优化。 更广泛的影响 建议的研究包括开发用于分析周期性输入的节奏同步的新软件(“入射计”)。该软件将免费提供，并且 对于想要可靠地测量夹带特征的广泛的科学家来说是有用的。该提案还包括重要的外展、教育和研究机会。Herzog博士和Herzel博士都坚定地致力于培养年轻科学家。赫尔佐格博士创建了神经科学学会的圣路易斯分会，通过该分会开展的主要推广活动包括神经日(1500名参赛者)、HealthFest(1500名参观者)和圣路易斯地区大脑蜜蜂(40名参赛者，200名参赛者)。他还为高中教师开设了一个为期一周的暑期课程，其中包括有关昼夜节律的材料。Herzog博士和Herzel博士都曾在国际时间生物学暑期学校任教和指导多年(包括2014年在日本札幌)。作为生物节律研究学会2014年的项目主席，Herzog博士向公众宣传(例如，讨论学校开始时间)和时间生物学教育(例如，如何利用时间生物学来激发学生对物理、化学、数学和生物的兴趣)。作为SRBR 2014-1016年度筹款主席，他继续分享他对节奏研究的热情。作为这项合作的一部分，PI将开发一个名为“生物钟模型”的教学模块，供世界各地的本科生和研究生教育工作者使用。