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: 9288233
• 负责人: Erik Herzog
• 金额: $ 18.36万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288233
• 关键词: Advocacy; Area; Bees; Behavior; Biological Models; Biological Rhythm; Biology; Brain; Cell Nucleus; Cells; Chemistry; Chronobiology; Circadian Rhythms; Collaborations; Computer Simulation; Computer software; Coupled; Coupling; Data; Development; Dose; Education; 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; Pharmacology; 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; education research; experimental study; flexibility; gamma-Aminobutyric Acid; in vitro Model; in vivo; novel; outreach; programs; receptor; shift work; suprachiasmatic nucleus; tool; undergraduate student

 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 Suparchiasmatic Nuitus（SCN）是一名昼夜节奏起搏器，可在脊椎动物行为和生理学方面每天驱动节奏。它产生了强大的自我维持的振荡，该振荡进入了当地的昼夜周期，包括骑马分泌物，代谢和睡眠效果。此外，SCN必须适应日期长度的季节性变化，并且随着跨时区的行程，在24小时的环境中会迅速变化。这是一个重要且基本的问题，振荡系统如何平衡强大的节奏性与灵活同步。 知识分子的优点： 我们假设两种耦合剂的相对作用有助于SCN细胞网络的稳健但敏感的循环。血管活性肠肽（VIP）和γ-氨基丁酸（GABA）是参与SCN节律的产生和维持的关键神经递质。遗传和药物实验揭示了VIP及其规范受体（VPAC2R）以及GABA和GABAA受体在昼夜节律细胞之间的中心作用。我们将检验以下假设：GABA信号传导使SCN定时管理不那么精确，但更适合通过外部刺激（例如光）转移。 我们将结合理论和实验工具，以研究VIP和GABA在细胞之间同步的协同作用和对环境的启蒙。 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，在体外简化并简化为切片或单个细胞，并在硅中进行建模。尽管它由数千个异质细胞组成，但SCN提供了一个独特的机会，可以理解可靠的节奏性和适应性同步之间的平衡。我们有三个具体的研究目的： 1。两个竞争耦合机制的数据驱动建模。 2。野生型和VIP缺陷小鼠的GABA阻滞和增强的实验研究。 3。通过苯二氮卓类药物的给药策略对调整进行调整的理论和实验优化。 更广泛的影响 拟议的研究包括开发新软件（“夹带计”），用于分析节奏同步到周期性输入。该软件将免费提供，并且 对于想要可靠地衡量入口特征的广泛科学家有用。该提案还包括大量的外展，教育和研究机会。两个博士。 Herzog和Herzel致力于培训年轻科学家。 Herzog博士创立了神经科学协会的圣路易斯分会，他通过该学会进行了主要的外展活动，包括Neuroday（1500名游客），HealthFest（1500名游客）和圣路易斯地区的脑蜂（40名竞争者，200名参与者）。他还为高中老师开设了为期1周的夏季课程，其中包括昼夜节律的材料。两个博士。赫尔佐格和赫泽尔已经教授并指导了国际年代生物学暑期学校多年（包括2014年在日本萨波罗）。作为2014年生物节奏研究协会计划主席，Herzog博士向公众推广了倡导公众（例如，讨论学校开始时代的讨论）和时间生物学教育（例如，如何利用年代生物学来激发学生有关物理，化学，数学和生物学）的兴奋。作为2014 - 1016年SRBR筹款主席，他继续分享自己对节奏研究的热情。作为这项合作的一部分，PIS将开发“昼夜节律”模型，这是一个教学模块，供本科和研究生教育者使用。

项目成果

Entrainment of Circadian Rhythms Depends on Firing Rates and Neuropeptide Release of VIP SCN Neurons.

• DOI: 10.1016/j.neuron.2018.06.029
• 发表时间: 2018-08-08
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Mazuski C;Abel JH;Chen SP;Hermanstyne TO;Jones JR;Simon T;Doyle FJ 3rd;Herzog ED
• 通讯作者: Herzog ED

Astrocytes Regulate Daily Rhythms in the Suprachiasmatic Nucleus and Behavior.

• DOI: 10.1016/j.cub.2017.02.037
• 发表时间: 2017-04-03
• 期刊: Current biology : CB
• 作者: Tso CF;Simon T;Greenlaw AC;Puri T;Mieda M;Herzog ED
• 通讯作者: Herzog ED