MECHANISMS AND MODELING OF NETWORKED CIRCADIAN PACEMAKER SYNCHRONIZATION

网络化昼夜节律起搏器同步的机制和建模

• 批准号: 8049511
• 负责人: FRANCIS J DOYLE
• 金额: $ 31.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049511
• 关键词: Adult; Behavior; Bilateral; Biological; Biological Neural Networks; Brain; Cell Communication; Cells; Circadian Rhythms; Clinical; Cognitive; Computer Simulation; Computing Methodologies; Coupled; Coupling; Cues; Data; Development; Equation; Fetal Development; Gene Expression; Graph; Heterogeneity; Hormones; Individual; Kinetics; Length; Maps; Measurement; Measures; Mediating; Metabolism; Methods; Metric; Modeling; Monitor; Mood Disorders; Neurons; Noise; Output; Pathway Analysis; Performance; Phase; Physiology; Prevention; Process; Public Domains; Regulation; Relative (related person); Resolution; Role; Series; Signal Transduction; Sleep Disorders; Sleep Wake Cycle; Solutions; Source; Statistical Models; System; Time; base; circadian pacemaker; fetal; high end computer; models and simulation; network models; novel; programs; research study; restoration; spatiotemporal; statistics; suprachiasmatic nucleus; theories; tool

DESCRIPTION (provided by applicant): The mammalian suprachiasmatic nucleus (SCN), required for daily cycles in behavior and physiology. How the cells of the SCN synchronize to coordinate behavior is largely unknown. We have established a collaborative program combining experimental and computational methods to study large numbers of circadian oscillators, their connections, and the real-time kinetics by which they self-synchronize and respond to perturbations in environmental timing cues. To understand circadian regulation within the brain, we must understand the topology and types of interactions between circadian neurons. Aim 1 will monitor the network of SCN oscillators as they synchronize during fetal development, during entrainment, following a phase shift, and after restoration of cell-cell communication in the adult SCN. Using novel wavelet-based time series analyses, we will estimate the strength and direction of individual connections in the SCN. Aim 2 will use graph theory and spatial statistics to quantify network features of the developing and adult SCN. These analyses will define the mechanisms of synchronization during normal development and following environmental perturbations and the relative contributions of local, regional or global coupling which contribute to period precision. Aim 3 will compare the performance of the SCN networks under the four conditions with both deterministic and stochastic model networks. The computational models will investigate the effects of intrinsic noise and cell-cell heterogeneity on circadian synchronization. Revealing how circadian oscillators interact to generate a coherent rhythmic output will have important clinical implications for prevention and treatment of circadian rhythm disruptions, including mood and sleep disorders. PUBLIC HEALTH RELEVANCE: Daily rhythms in behavior, physiology and cognitive performance are driven by circadian clocks in the brain. This project examines the role of network connections and noise in the synchronization of circadian oscillators during normal development and following environmental perturbations using novel modeling, statistical and network analysis tools.

描述(申请人提供)：哺乳动物的视交叉上核(SCN)，日常行为和生理周期所必需的。SCN的细胞如何同步以协调行为在很大程度上是未知的。我们已经建立了一个结合实验和计算方法的合作计划，以研究大量的昼夜节律振荡器，它们的联系，以及它们通过自同步和对环境时间线索中的扰动做出反应的实时动力学。为了了解大脑中的昼夜节律，我们必须了解昼夜节律神经元之间的拓扑结构和相互作用的类型。目标1将监测SCN振荡器的网络，因为它们在胎儿发育期间、夹带期间、相移后以及成年SCN细胞间通讯恢复后同步。使用新的基于小波的时间序列分析，我们将估计SCN中单个连接的强度和方向。目标2将使用图论和空间统计学来量化发育中的和成年的SCN的网络特征。这些分析将确定在正常发展期间和在环境扰动之后的同步机制，以及有助于周期精度的局部、区域或全球耦合的相对贡献。目标3将比较确定和随机模型网络在四种情况下的SCN网络的性能。计算模型将研究固有噪声和细胞-细胞异质性对昼夜节律同步的影响。揭示昼夜节律振荡器如何相互作用以产生连贯的节奏输出，将对预防和治疗包括情绪和睡眠障碍在内的昼夜节律紊乱具有重要的临床意义。 与公共健康相关：行为、生理和认知表现的日常节奏是由大脑中的生物钟驱动的。该项目使用新的建模、统计和网络分析工具，研究了在正常发育期间和在环境扰动之后，网络连接和噪声在昼夜节律振荡器同步中的作用。