MECHANISMS AND MODELING OF NETWORKED CIRCADIAN PACEMAKER SYNCHRONIZATION

描述（由申请人提供）：哺乳动物视交叉上核（SCN），行为和生理的日常周期所需。SCN的小区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合作计划，结合实验和计算方法来研究大量的昼夜节律振荡器，它们的连接，以及它们自同步和响应环境时间线索扰动的实时动力学。要了解大脑的昼夜节律调节，我们必须了解昼夜节律神经元之间的相互作用的拓扑结构和类型。目标1将监测SCN振荡器的网络，因为它们在胎儿发育期间同步，在夹带期间，相移之后，以及在成人SCN中恢复细胞间通信之后。使用新的基于小波的时间序列分析，我们将估计的强度和方向的SCN中的各个连接。目标2将使用图论和空间统计来量化发展中和成年SCN的网络特征。这些分析将确定在正常发展期间和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SCN网络在四种条件下与确定性和随机模型网络的性能。计算模型将研究内在噪声和细胞间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律输出将对预防和治疗昼夜节律中断（包括情绪和睡眠障碍）具有重要的临床意义。

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.