Multiscale Modeling & Analysis of Circadian Rhythm Generation & Synchronization

描述（由申请人提供）：将通过神经生理学实验、理论建模和多尺度系统分析和计算的综合计划开发哺乳动物昼夜节律产生和同步的多细胞模型。我们的假设是，个别起搏神经元的耦合介导的神经递质血管活性肠肽（VIP）普遍存在于视交叉上核（SCN）。实验将确定SCN神经元对VIP的昼夜同步的剂量和相位依赖性。这些实验将指导起搏细胞模型的开发，其中负责节律性电活动的基因调控网络的详细描述与昼夜节律耦合中涉及的VIP信号通路的简化描述相结合。起搏器模型将用作构建神经群体模型的构建块，该神经群体模型解释了SCN的已知解剖学和生理学，包括核心和外壳分裂以及VIP产生细胞在两个分裂中的分布。由此产生的模型将涵盖从基因调控水平到神经元信号传导水平再到组织水平的广泛的时间和长度尺度。确定性的模拟代码将被开发，以允许耦合SCN神经元的大合奏的有效模拟。在基因和信号水平的随机效应将通过开发相结合的确定性/随机模拟代码进行研究。人口模型和简化的代理模型的并行理论工作将产生大的神经元群体的随机效应的见解。结合实验，理论和计算工作将允许系统的扰动分析的作用，个别神经元和它们的相互连接的昼夜节律生成的精度和鲁棒性。

DESCRIPTION (provided by applicant): A multicellular model of mammalian circadian rhythm generation and synchronization will be developed through an integrated program ofneurophysiological experiments, theoretical modeling and multi-scale systems analysis and computation. Our hypothesis is that the coupling of individual pacemaker neurons is mediated by the neurotransmitter vasoactive intestinal peptide (VIP) prevalent in the suprachiasmatic nucleus (SCN). Experiments will identify the dose- and phase-dependence of SCN neurons on VIP for circadian synchrony. These experiments will guide the development of a pacemaker cell model in which a detailed description of the gene regulatory network responsible for rhythmic electrical activity is combined with a simplified description of the VIP signaling pathways implicated in circadian coupling. The pacemaker model will be used as a building block in the construction of neural population models that account for the known anatomy and physiology of the SCN including the core and shell divisions and the distribution of VIP producing cells in the two divisions. The resulting models will cover a wide range of time and length scales ranging from the gene regulation level to the neuron signaling level to the tissue level. Deterministic simulation codes will be developed to allow the efficient simulation of large ensembles of coupled SCN neurons. Stochastic effects at the gene and signaling levels will be studied by developing combined deterministic/stochastic simulation codes. Parallel theoretical work on the population model and a simplified surrogate model will yield insights into stochastic effects in large neuron populations. The combined experimental, theoretical and computational work will allow systematic perturbation analysis of the roles of individual neurons and their interconnections on the precision and robustness of circadian rhythm generation.