Multiscale Modeling & Analysis of Circadian Rhythm Generation & Synchronization

描述（由申请人提供）：哺乳动物昼夜节律产生和同步的多细胞模型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发展。我们的假设是，个体起搏器神经元的耦合是由普遍存在于视交叉上核（SCN）中的神经递质血管活性肠肽（VIP）介导的。实验将确定SCN神经元对VIP昼夜同步的剂量和相位依赖性。这些实验将指导起搏器细胞模型的发展，在该模型中，负责节律性电活动的基因调控网络的详细描述与涉及昼夜节律耦合的VIP信号通路的简化描述相结合。起搏器模型将被用作构建神经种群模型的基础，该模型将解释SCN的已知解剖学和生理学，包括核和壳分裂以及两个分裂中产生VIP的细胞的分布。由此产生的模型将涵盖从基因调控水平到神经元信号水平再到组织水平的广泛时间和长度尺度。将开发确定性仿真代码，以允许有效地模拟耦合SCN神经元的大集合。基因和信号水平上的随机效应将通过开发确定性/随机模拟代码来研究。在种群模型和简化的替代模型上并行的理论工作将使我们对大神经元种群中的随机效应有更深入的了解。实验、理论和计算相结合的工作将允许对单个神经元及其相互联系在昼夜节律产生的精度和鲁棒性中的作用进行系统的扰动分析。

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.