Multiscale Modeling & Analysis of Circadian Rhythm Generation & Synchronization

描述(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，单个起搏神经元之间的耦合是由视交叉上核(SCN)中普遍存在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的昼夜同步性的剂量和相位依赖性。这些实验将指导起搏细胞模型的发展，在该模型中，负责节律电活动的基因调控网络的详细描述与与昼夜节律耦合有关的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，该模型解释了SCN的已知解剖和生理学，包括核心和外壳分区以及VIP产生细胞在这两个分区中的分布。由此产生的模型将涵盖从基因调控水平到神经元信号水平再到组织水平的广泛的时间和长度尺度。确定性模拟代码将被开发，以允许对耦合的SCN神经元的大集合进行有效的模拟。将通过开发组合的确定性/随机模拟代码来研究基因和信号水平的随机效应。关于群体模型和简化的代理模型的并行理论工作将对大型神经元群体中的随机效应产生深刻的见解。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对昼夜节律产生的精度和稳健性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.