Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling

哺乳动物昼夜节律钟的多尺度建模：GABA 信号传导的作用

• 批准号: 9352333
• 负责人: Michael Henson
• 金额: $ 44.43万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352333
• 关键词: Address; Algorithms; Aminobutyric Acids; Area; Behavior; Benzodiazepines; Biological; Biological Models; Biological Pacemakers; Biophysics; Brain region; Cell model; Cells; Cereals; Circadian Rhythms; Clinical; Communication; Complex; Computational Technique; Computer Simulation; Coupled; Coupling; Data; Development; Dissection; Dose; Electric Stimulation; Genes; Goals; Heterogeneity; Hypothalamic structure; In Vitro; Individual; Ion Channel; Light; Link; Mediating; Metabolic Diseases; Modeling; Mood Disorders; Mus; Neurons; Neurotransmitters; Pacemakers; Pattern; Peptide Signal Sequences; Pharmaceutical Preparations; Population; Prevention; Property; Research; Research Personnel; Resolution; Role; Schedule; Signal Pathway; Signal Transduction; Sleep; Sleep Disorders; Synapses; System; Temperature; Testing; Tissues; Uncertainty; Vasoactive Intestinal Peptide; Work; base; circadian pacemaker; computerized tools; design; experimental study; gamma-Aminobutyric Acid; improved; in vivo; intercellular communication; multi-scale modeling; network models; novel; predictive modeling; public health relevance; relating to nervous system; shift work; simulation; suprachiasmatic nucleus; tool

 DESCRIPTION (provided by applicant): The synchronization and entrainment of coupled biological oscillators is an emerging research area in complex network systems. The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus consists of approximately 20,000 pacemaker neurons that are coupled together to produce a robust overall rhythm that drives other bodily functions such as sleep patterns. The SCN represents an ideal model system for studying biological network design and behavior due to accumulating data on individual SCN neurons and their interactions. Experimental studies have shown that SCN intercellular communication is primarily mediated by two neurotransmitters: vasoactive intestinal peptide (VIP) and -aminobutyric acid (GABA). While VIP is well established as an essential synchronizing agent, the role of GABA with respect to its inhibitory/excitatory, day/night, synchronizing and entrainment effects remains controversial. Improved understanding of neurotransmitter mediated intercellular signaling in the SCN will have important clinical implications for prevention and treatment of circadian rhythm disruptions, including mood and sleep disorders and metabolic diseases. The goal of this project is to develop a multiscale model of the SCN and to integrate this model with targeted experiments and novel computational tools to gain improved understanding of SCN connectivity, synchronization and entrainment properties. The research focuses on GABA signaling because its role in the SCN is prominent, not well understood, and recent advances by the three participating investigators will enable a complete and careful dissection of the role of this common neurotransmitter with synapse-level resolution across large arrays of circadian neurons. The multiscale model will establish a link between core clock genes and ion channels at the individual cell level and network synchronization and entrainment behavior at the SCN tissue level through cell-to-cell connectivity. Targeted experiments will be performed to inform the construction and validate the predictions of the network model. General computational techniques for model reduction and efficient simulation of heterogeneous cellular networks will be developed to facilitate analysis of model behavior over a wide range of environmental conditions. The research has the potential to be highly transformative by both advancing the multiscale modeling of coupled oscillators/complex networks and by fundamentally changing our understanding of GABA signaling in circadian timekeeping and potentially in other brain regions. Our participation in the Multiscale Modeling Consortium will provide a unique perspective on networked cellular systems where we will explore cross-cutting topics such as network topology, dynamics, robustness and function.

 描述（由适用提供）：耦合生物振荡器的同步和入口是复杂网络系统中的新兴研究领域。下丘脑的哺乳动物昼夜节律时钟位于下丘脑上的核核（SCN），由大约20,000个起搏器神经元组成，它们耦合在一起，以产生强大的整体节奏，从而驱动其他身体功能，例如睡眠模式。 SCN代表了研究生物网络设计和行为的理想模型系统，这是由于积累了有关单个SCN神经元及其相互作用的数据而导致的。实验研究表明，SCN互动通信主要是由两个神经递质介导的：血管活性肠肽（VIP）和-氨基丁酸（GABA）。虽然VIP已成为必不可少的同步剂，但GABA在其抑制/兴奋性，白天/夜晚，同步和入口效应方面的作用仍然存在争议。对SCN中神经递质介导的细胞间信号传导的了解，将对预防和治疗昼夜节律干扰具有重要的临床意义，包括情绪，睡眠障碍和代谢疾病。该项目的目的是开发SCN的多尺度模型，并将该模型与有针对性的实验和新颖的计算工具整合在一起，以提高人们对SCN连接性，同步和入口属性的了解。该研究的重点是GABA信号传导，因为其在SCN中的作用是突出的，不太了解的，三个参与研究人员的最新进展将使对这种常见的神经递质的作用进行完整而仔细的解剖，并在大量的昼夜神经元中具有突触级别的分辨率。多尺度模型将通过单个细胞级别的核心时钟基因与离子通道之间建立联系，以及通过细胞间连接在SCN组织级别的网络同步和入口行为。将进行有针对性的实验，以告知构建并验证网络模型的预测。将开发用于模型降低和有效模拟异质细胞网络的一般计算技术，以促进在广泛的环境条件下对模型行为的分析。这项研究具有通过推进耦合振荡器/复杂网络的多尺度建模以及从根本上改变我们对昼夜节时间内的GABA信号的理解以及在其他大脑区域中潜在的可能性来改变我们对GABA信号传导的理解的潜力。我们参与多尺度建模联盟将为网络蜂窝系统提供独特的观点，在该系统中，我们将探索跨切割主题，例如网络拓扑，动力学，鲁棒性和功能。