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

 描述(申请人提供)：耦合生物振子的同步和夹带是复杂网络系统中一个新兴的研究领域。哺乳动物的生物钟位于下丘脑的视交叉上核(SCN)，由大约20,000个起搏神经元组成，这些神经元耦合在一起产生强劲的整体节奏，从而驱动其他身体功能，如睡眠模式。由于积累了关于单个SCN神经元及其相互作用的数据，SCN代表了研究生物网络设计和行为的理想模型系统。实验研究表明，SCN的细胞间通讯主要由两种神经递质介导：血管活性肠肽和-氨基丁酸。虽然VIP已被公认为一种重要的同步剂，但GABA在其抑制/兴奋、昼夜同步和携带效应方面的作用仍存在争议。进一步了解SCN中神经递质介导的细胞间信号转导机制，将对预防和治疗昼夜节律紊乱，包括情绪和睡眠障碍以及代谢性疾病具有重要的临床意义。该项目的目标是开发一个多尺度的SCN模型，并将该模型与有针对性的实验和新颖的计算工具相结合，以更好地了解SCN的连通性、同步和携带特性。这项研究侧重于GABA信号，因为它在SCN中的作用是突出的，但还不清楚，三位参与研究的研究人员最近的进展将使我们能够全面和仔细地剖析这种具有突触水平分辨率的大型昼夜节律神经元阵列中这种常见神经递质的作用。多尺度模型将在单个细胞水平上的核心时钟基因和离子通道之间建立联系，并通过细胞到细胞的连接在SCN组织水平上建立网络同步和携带行为。将进行有针对性的实验，以告知网络模型的构建并验证网络模型的预测。将开发用于异质蜂窝网络的模型简化和有效模拟的通用计算技术，以便于在广泛的环境条件下分析模型行为。这项研究不仅推进了耦合振荡器/复杂网络的多尺度建模，而且从根本上改变了我们对GABA信号在昼夜计时中以及潜在地在其他大脑区域的理解，具有极大的变革潜力。我们参与多尺度建模联盟将提供一个关于网络蜂窝系统的独特视角，我们将在其中探索网络拓扑、动力学、健壮性和功能等交叉主题。

 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.