Synchronization and Entrainment of Circadian Systems: Oscillator Theory Meets Chronobiology

生物钟是一种内源性的起搏器，它允许生物体将其生理过程调整到太阳日周围最有利的时间。哺乳动物的生物钟是一个复杂的系统，整合了不同尺度的时空组织。草率的单细胞振荡器通过相互作用在组织水平上协调，导致精确的生理节律，在季节性变化的世界中可塑性地应对不同的环境需求。在这个项目中，我们将使用数学模型与实验工作紧密联系，研究时间生物学系统在其分层组织的不同层次上的同步和夹带。我们的目的是确定导致单细胞节律的细胞内基因调控负反馈回路的设计原则。我们将回答这种细胞内网络的振荡器特性和拓扑结构导致实验观察到的时钟基因的瞬态解耦。然而，哺乳动物生物钟的许多特性，如其精度或光周期编码，已被证明在视交叉上核（SCN）的网络水平上通过神经递质、突触偶联和间隙连接的大约20,000个神经元的相互作用而出现。各种偶联剂的不同作用仍不清楚。我们将应用先前发明的数据分析技术，构建数据驱动的网络模型，以揭示在不同药物处理、突变背景和携带线索下网络振荡特性和相组织（波、簇）背后的设计原则。此外，我们之前已经表明，主时钟（SCN）不仅将其节律性传递给外周振荡器，而且其本身也受到另一个强劲振荡的非神经元脑区脉络丛（CP）的影响。我们发现，CP通过单细胞振荡器的间隙连接同步实现了其鲁棒性，这些单细胞振荡器表现出“扭曲”（即固有振幅和周期之间的相关性）。通过相互关联的数据分析和建模，我们旨在进一步解开CP组织中基因表达的时空组织及其对SCN动力学的影响。最后，我们将研究在不同的诱导信号（不同的授时信号、光照时间）下，单细胞和突现网络特性如何影响昼夜节律系统的诱导特征。所有不同层次的调节对于整个昼夜节律系统的正常运作都很重要。我们的综合研究，调查单细胞节律到有机体夹带，将有助于进一步了解昼夜节律系统的分层细胞内和细胞间组织的不同贡献。

Circadian clocks are endogenous pacemakers that allow an organism to align its physiological processes to a most beneficial time around the solar day. The mammalian circadian clock is a complex system, integrating different scales of spatiotemporal organization. Sloppy single cell oscillators coordinate at the tissue level through mutual interactions, leading to precise physiological rhythms that plastically cope with different environmental demands in a seasonally changing world. In this project we will use mathematical modeling in tight interconnection with experimental work to investigate the synchronization and entrainment of chronobiological systems across different levels of its hierarchical organization. We aim to identify design principles of the intracellular gene-regulatory negative feedback loops that lead to single cell rhythmicity. We will answer which oscillator properties and topologies of this intracellular network lead to the experimentally observed transient decoupling of clock genes. However, many properties of the mammalian circadian clock such as its precision or photoperiodic encoding have been shown to emerge at the network level of the suprachiasmatic nucleus (SCN) through mutual interactions of its approximately 20,000 neurons via neurotransmitters, synaptic couplings and gap junctions. The differential contributions of the various coupling agents remains unclear. We will apply previously invented data analysis techniques and construct data driven network models to unravel the design principles behind the networks oscillatory properties and phase organizations (waves, clusters) under different pharmacological treatments, mutant backgrounds and entrainment cues. Additionally, we have previously shown that the master clock (SCN) is not only transmitting its rhythmicity to peripheral oscillators but itself is influenced by another robustly oscillating non-neuronal brain area, the choroid plexus (CP). We showed that the CP achieves its robustness through gap-junctional synchronization of single cell oscillators exhibiting „twist“ (i.e., a correlation between intrinsic amplitudes and periods). By interconnected data analysis and modeling we aim to further untangle the spatiotemporal organization of gene expression in the CP tissue and its impact on the SCN dynamics. Finally, we will study how single cell and emergent network properties affect the entrainment characteristics of circadian systems under different entrainment cues (different Zeitgeber signals, light-schedules). All different layers of regulation are important for the proper functioning of the circadian system as a whole. Our integrative study, investigating single cell rhythms up to organismal entrainment will help to further understand the differential contributions of the hierarchical intra- and inter-cellular organization of circadian systems.