Synchronization and Entrainment of Circadian Systems: Oscillator Theory Meets Chronobiology

• Applicant: Dr. Christoph Schmal
• Subject Area: Bioinformatics and Theoretical Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 414704559

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.

• DFG Programme: Research Grants