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Global parameter search reveals design principles of the mammalian circadian clock

Locke, James C. W. and Westermark, Pål O. and Kramer, Achim and Herzel, Hanspeter (2008) Global parameter search reveals design principles of the mammalian circadian clock. BMC Systems Biology, 2 . Art. No. 22. ISSN 1752-0509. PMCID PMC2277373. doi:10.1186/1752-0509-2-22.

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Background: Virtually all living organisms have evolved a circadian (~24 hour) clock that controls physiological and behavioural processes with exquisite precision throughout the day/night cycle. The suprachiasmatic nucleus (SCN), which generates these ~24 h rhythms in mammals, consists of several thousand neurons. Each neuron contains a gene-regulatory network generating molecular oscillations, and the individual neuron oscillations are synchronised by intercellular coupling, presumably via neurotransmitters. Although this basic mechanism is currently accepted and has been recapitulated in mathematical models, several fundamental questions about the design principles of the SCN remain little understood. For example, a remarkable property of the SCN is that the phase of the SCN rhythm resets rapidly after a 'jet lag' type experiment, i.e. when the light/dark (LD) cycle is abruptly advanced or delayed by several hours. Results: Here, we describe an extensive parameter optimization of a previously constructed simplified model of the SCN in order to further understand its design principles. By examining the top 50 solutions from the parameter optimization, we show that the neurotransmitters' role in generating the molecular circadian rhythms is extremely important. In addition, we show that when a neurotransmitter drives the rhythm of a system of coupled damped oscillators, it exhibits very robust synchronization and is much more easily entrained to light/dark cycles. We were also able to recreate in our simulations the fast rhythm resetting seen after a 'jet lag' type experiment. Conclusion: Our work shows that a careful exploration of parameter space for even an extremely simplified model of the mammalian clock can reveal unexpected behaviours and non-trivial predictions. Our results suggest that the neurotransmitter feedback loop plays a crucial role in the robustness and phase resetting properties of the mammalian clock, even at the single neuron level.

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Additional Information:© 2008 Locke et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 30 May 2007. Accepted: 29 February 2008. Published: 29 February 2008. We would like to thank S. Bernard and S. Legewie for useful discussions. This work was supported by the European Commission (BioSim Network, contract No. LSHB-CT-2004.005137 and the Deutsche Forschungsgemeinschaft (SFB 618). Research in AKs lab is also supported by the 6th EU framework program EUCLOCK. Computer facilities were provided by the Centre for Scientific Computing at the University of Warwick. Authors' contributions: JCWL, PW and HH conceived and designed the study. JCWL and PW performed the numerical experiments. JCWL, PW, HH, and AK analyzed the data. All authors contributed to writing the paper, and read and approved the final manuscript.
Funding AgencyGrant Number
European CommissionLSHB-CT-2004.005137
Deutsche Forschungsgemeinschaft (DFG)SFB 618
PubMed Central ID:PMC2277373
Record Number:CaltechAUTHORS:LOCbmcsb08
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ID Code:10012
Deposited By: Archive Administrator
Deposited On:05 Apr 2008
Last Modified:01 Jun 2023 23:37

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