Location of Repository

Global parameter search reveals design principles of the\ud mammalian circadian clock

By James C. W. Locke, Pål O. Westermark, Achim Kramer and Hanspeter Herzel


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\ud 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\ud 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.\ud 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\ud 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.\ud 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\ud robustness and phase resetting properties of the mammalian clock, even at the single neuron level

Topics: QH301
Publisher: BioMed Central Ltd.
Year: 2008
OAI identifier: oai:wrap.warwick.ac.uk:525

Suggested articles



  1. (2007). 3rd: A molecular model for intercellular synchronization in the mammalian circadian clock. Biophysical journal doi
  2. (2006). A: Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev doi
  3. (2004). A: Modeling feedback loops of the Mammalian circadian oscillator. Biophysical journal doi
  4. (2007). A: Synchronization-Induced Rhythmicity of Circadian Oscillators in the Suprachiasmatic Nucleus. PLoS Comput Biol doi
  5. (2003). Achermann P: Simulation of circadian rhythm generation in the suprachiasmatic nucleus with locally coupled selfsustained oscillators. doi
  6. (1967). Biological rhythms and the behavior of populations of coupled oscillators. doi
  7. (2004). Clock genes, oscillators, and cellular networks in the suprachiasmatic nuclei. doi
  8. (2005). Come together, right...now: synchronization of rhythms in a mammalian circadian clock. Neuron doi
  9. (1993). Coupled oscillators and biological synchronization. Scientific American doi
  10. (2003). DG: Phase resetting light pulses induce Per1 and persistent spike activity in a subpopulation of biological clock neurons.
  11. (2003). DG: The biological clock nucleus: a multiphasic oscillator network regulated by light.
  12. (2004). Diversity in the circadian periods of single neurons of the rat suprachiasmatic nucleus depends on nuclear structure and intrinsic period. Neurosci Lett doi
  13. (2005). ED: Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci doi
  14. (2006). Forger DB: An opposite role for tau in circadian rhythms revealed by mathematical modeling. doi
  15. (2000). From Kuramoto to Crawford: exploring the onset of synchronization in populations of coupled oscillators. Physica D doi
  16. (2005). GD: Differential response of Period 1 expression within the suprachiasmatic nucleus.
  17. (2003). Goldbeter A: Toward a detailed computational model for the mammalian circadian clock. doi
  18. (2005). Herzel H: Spontaneous synchronization of coupled circadian oscillators. Biophysical journal doi
  19. (1993). Kopell N: Rapid Synchronization through Fast Threshold Modulation. Biological Cybernetics doi
  20. (1968). Mathematics of cellular control processes. I. Negative feedback to one gene. doi
  21. (2005). Meijer JH: A GABAergic mechanism is necessary for coupling dissociable ventral and dorsal regional oscillators within the circadian clock. Curr Biol doi
  22. (2003). MH: A hVIPR transgene as a novel tool for the analysis of circadian function in the mouse suprachiasmatic nucleus. The European journal of neuroscience doi
  23. (1999). MH: Rapid resetting of the mammalian circadian clock.
  24. (2006). MH: Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol doi
  25. (1999). Modeling circadian rhythm generation in the suprachiasmatic nucleus with locally coupled self-sustained oscillators: phase shifts and phase response curves. Journal of biological rhythms doi
  26. (1999). Molecular bases for circadian clocks. Cell doi
  27. (2005). MS: Modelling genetic networks with noisy and varied experimental data: the circadian clock in Arabidopsis thaliana. doi
  28. (1995). Neuropeptides phase shift the mammalian circadian pacemaker.
  29. (1997). Okamura H: Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript. Cell doi
  30. (2005). Orchestrating time: arrangements of the brain circadian clock. Trends in neurosciences doi
  31. (1965). Oscillatory behavior in enzymatic control processes. Adv Enzyme Regul doi
  32. (2003). Peskin CS: A detailed predictive model of the mammalian circadian clock. doi
  33. (2005). Peskin CS: Stochastic simulation of the mammalian circadian clock. doi
  34. (1997). Regulation of the vgf gene in the golden hamster suprachiasmatic nucleus by light and by the circadian clock. doi
  35. (1995). Reppert SM: Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron doi
  36. (2000). Resetting central and peripheral circadian oscillators in transgenic rats.
  37. (2007). SA: Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell doi
  38. (2003). Shigeyoshi Y: An abrupt shift in the day/ night cycle causes desynchrony in the mammalian circadian center.
  39. (2005). Systems biology. Less is more in modeling large genetic networks. doi
  40. (1989). The mammalian circadian clock in the suprachiasmatic nuclei is reset in vitro by cAMP.
  41. (2002). transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature doi
  42. (1998). Yocca FD: Phase shifting of circadian rhythms and depression of neuronal activity in the rat suprachiasmatic nucleus by neuropeptide Y: mediation by different receptor subtypes.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.