Emergence of noise-induced oscillations in the central circadian pacemaker

PLoS Biol. 2010 Oct 12;8(10):e1000513. doi: 10.1371/journal.pbio.1000513.

Abstract

Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN) of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cell-autonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • Cell Communication / physiology
  • Circadian Clocks / physiology*
  • Circadian Rhythm / physiology*
  • Cyclic AMP / metabolism
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Stochastic Processes
  • Suprachiasmatic Nucleus / cytology
  • Suprachiasmatic Nucleus / physiology*
  • Tissue Culture Techniques

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Cyclic AMP