Emergence of noise-induced oscillations in the central circadian pacemaker.
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.
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Caroline H
CH
Ko
Yujiro R
YR
Yamada
David K
DK
Welsh
Ethan D
ED
Buhr
Andrew C
AC
Liu
Eric E
EE
Zhang
Martin R
MR
Ralph
Steve A
SA
Kay
Daniel B
DB
Forger
Joseph S
JS
Takahashi
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002450:Cell Communication / Q000502:physiology; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D013269:Stochastic Processes; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000502:physiology*; D046509:Tissue Culture Techniques
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D000242:Cyclic AMP