Scheduled Feeding Alters the Timing of the Suprachiasmatic Nucleus Circadian Clock in Dexras1-Deficient Mice

Abstract

Restricted feeding (RF) schedules are potent zeitgebers capable of entraining metabolic and hormonal rhythms in peripheral oscillators in anticipation of food. Behaviorally, this manifests in the form of food anticipatory activity (FAA) in the hours preceding food availability. Circadian rhythms of FAA are thought to be controlled by a food-entrainable oscillator (FEO) outside of the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. Although evidence suggests that the FEO and the SCN are capable of interacting functionally under RF conditions, the genetic basis of these interactions remains to be defined. In this study, using dexras1-deficient (dexras1^−/−) mice, the authors examined whether Dexras1, a modulator of multiple inputs to the SCN, plays a role in regulating the effects of RF on activity rhythms and gene expression in the SCN. Daytime RF under 12L:12D or constant darkness (DD) resulted in potentiated (but less stable) FAA expression in dexras1^−/− mice compared with wild-type (WT) controls. Under these conditions, the magnitude and phase of the SCN-driven activity component were greatly perturbed in the mutants. Restoration to ad libitum (AL) feeding revealed a stable phase displacement of the SCN-driven activity component of dexras1^−/− mice by ∼2 h in advance of the expected time. RF in the late night/early morning induced a long-lasting increase in the period of the SCN-driven activity component in the mutants but not the WT. At the molecular level, daytime RF advanced the rhythm of PER1, PER2, and pERK expression in the mutant SCN without having any effect in the WT. Collectively, these results indicate that the absence of Dexras1 sensitizes the SCN to perturbations resulting from restricted feeding. (Author correspondence: [email protected])

Keywords:

• Circadian rhythms
• Coupling
• Dexras1
• MAPK signaling
• Period genes
• Suprachiasmatic nucleus
• Temporal restricted feeding

ACKNOWLEDGMENTS

The authors wish to thank Drs. Christian Beaulé and Sean W. Cain for helpful discussion, and Drs. Steven Reppert and David Weaver for providing the PER1 and PER2 antibodies, respectively.

Declaration of Interest: This work was supported by operating grants to H.-Y.M.C. from the Canadian Institute of Health Research (CIHR) and the National Sciences and Engineering Research Council (NSERC) of Canada. H.-Y.M.C. is the recipient on an Ontario Early Researcher Award. P.B.-C. is supported by a graduate scholarship from the Fonds de Recherche du Québec Nature et Technologies (FQRNT).

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.