Loss of dexras1 Alters Nonphotic Circadian Phase Shifts and Reveals a Role for the Intergeniculate Leaflet (IGL) in Gene-Targeted Mice

Abstract

Loss of Dexras1 in gene-targeted mice impairs circadian entrainment to light cycles and produces complex changes to phase-dependent resetting responses (phase shifts) to light. The authors now describe greatly enhanced and phase-specific nonphotic responses induced by arousal in dexras1^−/− mice. In constant conditions, mutant mice exhibited significant arousal-induced phase shifts throughout the subjective day. Unusual phase advances in the late subjective night were also produced when arousal has little effect in mice. Bilateral lesions of the intergeniculate leaflet (IGL) completely eliminated both the nonphotic as well as the light-induced phase shifts of circadian locomotor rhythms during the subjective day, but had no effect on nighttime phase shifts. The expression of FOS-like protein in the suprachiasmatic nucleus (SCN) was not affected by either photic or nonphotic stimulation in the subjective day in either genotype. Therefore, the loss of Dexras1 (1) enhances nonphotic phase shifts in a phase-dependent manner, and (2) demonstrates that the IGL in mice is a primary mediator of circadian phase-resetting responses to both photic and nonphotic events during the subjective day, but plays a different functional role in the subjective night. Furthermore, (3) the change in FOS level does not appear to be a critical step in the entrainment pathways for either light or arousal during the subjective day. The cumulative evidence suggests that Dexras1 regulates multiple photic and nonphotic signal-transduction pathways, thereby playing an essential role modulating species-specific characteristics of circadian entrainment. (Author correspondence: [email protected])

Keywords:

• IGL ablation
• Nonphotic
• Phase-response curve
• Phase shift
• Suprachiasmatic nucleus

ACKNOWLEDGMENTS

This work was supported by a Natural Sciences and Engineering Research Council Discovery grant (no. 170040) to M.R.R. We wish to acknowledge Drs. Nicholas Mrosovsky, Robert Dallmann, and Mary Harrington for their helpful discussions during this project, and Dr. Harrington for her assessment of IGL lesion experiments.

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