Estrogen signaling is necessary for the sex difference in simulated jet lag in mice

The circadian system coordinates 24-h cycles of internal biological processes with the environmental light-dark cycle. Abrupt shifts in the timing of the light-dark cycle misalign internal circadian clocks with the environment and cause jet lag until resynchronization occurs. The objective of this study was to investigate the sex difference in simulated jet lag in mice. Female mice resynchronized faster than male mice to 6-h advances of the light-dark cycle that mimicked eastward travel. Circulating estradiol was necessary and sufficient for rapid resynchronization in female mice since ovariectomized females resynchronized slower than mice treated with estradiol. Disabling estrogen receptor α (ERα), but not estrogen receptor β (ERβ) or G-protein-coupled estrogen receptor 1 (GPER1), abolished the sex difference in resynchronization. To investigate ERα-dependent mechanisms that regulate the rate of resynchronization, we measured the endogenous circadian period and the magnitudes of phase shifts to light pulses in male and female wild-type and ERα knockout mice. Wild-type females had shorter periods and greater phase delays in response to light pulses given in the early subjective night than male mice. Disabling ERα abolished these sex differences by lengthening the circadian period and reducing the magnitudes of phase delays. Together, these data suggest that ERα alters the rate of resynchronization to shifted light-dark cycles by regulating period length and phase shift magnitude in female mice. Understanding the mechanisms underlying the sex difference in resynchronization to shifted light-dark cycles can be used to develop strategies to alleviate jet lag and circadian misalignment.<b>NEW & NOTEWORTHY</b> Coordination of circadian rhythms with environmental cycles of light and dark is critical to well-being and healthspan. Jet lag is circadian misalignment that causes fatigue, insomnia, poor mood, impaired alertness, and gastrointestinal symptoms after travel across time zones. We show there is a sex difference in simulated jet lag in mice that is regulated by ERα signaling. Our findings reveal novel mechanisms that underlie jet lag to understand and develop interventions for circadian misalignment.