7861 Estrogen Receptor Alpha Regulates the Sex Difference in Jet Lag in Mice

Abstract Disclosure: M.A. Venegas: None. N. Westray: None. J.S. Pendergast: None. The circadian system aligns 24-hour cycles of internal biological processes with the environmental light-dark cycle. Abrupt shifts in the timing of the light-dark cycle that occur during travel across time zones misalign internal circadian clocks with the environment and cause jet lag. The symptoms of jet lag subside when circadian clocks resynchronize to the new light-dark cycle. Female mice in proestrus resynchronize to shifted light-dark cycles faster than males. The objective of this study was to investigate the estrogen signaling mechanisms underlying this sex difference in jet lag in mice. We measured wheel-running activity rhythms in C57BL/6J male and female wild-type (WT) and ERα knockout (ERαKO) mice. Female WT mice had 2-fold greater daily activity than male mice. Disabling the function of ERα ablated the sex difference in daily activity; both male and female ERαKO mice had markedly reduced activity compared to WT mice. Next, we advanced the timing of the light-dark cycle by 6 hours to simulate eastward travel. Female WT mice resynchronized to the new light-dark cycle faster than WT males. This sex difference was abolished in ERαKO mice. The rate of resynchronization was slower in female ERaKO mice compared to WT females and was indistinguishable from males. We next investigated 2 putative mechanisms underlying the accelerated rate of resynchronization in WT females. First, mice with faster endogenous clocks resynchronize to new light-dark cycles faster. However, we found that the velocity of the endogenous clock (circadian period) did not differ between WT and ERαKO male and female mice. Second, mice with greater phase advances to light exposure in the late night also resynchronize faster. To determine the magnitude of phase advances, we housed mice in constant darkness and then exposed them to a 15-minute light pulse during the late subjective night. We found no differences in the magnitudes of phase shifts between WT and ERαKO male and female mice. Together these studies show that ERα regulates the rate of resynchronization to shifted light-dark cycles in female mice but does not do so by altering conventional circadian rhythm parameters. Uncovering the mechanisms underlying the sex difference in resynchronization to shifted light-dark cycles can be used to develop strategies to alleviate jet lag and shift work symptoms. Presentation: 6/3/2024