Author ORCID Identifier

https://orcid.org/0009-0001-1703-363X

Date Available

12-3-2024

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Arts and Sciences

Department/School/Program

Biology

Advisor

Julie Pendergast

Abstract

The circadian system coordinates 24-hour 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 mechanisms underlying sex differences in jet lag in mice. Female mice resynchronized faster than male mice to 6-hour advances and delays of the light-dark cycle, which mimicked eastward and westward travel, respectively. Circulating estradiol was necessary for rapid resynchronization in female mice since ovariectomized females resynchronized slower than mice treated with estradiol. We next investigated the estrogen signaling mechanism that conferred the sex difference in jet lab. We studied jet lag in mice with disabled estrogen receptor alpha (ERα KO), estrogen receptor beta (ERβ KO), and G-protein coupled estrogen receptor 1 (GPER1 KO). We advanced the timing of the light-dark cycle by 6 hours to simulate eastward travel. Disabling ERα), but not ERβ or GPER1, in mice abolished the sex difference in resynchronization. We next delayed the timing of the LD cycle by 6 hours to simulate westward travel. Disabling ERα but not ERβ ablated the sex difference in resynchronization to a delayed light-dark cycle. 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 KO mice. Circadian period is a measure of the velocity of the endogenous circadian clock. If female mice had faster clocks than male mice, they could advance faster to the shifted light-dark cycle. Phase shift magnitude is the maximum phase shift that can occur in one day and thus sets the rate of resynchronization. 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 lengthened circadian periods and reduced the magnitudes of phase delays. Together these studies suggest that ERα alters the rate of resynchronization to shifted light-dark cycles by regulating period length and phase shift magnitude. 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.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.424

Funding Information

This study was funded by the NSF Career IOS-2045267, and NIH RO1DK124772.

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