Altered responsiveness to estrogens at estrogen receptor subtype 1 modifies the expression of circadian rhythms and daily activity patterns in mice

Biological rhythms are critical for the timing of hormone secretion, reproduction, and rest-wake activity patterns. Sex differences in daily (circadian) rhythms have been described for a number of species including humans. Women have a higher incidence of sleep disorders than men and are twice as likely to have difficulty falling and staying asleep. Additionally, women report sleep problems that change across their menstrual cycle and during the peri-menopausal period. Hormone replacement studies in women and in animals indicate that estrogen can modify the expression of daily rhythms; however, the exact mechanism and sites of action for steroid hormones have not been determined. Understanding the relationship of gonadal hormones on the normal functioning of circadian rhythms will shed light on the etiology of sex differences in sleep disorders and the basic mechanisms of hormonal regulation of activity patterns. The overarching goal of my research is to determine the mechanisms by which estrogens can modify circadian rhythms both during development and in the adult animal. I hypothesize that estrogens modify the expression of daily and circadian rhythms via the estrogen receptor subtype 1 (ESR1) and via “non-classical” estrogenic mechanisms. I hypothesize that impaired estrogen signaling results in a decreased sensitivity to the light-dark cues that allow normal circadian entrainment. To test these hypotheses I determined if estrogen receptor 1 (ESR1) is necessary for normal entrainment to the light-dark (LD) cycle and for the expression of circadian rhythms in activity by characterizing circadian entrainment in intact NERKI and ERKO mice. I also quantified free-running parameters in intact NERKI and ERKO mice and compared them to wildtype (WT) counterparts (Chapter 1). To determine if estrogens alter the ability to respond to changes in the LD cycle via the ESR1 and/or non-classical estrogen signaling, I quantified and compared the behavioral response to light pulse in NERKI and ERKO male and female mice. I also measured the cellular response to light pulse to test the hypothesis that behavioral shifts in light response are mediated through the master circadian clock, the suprachiasmatic nucleus (SCN) (Chapter 2). In addition to describing how impaired response to estrogens at ESR1 modifies circadian rhythms and patterns of daily activity in intact NERKI and ERKO mice, I determined the developmental role of estrogens acting at ESR1 and via non-classical mechanisms by examining circadian behaviors in gonadectomized NERKI and ERKO male and female mice. Specifically, I characterized the circadian behavior of male and female gonadectomized mice with and without estradiol replacement in entrainment and free-running conditions (Chapter 3, 4). Finally, I confirmed the organizational and activational roles of estrogenic modification of circadian rhythms via an ESR1-mediated mechanism by looking at the expression of circadian behaviors with ESR1 over-expressing mice (EROE). I quantified the activity patterns of intact EROE male and female mice in entrained and free-running conditions, and established a role of ESR1 on organization of circadian rhythms during development by looking at behavior of gonadectomized EROE mice compared to control littermates (Chapter 5). I hypothesized that estrogens acting via both organizational and activational mechanisms influence the development and the expression of circadian behaviors in adulthood. I have established that the differential ability to respond to estrogens at ESR1 results in differences in entrainment and circadian rhythms (Chapter 1) and behavioral response to light (Chapter 2). Genotype and sex differences that are present in gonadectomized mice indicate that estrogens acting via ESR1 and “non-classical” pathways during development permanently change circadian rhythms (Chapters 3 and 4). Lastly, I characterized the daily activity patterns in ESR1 over-expressing mice that have heightened response to circulating estrogen, which indicate that estrogens modulate circadian behaviors via organizational and activational action at ESR1 (Chapter 5)