Estradiol exerts activational and organizational control over the expression of daily and circadian activity rhythms in mice
Robust sex differences in daily and circadian activity rhythms, as well as the manifestation of circadian disruption-associated pathologies, have been reported in numerous species, including humans and laboratory models. These differences are mediated, at least in part, by sexually dichotomous estrogenic signaling throughout life. However, the mechanism(s) underlying the impact of estrogens on the formation and expression of circadian activity outputs remains poorly characterized. A more comprehensive understanding of both the full effect(s) of estrogenic signaling on circadian rhythms throughout life and the precise method by which these effects are exacted will expand our understanding of the intersection of endocrinology and chronobiology, provide greater insight regarding disease pathogenesis, and provide novel targets for the development of efficacious therapies aimed at circadian disruption prevention and alleviation. Accordingly, I have three primary goals for this thesis. First, I will fully characterize the effects of acutely circulating estradiol on the expression of daily and circadian wheel running rhythms in female mice. Simultaneously, I will further elucidate the estrogen receptor-dependent mechanism(s) underlying these functional effects (Chapter 2). Second, I will examine the impact of developmental estradiol on adult daily and circadian activity rhythms during a neonatal critical period associated with maturation of the suprachiasmatic nucleus (SCN), a hypothalamic structure regarded as the ‘master oscillator’ (Chapter 3). Finally, because the adult timekeeping system is dependent upon transcriptional regulation in the SCN, I will determine the impact of estradiol on gene expression within the SCN (Chapter 4). In the work presented here, I show that acutely circulating estradiol increases total wheel activity, consolidates this activity to the dark phase, and enhances wheel running amplitude through mechanism(s) dependent upon estrogen receptor subtype 1 (ESR1) in female mice. Additionally, estradiol more uniformly distributes wheel running activity across the dark phase compared to control treatment, delays the time of peak activity (acrophase), reduces the phase angle of activity onset, and dampens the behavioral response elicited by a pulse of light administered in the early subjective night, though these effects are mediated by estrogen receptor subtype 2 (ESR2). Activation of either ESR1 or ESR2 shortens the length of the endogenous day. I further discovered that developmental exposure to estradiol plays a distinct role in organizing the adult time keeping system. Lack of estradiol during a neonatal period associated with SCN maturation increases total wheel running in adult male mice, an effect rescued by exogenous estradiol administration during this critical period. Treatment with estradiol during this same period in female mice reduces the quantity and amplitude of adult wheel running, advances activity acrophase, and condenses the majority of activity completed during the dark phase to the early subjective night. Exogenous estrogen given during SCN organization shortens the length of the active phase in adult male mice, and robustly effects responsiveness to light at varying times of day, though in a highly sex-dependent manner. Finally, activational estradiol strongly alters the transcriptional makeup within the SCN of female mice, primarily through message downregulation. Enriched molecular pathways in which estradiol decreased transcript expression of critical players include circadian rhythms, mitogen activated peptide kinase (MAPK) signaling, neurotrophin signaling, and long-term potentiation, suggesting that estradiol may be dampening plasticity within the SCN. These effects may contribute to the behavioral impact of estradiol outlined in Chapter 2. Together, these data significantly increase our understanding of the activational and organizational effects of estradiol on daily and circadian wheel running activity rhythms, and provide foundational targets for future work further elucidating the causative mechanism(s) underlying their expression.
Circadian, Estrogen, Activational, Organizational
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign