Circadian parameters are altered in two strains of mice with transgenic modifications of estrogen receptor subtype 1.

There are sex differences in free-running rhythms, activity level and activity distribution that are attributed, in part, to the action of gonadal hormones. We tested the hypothesis that non-classical estrogenic signaling pathways at estrogen receptor subtype 1 (ESR1) modify the amplitude and phase of activity. We used ESR1 knock-out mice (ERKO) and non-classical estrogen receptor knock-in mice (NERKI). ERKO animals are unable to respond to estrogen at the ESR1 and NERKI animals lack the ability to respond to estrogens via the estrogen response element-mediated pathway, but can still respond via non-classical mechanisms. We compared intact male and female ERKO, NERKI and wildtype (WT) mice with respect to total wheel-running activity, activity distribution across the 24-h day, phase angle of activity onset and free-running period (τ) and the duration of activity in constant conditions. WT females had significantly greater activity than WT males, and this activity was more consolidated to the dark phase of the light:dark cycle. These sex differences were absent in the NERKI and ERKO animals. Among females, NERKI and ERKO animals had greater activity during the light phase than WT counterparts. Additionally, we have identified a novel contribution of non-classical estrogen signaling pathways on the distribution of activity. Our data suggest that total activity is ESR1-dependent and daily activity patterns depend on both classical and non-classical actions of estrogens. These data will aid in identifying the mechanisms underlying sex differences in sleep-wake cycles and the influence of steroid hormones on circadian patterns.