Photic Phase-Response Curve in 2 Strains of Mice with Impaired Responsiveness to Estrogens

Abstract

Steroid hormones including estrogens modulate the expression of daily activity and circadian rhythms, including free-running period, phase angle of activity onset, and response to light. The mechanisms underlying these effects, however, are not fully understood. We tested the hypothesis that estrogen signaling is required for photic responsiveness of the circadian timing system. We used estrogen receptor subtype 1 (ESR1) knock-out mice (ERKO) and nonclassic estrogen receptor knock-in mice (NERKI). ERKO animals are unable to respond to estrogen at ESR1, and NERKI animals lack the ability to respond to estrogens via estrogen response element-mediated transcription but still respond via nonclassical mechanisms. We analyzed behavioral shifts in activity onset in response to 1-h light pulses given across the subjective 24-h day in gonadally intact male and female NERKI, ERKO, and wild-type (WT) littermates. We also examined Fos protein expression in the suprachiasmatic nucleus, the site of the master circadian pacemaker, at 2 times of day. We found a significant effect of genotype on phase shifts in response to light pulses given in the subjective night. Female WT mice had a significantly larger phase response than ERKO females during the early subjective night (phase shift of 98 min and 58 min, respectively; p < 0.05). NERKI females were intermediate to WT and ERKO females, suggesting a contribution of nonclassical estrogen signaling on circadian timekeeping functions. This genotype effect is not observed in males; they did not have a difference in phase shifts following a light pulse at any time point. WT males, however, shifted an average of 47 min less than did females at zeitgeber time (ZT) 16 (ZT 0 lights-on and ZT 12 lights-off). These data indicate that estrogens modify the response of the circadian timekeeping system to light via classical and nonclassical signaling pathways.

Oestradiol Exposure Early in Life Programs Daily and Circadian Activity Rhythms in Adult Mice

“…We used a photic phase response paradigm to determine that oestradiol during early development programs the behavioural response to a light pulse at select times of day, and that these effects are sex‐specific. As demonstrated previously , LD entrained mice released into DD phase advanced slightly. A light pulse at ZT4 induced a similar phase advance in most treatment groups.…”

“…Several distinct patterns emerged from our data. First, some variables, despite being sensitive to oestradiol in adulthood , were not altered by treatment with oestradiol in early postnatal development. LD proportion, tau and phase angle of activity onset were relatively unaffected, suggesting that these variables are either not sensitive to permanent organisation by oestrogenic signalling, or that oestradiol can program them but not during the critical period tested.…”

Machine Learning Helps Identify CHRONO as a Circadian Clock Component

“…A modified Aschoff type II procedure was used, facilitating the exposure of animals to light pulses before their free-running rhythms had drifted apart significantly [84],[85]. Animals were entrained to a 12∶12 L∶D cycle and then placed in constant darkness (D∶D) prior to a 30-min light pulse.…”

“…The phase response was calculated as the difference between activity onset predictions as determined by prepulse and postpulse regression lines computed in R. The prepulse regression line was fit from activity onset data for 5 d prior to the light pulse. The postpulse regression line was determined from the first through seventh days in D∶D following the pulse [85].…”

Estrogen receptor 1 modulates circadian rhythms in adult female mice

“…Previous data from this and other labs provide strong evidence that estrogens acting at ESR1 increase wheel-running activity. Further, classical and non-classical actions of ESR1 regulate the distribution of activity across the LD cycle and the response to light (Blattner & Mahoney, 2013;Ogawa et al, 2003). However, it is unknown if these modulatory effects of estrogens occur developmentally, in adulthood, or as some combination of these factors.…”