Estrogen receptor 1 modulates circadian rhythms in adult female mice

• Published in: Chronobiology international 2014-06, Vol.31 (5), p.637-644
• Main Authors: Blattner, Margaret S., Mahoney, Megan M.
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Circadian Rhythm - drug effects; Circadian Rhythm - genetics; Circadian Rhythm - radiation effects; ERKO; ERα; Estradiol; Estradiol - administration & dosage; Estrogen Receptor alpha - agonists; Estrogen Receptor alpha - deficiency; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Genotype; Hormone Replacement Therapy; Light; locomotor activity; Mice, Inbred C57BL; Mice, Knockout; Motor Activity - drug effects; Motor Activity - genetics; Motor Activity - radiation effects; Mutation; Ovariectomy; phase angle; phase response; Phenotype; Photoperiod; Running; Sex Factors; Signal Transduction; tau; Time Factors
• ISSN: 0742-0528; 1525-6073
• DOI: 10.3109/07420528.2014.885528

Estradiol influences the level and distribution of daily activity, the duration of the free-running period, and the behavioral phase response to light pulses. However, the mechanisms by which estradiol regulates daily and circadian rhythms are not fully understood. We tested the hypothesis that estrogens modulate daily activity patterns via both classical and "non-classical" actions at the estrogen receptor subtype 1 (ESR1). We used female transgenic mice with mutations in their estrogen response pathways; ESR1 knock-out (ERKO) mice and "non-classical" estrogen receptor knock-in (NERKI) mice. NERKI mice have an ESR1 receptor with a mutation in the estrogen-response-element binding domain, allowing only actions via "non-classical" genomic and second messenger pathways. Ovariectomized female NERKI, ERKO, and wildtype (WT) mice were given a subcutaneous capsule with low- or high-dose estradiol and compared with counterparts with no hormone replacement. We measured wheel-running activity in a light:dark cycle and constant darkness, and the behavioral phase response to light pulses given at different points during the subjective day and night. Estradiol increased average daily wheel-running, consolidated activity to the dark phase, and shortened the endogenous period in WT, but not NERKI and ERKO mice. The timing of activity onset during entrainment was advanced in all estradiol-treated animals regardless of genotype suggesting an ESR1-independent mechanism. We propose that estradiol modifies period, activity level, and distribution of activity via classical actions of ESR1 whereas an ESR1 independent mechanism regulates the phase of rhythms.