The Median Preoptic Nucleus is a Key Site for Estradiol Regulation of Sleep-Wake Behaviors in Females Rats

Study ObjectivesWomen experience more sleep disruptions than men, particularly during hormonal transitions such as puberty, pregnancy, and menopause. This study investigated the role of estradiol (E2) in regulating sleep-wake behavior in female rats and identified the brain regions involved. MethodsUsing an exogenous E2 replacement model in ovariectomized rats, we assessed changes in sleep-wake patterns via EEG/EMG telemetry. The effects of E2 and progesterone, selective estrogen receptor agonists, and direct brain infusions of E2 and receptor antagonists were evaluated. ResultsE2 administration increased wakefulness, reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and decreased NREM slow-wave activity (SWA), predominantly during the dark phase. These effects required both estrogen receptor alpha (ER) and beta (ER{beta}) activation and were mediated by estrogen receptor signaling within the median preoptic nucleus (MnPO). Direct infusion of E2 into the MnPO was sufficient to replicate systemic effects, while local infusion of the pure estrogen receptor antagonist ICI 182,780 (Fulvestrant) attenuated them. Progesterone did not augment E2s actions, and males showed no sleep-wake changes in response to E2, highlighting sex-specific mechanisms. ConclusionsThe MnPO is a critical site where E2 regulates sleep-wake behavior. These findings provide a neurobiological framework for understanding how ovarian hormones contribute to sleep disruptions in women, offering potential therapeutic targets for sleep disorders related to hormonal changes. Statement of significanceSleep disturbances disproportionately affect women, particularly during hormonal transitions such as puberty, pregnancy, and menopause. Despite this, the underlying mechanisms by which estradiol (E2) influences sleep-wake behavior have remained unclear. This study identifies the median preoptic nucleus (MnPO) as a critical site where E2 signaling regulates sleep-wake patterns in female rats. Our findings demonstrate that E2 increases wakefulness and reduces both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, with effects primarily observed during the dark phase. By showing that local E2 signaling in the MnPO is both necessary and sufficient for these changes, this work offers a novel neurobiological framework for understanding how fluctuations in ovarian hormones contribute to sleep disruptions in women. These insights lay the groundwork for developing targeted therapies to improve sleep health in women, particularly those experiencing hormonal changes.