Estradiol Modulates Recovery of Rem Sleep in a Time-of-Day-Dependent Manner

Abstract

Ovarian hormones are thought to modulate sleep and fluctuations in the hormonal milieu are coincident with sleep complaints in women. In female rats, estradiol increases waking and suppresses sleep. In this study, we asked whether this effect is mediated via circadian or homeostatic regulatory mechanisms. Ovariectomized female rats received daily injections of estradiol benzoate (EB) or sesame oil that mimicked the rapid increase and subsequent decline of circulating estradiol at proestrus. In one experiment, animals were sleep deprived for 6 h starting at lights-on, so that recovery began in the mid-light phase; in the second experiment, animals were sleep deprived starting in the mid-light phase, so that recovery began at lights-off. EB suppressed baseline rapid eye movement (REM) and non-REM (NREM) sleep and increased waking in the dark phase. In both experiments, EB enhanced REM recovery in the light phase while suppressing it in the dark compared with oil; this effect was most pronounced in the first 6 h of recovery. By contrast, NREM recovery was largely unaffected by EB. In summary, EB enhanced waking and suppressed sleep, particularly REM sleep, in the dark under baseline and recovery conditions. These strong temporally dependent effects suggest that EB consolidates circadian sleep-wake rhythms in female rats.

Women have increased risk for insomnia or insufficient sleep compared with men. Short- and long-term alterations in the circulating ovarian hormone profile, either at major life events such as adolescence, pregnancy, and at menopause or across the menstrual cycle, are associated with elevated sleep disturbance, suggesting that these hormones may play a role in the physiological regulation of sleep. For example, delta sleep and wake after sleep onset are associated with the rate of change in ovarian hormones across the menopausal transition, whereas nighttime elevations in luteinizing hormone pulses are associated with increased wakefulness in postmenopausal women. In younger women, low circulating estradiol levels across the menstrual cycle reduce subjective variability in sleep. Rapid-eye movement (REM) sleep decreases, whereas stage 2 non-REM (NREM) sleep and spindle frequency activity increase in the luteal phase of the menstrual cycle. In addition, nighttime alertness and cognitive performance during an all-night sleep deprivation are increased at the luteal phase, consistent with reduced sleep propensity at this time. Exogenous ovarian hormones have also been shown to alter subjective and objective sleep measures. Thus both endogenous and exogenous ovarian hormones alter sleep in women over much of their lifespan. However, the biological basis for these effects is still unknown.

The regulation of sleep by gonadal steroids can be directly studied in laboratory rodents whose ovulatory cycles are much shorter in length but have a strikingly similar hormonal profile to those of humans. Cycling female rats and mice suppress sleep at proestrus, when circulating estradiol (E2) levels peak. The periovulatory decrease in sleep is abolished by ovariectomy (OVX) and is restored by exogenous E2 treatment in OVX rats and mice, demonstrating that E2 powerfully and directly influences spontaneous sleep in both intact and OVX/hormone-replaced rodents. Interestingly, intact rats suppress both REM and NREM sleep in the dark phase, particularly around the light-to-dark transition when circadian promotion of wakefulness is strong; similarly, OVX rats treated with E2 exhibit more frequent brief awakenings, shorter NREM episodes, and fewer REM episodes in the dark phase. Together, these data suggest that E2-mediated sleep suppression is more powerful in the nighttime (i.e., the dark phase of a LD cycle), when rats are normally awake, than in the daytime, when they normally sleep.

We have recently used sleep deprivation paradigms to investigate effects of E2 on sleep. Sleep is regulated by a homeostatic drive that increases sleep propensity in proportion to the duration of prior waking and a circadian drive that alternately promotes sleep and waking across the day. Sleep deprivation (SD) induces a compensatory increase or “rebound” that is proportional to the duration of the SD and to the stage of sleep that was lost (e.g., REM vs. NREM). However, rebound may be attenuated when circadian promotion of wakefulness is strong. Previously, we and others have shown that spontaneous REM and NREM sleep decrease on the day of proestrus without a subsequent REM recovery, whereas NREM sleep and delta power increase on the day of estrus (when E2 levels are declining). Furthermore, OVX rats exposed to low physiological doses of E2 suppress spontaneous REM sleep in the dark phase and significantly attenuate REM recovery in the dark following a 12-h SD in the light phase. Based on this, we hypothesize that E2 acts to consolidate or otherwise strengthen the circadian sleep-wake rhythm. If this hypothesis is true, SD ending in the light phase (the rat’s normal rest phase) should induce a larger rebound in E2-treated rats than a similar SD ending in the dark phase. Conversely, if E2 acts on homeostatic mechanisms that regulate NREM and/or REM sleep, SD should attenuate sleep rebound in E2-treated rats regardless of what time of day the deprivation ends. We therefore asked whether physiological doses of exogenous E2 would attenuate the recovery from a 6-h SD during the light phase when recovery was initiated in either the light phase or the dark phase.