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.

Keywords: hormone; insomnia; menopause; paradoxical sleep; sex differences.

Fig. 1.

Schematic showing the experimental schedule. Light-dark (LD) cycle is represented by alternating light and dark bars. Animals received daily injections of oil followed by estradiol benzoate (EB) (black arrows) or oil only (gray arrows) before baseline and sleep deprivation (SD). In the first experiment, SD began at lights on (A), whereas in the second experiment SD began in the midlight phase (B). Recovery thus consisted of 6 h of light followed by 12 h of darkness (Recovery-Light; A) or vice versa (Recovery-Dark; B).

Fig. 2.

Mean serum estradiol (E2) concentrations following EB treatment. Values are presented at means ± SE. *P < 0.05 vs. oil; ***P < 0.0005 vs. oil.

Fig. 3.

Total minutes spent in rapid eye movement (REM) (A), non-REM (NREM) (B), and wake (C) during baseline in ovariectomized (OVX) rats after EB (black lines) and oil (gray lines) injections. Time of day is expressed as Zeitgeber time (ZT), where ZT 0 = lights on, indicated below LD bar on X-axis. *P < 0.05 vs. oil.

Fig. 4.

Total minutes spent in REM (A), NREM (B), and wake (C) during SD from ZT 0-ZT 6 and subsequent 18 h recovery in OVX rats treated with EB (black) or oil (gray). *P < 0.05 vs. oil.

Fig. 5.

Total minutes spent in REM (A), NREM (B), and wake (C) during SD from ZT 6-ZT 12 and subsequent 18 h recovery in OVX rats treated with EB (black) or oil (gray). *P < 0.05 vs. oil.

Fig. 6.

Total minutes spent in REM (A) and NREM (B) sleep during the first 6 h of recovery from each of the two sleep deprivation conditions in OVX rats treated with EB (black) or oil (gray). #P < 0.05 vs. Recovery-Dark.

Fig. 7.

Gain-loss ratios for REM (A and B) and NREM sleep (C and D) in the 18-h recovery starting in the midlight phase (A, C) or at lights off (B, D) in OVX rats treated with EB (dark bars) or oil (light bars). Gain-loss ratios were calculated according to the formula (sleep gained over baseline/sleep lost during recovery).

Fig. 8.

Normalized NREM delta power in OVX rats treated with EB (black) or oil (gray). For each individual under each hormone condition, total delta power per 3-h bin was normalized to the 24-h mean baseline delta power. Data are shown for baseline day (A), recovery starting in the light phase (B), and recovery starting in the dark phase (C). LD cycle is indicated on X-axis. *P < 0.05 vs. oil.