Identification of Key Preoptic Area Nuclei Mediating Sex Differences and Estrogenic Modulation of Sleep in a Rodent Model

Abstract

Women are twice as likely as men to experience sleep disruptions and insomnia throughout their lifespan. The reason for this sex difference in sleep is unknown. In females, findings from clinical and basic research studies strongly implicate a role for gonadal steroids in sleep modulation. Sleep disruptions and complaints in women typically coincide with marked changes in the gonadal steroidal profile during puberty, the menstrual cycle, pregnancy, and menopause. Likewise, fluctuations in the ovarian hormonal milieu across the estrous cycle in female rodents correlate with changes in sleep and wakefulness, such that when estradiol levels are elevated sleep is suppressed. In male rodents, sleep remains relatively unchanged following changes in testosterone levels. Here, we sought to address the mechanism by which gonadal steroids selectively suppress sleep in females. Using a rat model, we found that sex differences in sleep resulted from activational effects of estradiol on sexually differentiated brain circuitry. Sexual differentiation of the brain organized the sleep circuitry, specifically the ventrolateral peroptic area (VLPO) and the median preoptic nucleus (MnPN). We found that estrogen receptor alpha expression in the MnPN was higher in females compared to males, making this nucleus an ideal target for estradiol's actions on sleep. In females, antagonism of estrogen receptors within the MnPN attenuated the estradiol-mediated suppression of sleep. Furthermore, direct infusion of estradiol into the MnPN induced wakefulness and suppressed sleep. The orexinergic neurons in the lateral hypothalamus are regulated by MnPN activity and orexin is a key neuropeptide involved in arousal and suppression of sleep. We hypothesized that estradiol action in the MnPN would release the inhibitory tone on orexin but antagonism of orexin receptors did not completely block estradiol's suppressive effects on sleep. We also found a sex difference in the sleep-promoting effect of the dual orexin receptor antagonists, such that females experienced prolonged wake suppression compared to males. Together, these data begin to address major gaps in our knowledge regarding sex differences and hormonal modulation of sleep. Advancing our understanding of the mechanisms underlying hormonal modulation of sleep is imperative for better treatment of sleep disruption in women.