Estradiol Influences Adenosinergic Signaling and NREM Sleep Need in Adult Female Rats

Abstract Studies report estradiol (E2) suppresses sleep in females; however, the mechanisms of E2 action remain largely undetermined. Our previous findings suggest that the median preoptic nucleus (MnPO) is a key nexus for E2 action on sleep. Here, using behavioral, neurochemical and pharmacological approaches, we investigated whether E2 influenced the sleep homeostat as well as adenosinergic signaling in the MnPO of adult female rats. During the Light Phase, where rats accumulate the majority of sleep, E2 markedly reduced NREM-SWA (a measure of the homeostatic sleep need). Following 6-hours of sleep deprivation, levels of NREM-SWA were significantly increased compared to baseline sleep. However, the NREM-SWA levels were not different between E2 and control treatment despite a significant increase in wake at the expense of NREM sleep. Analysis of NREM-SWA differences between baseline and recovery sleep following sleep deprivation demonstrated that E2 induced a 2-fold increase in delta power compared to controls suggesting that E2 significantly expanded the dynamic range for the sleep homeostat. Correlated with E2-induced changes in physiological markers of homeostatic sleep was a marked increase in extracellular adenosine (a molecular marker of homeostatic sleep need) during unrestricted and recovery sleep following a 6-hour deprivation. Additionally, E2 blocked the ability of an adenosine A2A receptor agonist (CGS-21680) to increase NREM sleep compared to controls. Thus, taken together, the findings that E2 increased extracellular adenosine content, while blocking A 2A signaling in the MnPO suggests a potential mechanism for how estrogens impact sleep in the female brain. Statement of Significance While gonadal steroids and gender are implicated as risk factors for sleep disruptions and insomnia, the relationship between ovarian steroids and sleep is poorly understood. Understanding the mechanisms through which estradiol (E2) is working to influence sleep-wake behavior is a critical first step toward a better understanding of the role of estrogens in sleep pathologies. Using a rodent model, the current study presents novel findings suggesting that estradiol (E2) is influencing adenosinergic actions in the MnPO. The ability of E2 to attenuate the local effects of the A 2A receptors in the MnPO suggests that E2 modulation of A 2A receptor signaling may underlie estrogenic suppression of sleep behavior as well as changes in homeostatic sleep need.