Estradiol influences adenosinergic signaling and nonrapid eye movement sleep need in adult female rats

Abstract

Gonadal steroids and gender are risk factors for sleep disruptions and insomnia in women. However, the relationship between ovarian steroids and sleep is poorly understood. In rodent models, estradiol (E2) suppresses sleep in females suggesting that E2 may reduce homeostatic sleep need. The current study investigates whether E2 decreases sleep need and the potential mechanisms that govern E2 suppression of sleep. Our previous findings suggest that the median preoptic nucleus (MnPO) is a key nexus for E2 action on sleep. Using behavioral, neurochemical and pharmacological approaches, we tested whether (1) E2 influenced the sleep homeostat and (2) E2 influenced adenosine signaling in the MnPO of adult female rats. In both unrestricted baseline sleep and recovery sleep from 6-hour sleep deprivation, E2 significantly reduced non-rapid eye movement sleep (NREM)-delta power, NREM-Slow Wave Activity (NREM-SWA, 0.5-4.0Hz), and NREM-delta energy suggesting that E2 decreases homeostatic sleep need. However, coordinate with E2-induced changes in physiological markers of homeostatic sleep was a marked increase in MnPO extracellular adenosine (a molecular marker of homeostatic sleep need) during unrestricted and recovery sleep in E2-treated but not oil control animals. While these results seemed contradictory, systemically administered E2 blocked the ability of CGS-21680 (adenosine A2A receptor agonist) microinjected into the MnPO to increase NREM sleep suggesting that E2 may block adenosine signaling. Together, these findings provide evidence that E2 may attenuate the local effects of the A2A receptors in the MnPO which in turn may underlie estrogenic suppression of sleep behavior as well as changes in homeostatic sleep need.

Molecular targets and mechanisms involved in the action of Banxia Shumi decoction in insomnia treatment

“…Notably, among the GSEA-enriched items, previous studies have proved the role of SD in phosphatidylinositol signaling system, [36] inositol phosphate metabolism, [37,38] hematopoietic cell lineage [39] ; glycine, serine, and threonine metabolism, [40] and estrogen signaling. [41]…”

“…Notably, among the GSEA-enriched items, previous studies have proved the role of SD in phosphatidylinositol signaling system, [36] inositol phosphate metabolism, [37,38] hematopoietic cell lineage [39] ; glycine, serine, and threonine metabolism, [40] and estrogen signaling. [41] Sleep is regulated through homeostatic and circadian processes. [42] Thus, genetic changes in the circadian clock system and/or the genes that regulate it can have broad effects on various parameters of sleep and wakefulness, including sleep homeostatic regulation.…”

The stress of losing sleep: Sex-specific neurobiological outcomes

“…Yet, gonadectomy, which eliminates circulating gonadal hormones, abolished the sex difference in wakefulness and restored basal reductions in NREM sleep in females ( Cusmano et al, 2014 ; Paul et al, 2006 ). Further, estrogen given to only gonadectomized females, and not males, increased wakefulness while reinstating estradiol to ovariectomized females reduced various features of NREM sleep including duration, spectral delta power, and slow-wave activity ( Cusmano et al, 2014 ; Deurveilher et al, 2013 ; Paul et al, 2006 ; Smith et al, 2022 ). Regarding REM sleep, estrogens seem to suppress this sleep stage, as females spend less time in REM sleep during stages of the estrous cycle when estrogens are high ( Dib et al, 2021 ).…”

“…Inhibition of adenosine signaling, like with caffeine, enhances the phase-shifting effects of light whereas adenosine agonists diminish the impact of light ( Burke et al, 2015 ; Jagannath et al, 2021 ), showing that light signaling to the molecular clockwork can be directly altered by adenosine signaling. Recent evidence demonstrates that estrogen can block adenosine signaling in the median preoptic nucleus and attenuate the local effects of adenosine 2 A receptors in this brain region ( Smith et al, 2022 ). This action on adenosine may underly estrogenic suppression of sleep behavior seen in female rodents.…”

Estradiol Action at the Median Preoptic Nucleus is Necessary and Sufficient for Sleep Suppression in Female Rats

“…where vigilant states were automatically scored using a custom program developed by the lab which has been shown to be ~88% in agreement with hand scored traces. 24…”