Orexins as Mediators of the Effects of Low Estradiol on Fragmented Sleep and Stress Responses

Background. Women experience numerous physiological changes through their perimenopausal and menopausal transition, including severe sleep disturbances, mood changes and hot flashes. Hypothalamic neurons that express the wake-promoting orexin neuropeptides may be a key site through which low estradiol mediates these challenging symptoms. The orexin neurons coordinate many responses to stress from behavioral to physiological. Furthermore, expression of the orexin peptides appears to be regulated by estradiol: after ovariectomy, expression of prepro-orexin mRNA is increased and replacement with estradiol decreases expression. Does this change in orexin expression contribute to the physiological and behavioral symptoms seen with chronically low estradiol? Do the changes in estradiol with menopause result in different responses to stress and influence cognitive flexibility or risk of mood disorders?

Objectives. We hypothesize that low estradiol increases orexin signaling, resulting in less sleep and heightened responses to stress.

Methods. We will use histological, chemogenetic and behavioral assays to determine expression levels of orexins, sleep responses to stress, and the role orexins have in regulating the stress response in ovariectomized mice.

Conclusion. Collectively, these multidisciplinary experiments will improve our understanding of how the orexin system contributes to the poor sleep and heightened stress responses that occur with chronic low estradiol in a mouse model of menopause. From a translational perspective, these experiments will help guide the potential treatment of the symptoms of menopause using orexin agonists and antagonists.”