Orexins and severity of menopausal symptoms in mice

PROJECT SUMMARY/ABSTRACT In the United States, over a million women experience menopause each year. Women experience many physiological changes through their menopausal transition that often include severe sleep disturbances, anxiety, and hot flashes. Up to 60% of menopausal women have sleep disturbances that impact their daily life. In addition, they have higher rates of anxiety and longer lasting responses to stressful events. Though these menopausal problems impact the lives of women in many ways, the underlying neuronal mechanisms are largely unknown. Long- term hormone replacement therapies carry health risks. Identifying the neuronal mechanisms that drive these symptoms will provide additional therapeutic opportunities, with potentially fewer side effects. Hypothalamic neurons that express the orexin neuropeptides may be a key site influenced by the chronic low estradiol (E2) environment that leads to menopausal symptoms. The orexin neurons promote high arousal and increased sympathetic tone. Post-menopausal women have higher plasma levels of orexin, and rodents with E2 deficiency from ovariectomy (OVX) have increased expression of the orexins which is normalized by E2 replacement. Identifying the mechanisms through which low E2 disrupts sleep and stress systems is crucial for improving the lives of menopausal women We hypothesize chronically low E2 results in high orexin tone, and consequently, more frequent waking from sleep and increased time awake. As the orexin neurons also regulate autonomic responses, we predict that this high orexin tone increases the frequency of vasomotor responses (VMRs). Collectively, these multidisciplinary experiments will improve our understanding of how the orexin system contributes to poor sleep and VMR observed in a mouse model of menopause. From a translational perspective, these experiments should enable more targeted treatment of menopause symptoms using medications such as orexin antagonists.