Mechanisms Governing the Estrogenic Modulation of Sleep

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 DESCRIPTION (provided by applicant): Sleep complaints such as insufficient sleep and insomnia are twice as prevalent in women than men. As quality sleep is imperative for the maintenance of good health, women suffering from sleep disturbances are at risk for affective mood disorders, increased stress and anxiety, impaired cognitive function and metabolic, reproductive and cardiovascular dysfunction. Evidence from several recent epidemiological studies shows a strong correlation between insufficient sleep in women and the incidence of depression, increased anxiety and impaired cardiovascular function. Symptoms of sleep disruption are often coincident with changes in the ovarian steroid profiles across a women's lifespan. 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. Basic research directed to the understanding of the mechanisms underlying estrogenic modulation of sleep is significant if we are to (i) understand how a dysregulated neuroendocrine-sleep circuitry system influences the risk for sleep disorders in women and (ii) develop appropriate therapies that are informed by the female physiology. In our work, we employ a rodent model to examine the effects of ovarian steroids on sleep behavior and its underlying neurocircuitry. Thus, the broad, long-term objective of the current application is to understand the cellular mechanisms and functional consequences of estrogen-mediated changes in vigilance states. We will employ a multidisciplinary approach that utilizes cell-specific lesions, functional neuroanatomical techniques, slice electrophysiology and sleep behavior to address the actions of estradiol on putative sleep generating pathways in the preoptic area. Our central hypothesis is that in female rodents estradiol (E2) mediates the suppression of sleep by attenuating the neuronal activity of a subpopulation of MnPN neurons that are active during sleep. The specific aims of the current proposal address the following gaps in our knowledge (i) Does E2 act directly in the MnPN to suppress sleep, (ii) Does E2 reduce activity of MnPN sleep active neurons, and (iii) Does altering activity in MnPN neurons alter neuronal activity in wake-associated nuclei and ultimately sleep. The significance of advancing our understanding of the mechanisms underlying estradiol modulation of sleep is the potential to uncover new perspectives on the root of sleep disturbance in the female brain. Ultimately, this may serve to uncover novel drug targets as an alternative to hormone based therapies.