2004 WHRG Grant Program

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Estradiol Modulation of Sleep: Actions in Ventrolateral Preoptic Area
Jessica A. Mong, Ph.D.
School of Medicine, University of Maryland, Baltimore

Quality sleep is imperative for the maintenance of good health. Persons suffering from sleep disturbances are not only fatigued but have impaired memory and learning, increased stress and anxiety and decreased quality of daily life. In America, between 31% and 50% of middle-aged people report having sleep problems and sleep disturbances are twice as common among women compared to men. In fact, complaints by women of insomnia, disturbed sleep, difficulty returning to sleep and fatigue rise sharply during their perimenopausal and menopausal years when estrogen levels decrease markedly. Studies from a number of different species, including humans, suggest that sex hormones (estrogens, progestins and androgens) influence the physiology and pathology of sleep. However, the molecular and cellular mechanisms by which hormones act to influence sleep behavior are unknown.

This proposal seeks to investigate potential molecular pathways through which hormones influence sleep. The rat serves as a valuable model in this regard because of the extensive knowledge on general sleep patterns already gained. The ventrolateral preoptic area (VLPO) is a putative sleep center in the brain. In sleeping rodents, the VLPO contains a population of sleep-active neurons and lesions of this nucleus interrupt normal sleep patterns resulting in insomnia. Because the VLPO is tightly linked to the main arousal center in the brain such as the tuberomammilary nucleus (TMN), we hypothesize that estrogens acting at the level of the VLPO increase general arousal and decrease sleep. In support of this hypothesis, our studies measuring the activation state of the VLPO in female rodents suggests that the animal's sleep-drive is decreased in the presence of estrogens. However, these observations are correlative, and it is unknown if hormonal modulation of the activation state of the VLPO affects sleep homeostasis. To gain a better understanding of the potential significance of estrogen's ability to mediate activation states of sleep-active neurons in the VLPO, the first aim of the project is to correlate estradiol-induced changes in neuronal activation in the VLPO with changes in sleep behavior. Secondly, this study proposes to examine the site of estradiol actions, that is, which cell types are involved in the hormonal regulation of sleep.

In light of the recent and abrupt cessation of the Women's Health Initiative trial, it is imperative that we gain a clearer understanding of how ovarian hormones act in the brain throughout the life-span of women, especially since women are living longer in the absence of their endogenous ovarian steroids. A better understanding of estrogenic action in the brain can only help individual women and their doctors weigh the advantages and disadvantages of hormone replacement therapy. The potential findings of this research will advance our understanding of steroid associated control of sleep and may present opportunities to find alternatives to hormone replacement therapy for the alleviation of sleep disturbances in menopausal women.