Mechanisms Governing the Estrogenic Modulation of Sleep

 描述(申请人提供)：睡眠不足和失眠等睡眠主诉在女性中普遍存在，是男性的两倍。由于高质量的睡眠对保持良好的健康至关重要，患有睡眠障碍的女性面临情感情绪障碍、压力和焦虑增加、认知功能受损以及新陈代谢、生殖和心血管功能障碍的风险。最近几项流行病学研究的证据表明，女性睡眠不足与抑郁、焦虑增加和心血管功能受损的发生率有很强的相关性。睡眠障碍的症状通常与女性一生中卵巢类固醇水平的变化相吻合。虽然性腺类固醇和性别被认为是睡眠中断和失眠的危险因素，但卵巢类固醇和睡眠之间的关系却鲜为人知。如果我们要(I)了解失调的神经内分泌-睡眠回路系统如何影响女性睡眠障碍的风险，以及(Ii)开发由女性生理学提供信息的适当疗法，则针对睡眠的雌激素调节睡眠的潜在机制的基础研究具有重要意义。在我们的工作中，我们使用了一个啮齿动物模型来检查卵巢类固醇对睡眠行为及其潜在神经回路的影响。因此，目前应用的广泛的、长期的目标是了解雌激素介导的警戒状态变化的细胞机制和功能后果。我们将采用一种多学科的方法，利用细胞特异性损伤、功能神经解剖学技术、脑片电生理学和睡眠行为来研究雌二醇在视前区可能的睡眠产生途径中的作用。我们的中心假设是，在雌性啮齿类动物中，雌二醇(E2)通过减弱睡眠中活跃的一组MnPN神经元的神经元活动来调节睡眠抑制。目前提案的具体目的是解决我们知识中的以下空白：(I)E2是否直接在MnPN中作用以抑制睡眠，(Ii)E2是否降低MnPN睡眠活动神经元的活动，以及(Iii)MnPN神经元活动的改变是否改变觉醒相关核团中的神经元活动，并最终改变睡眠。提高我们对雌激素调节睡眠的潜在机制的理解的意义在于有可能发现女性大脑睡眠障碍的根源的新视角。最终，这可能有助于发现新的药物靶点，作为激素疗法的替代方案。

 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.