Mechanisms Governing the Estrogenic Modulation of Sleep

 描述（由申请人提供）：睡眠不足和失眠等睡眠投诉在女性中的发生率是男性的两倍。由于高质量的睡眠对保持良好的健康至关重要，因此患有睡眠障碍的妇女有可能患情感性情绪障碍、压力和焦虑增加、认知功能受损以及代谢、生殖和心血管功能障碍。最近几项流行病学研究的证据表明，妇女睡眠不足与抑郁症、焦虑增加和心血管功能受损之间存在很强的相关性。睡眠中断的症状通常与女性一生中卵巢类固醇的变化一致。虽然性腺类固醇和性别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知之甚少。基础研究旨在了解潜在的雌激素调节睡眠的机制是重要的，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）根据女性生理学制定适当的治疗方法。 在我们的工作中，我们采用啮齿动物模型来研究卵巢类固醇对睡眠行为及其潜在神经回路的影响。因此，本申请的广泛、长期目标是了解雌激素介导的警觉状态变化的细胞机制和功能后果。我们将采用多学科的方法，利用细胞特异性病变，功能性神经解剖技术，切片电生理学和睡眠行为，以解决雌二醇的作用，在视前区推定的睡眠产生途径。我们的中心假设是，在雌性啮齿动物中，雌二醇（E2）通过减弱在睡眠期间活跃的MnPN神经元亚群的神经元活动来介导睡眠抑制。当前提案的具体目标解决了我们知识中的以下空白：（i）E2是否直接作用于MnPN以抑制睡眠，（ii）E2是否降低MnPN睡眠活性神经元的活性，以及（iii）改变MnPN神经元的活性是否改变唤醒相关核中的神经元活性并最终睡眠。推进我们对雌二醇调节睡眠的机制的理解的重要性在于有可能揭示女性大脑中睡眠障碍根源的新观点。最终，这可能有助于发现新的药物靶点，作为激素治疗的替代方案。

 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.