Mechanisms of Estrogenic Modulation of Adenosinergic Sleep Pressure

项目总结： 原发性睡眠障碍是最常见的疾病之一，临床数据显示，女性的睡眠障碍 在他们的一生中更有可能经历睡眠障碍。这种增加的风险在青春期出现，并已 与卵巢类固醇，特别是雌激素的波动有关，这表明性腺类固醇 和生物性行为是睡眠中断的重要风险因素。尽管人们对睡眠的了解越来越多 对于雌激素如何影响睡眠回路的调节机制，人们知之甚少。从历史上看，男性 啮齿动物一直是阐明支配睡眠的神经回路的基石。不幸的是，这 导致了我们对雌激素如何调节女性这些回路的理解上的巨大差距。这个 雌性啮齿动物提供了探索睡眠回路的机会，以阐明卵巢 类固醇调节睡眠，因为雌性大鼠的睡眠模式对激素的自然波动非常敏感。 卵巢类固醇，如雌二醇(E2)。利用成年雌性Spraogue-Dawley大鼠，我们的研究小组取得了进展 了解雌激素对正常觉醒和睡眠模式的影响。我们的研究始终如一 证明当内源性卵巢类固醇或外源性E2被 在女性中升高，但在男性中没有。这种作用是通过抑制脑内睡眠活动神经元来实现的。 正中视前核(MnPN)。此外，我们已经证明了E2能够显著地抑制 在睡眠不足的情况下，当动态平衡睡眠需求增加时，也称为睡眠压力。 结合我们之前的发现，这一观察结果表明，雌二醇可能会消除体内平衡的需要 睡觉用的。此外，初步数据表明，E2减弱了腺苷信号在体内的作用。 促进睡眠的A2a受体，导致睡眠持续时间缩短。这一发现意义重大，因为腺苷 是睡眠压力的已知中介物，在MnPN和密切相关的(但非E2) 敏感)核，腹侧视前区(VLPO)。这些数据表明，雌二醇组之间存在相互作用 还有腺苷，它调节腺苷产生睡眠压力的能力。然而，具体的 这种相互作用的机制仍未确定。这个项目将检验雌激素的假说 睡眠压力的调节需要腺苷信号效力的减弱。我们将对此进行测试 假说通过(1)确定雌二醇是否通过两种行为来降低睡眠的稳态需求 腺苷含量、合成和清除的实验和分子分析，以及(2)确定是否 雌二醇通过抑制睡眠激活的MnPN神经元的细胞作用而减弱其神经元活性。 腺苷在睡眠回路中，通过实验在受体药理和神经元活动两方面发挥作用。 了解雌二醇和腺苷的相互作用可能会阐明激素含量和睡眠之间的联系，以及 为睡眠障碍的治疗提供机会，将女性的性别和荷尔蒙状态考虑在内。

Project Summary: Primary sleep disorders are among the most common medical conditions, and clinical data show women are far more likely to experience sleep disorders over their lifespan. This increased risk emerges at puberty and has been associated with fluctuations in ovarian steroids, particularly estrogens, suggesting that gonadal steroids and biological sex are significant risk factors for sleep disruptions. Despite a growing understanding of sleep regulatory mechanisms, how estrogens influence the sleep circuitry is poorly understood. Historically, male rodents have served as the cornerstone for elucidating the neural circuitries governing sleep. Unfortunately, this has resulted in a significant gap in our understanding of how estrogens modulate these circuits in females. The female rodent offers the opportunity to probe the sleep circuitry to elucidate the mechanisms by which ovarian steroids modulate sleep, as sleep patterns in the female rat are exquisitely sensitive to natural fluctuations in ovarian steroids such as estradiol (E2). Using adult female Sprague-Dawley rats, our group has made inroads into understanding estrogenic influences over normal wake and sleep patterns. Our studies consistently demonstrate that sleep time is significantly reduced when endogenous ovarian steroids or exogenous E2 are elevated in females but not males. This effect is mediated through the inhibition of sleep-active neurons in the median preoptic nucleus (MnPN). Moreover, we have demonstrated that E2 is capable of marked suppression of sleep under sleep deprivation, when homeostatic sleep need, also known as sleep pressure, is increased. Taken together with our previous findings, this observation suggests that E2 may dissipate the homeostatic need for sleep. Furthermore, preliminary data suggest that E2 attenuates the action of adenosine signaling at the sleep-promoting A2A receptor, resulting in reduced sleep duration. This finding is significant because adenosine is a known mediator of sleep pressure, with established actions at the MnPN and a closely related (but non-E2 sensitive) nucleus, the ventral lateral preoptic (VLPO). These data suggest that there is an interplay between E2 and adenosine which modulates the ability of adenosine to generate sleep pressure. However, the specific mechanism for this interplay remains undetermined. This project will test the hypothesis that estrogenic modulation of sleep pressure requires the attenuation of adenosine signaling efficacy. We will test this hypothesis by (1) determining if estradiol reduces the homeostatic need for sleep through both behavioral experiments and molecular assays of adenosine content, synthesis, and clearance, and (2) determining if estradiol attenuates neuronal activity of sleep active MnPN neurons, through inhibiting the cellular action of adenosine in the sleep circuitry, through experiments in both receptor pharmacology and neuronal activity. Understanding interactions of E2 and adenosine may illuminate ties between hormonal content and sleep, and provide opportunities for sleep disorder treatments that take female sex and hormonal state into account.