A Role for the Orphan Receptor, GPR37, in Estradiol-induced Changes in Sleep-Wake States

项目摘要 研究表明，女性报告的睡眠困难更多，更有可能被诊断为失眠 与男人相比。在荷尔蒙波动期间，女性更有可能出现睡眠障碍， 包括怀孕和更年期，这表明性激素在睡眠-觉醒周期中发挥作用。 更多地了解性激素如何影响睡眠可以帮助我们开发有针对性的治疗方法 适用于患有睡眠障碍的女性。大脑中有两个主要的睡眠中心，都位于 下丘脑--正中视前核(MnPO)和腹外侧视前核(VLPO)。确实有 雌激素受体定位于MnPO，但不位于VLPO，提示雌激素通过MnPO作用于 调节睡眠-觉醒状态。MnPO被认为通过抑制脑内促进觉醒的神经元来促进睡眠 大脑。已发现向MnPO内注入雌二醇(E_2)可增加觉醒和减少睡眠 然而，雌激素扰乱睡眠的机制在很大程度上还不清楚。 在清醒状态下，腺苷在大脑中积聚，增加睡眠压力，导致疲倦。这个 A1和A2A受体(A1R和A2AR)在MnPO中表达，并在调节细胞周期中发挥重要作用。 腺苷对大脑的影响。已发现在MnPO中注入A1R激动剂可以增加觉醒 并减少大鼠的睡眠，而注射A2AR激动剂被发现可以增加睡眠和减少睡眠 醒醒吧。已有假说认为E2影响MnPO、AS、 在E2存在的情况下，A2AR激动剂的促进睡眠的作用被阻断。E2的一个潜在目标是 G蛋白偶联受体37(GPR37)，已被证明抑制A2AR表面的表达和功能 纹状体。该项目将测试E2减少NREM睡眠和增加觉醒的假设 通过GPR37调制衰减A2AR信号。为了研究GPR37在MnPO中的作用， 我们将(1)确定E2是否足以在MnPO中上调GPR37，(2)确定A2AR和 GPR37在MnPO的睡眠活动细胞中形成相互作用，以及(3)确定GPR37是否是必要的 引起雌激素引起的睡眠-觉醒状态的改变。了解雌二醇在睡眠中断中的作用- 唤醒周期将帮助我们更深入地了解女性失眠的独特机制之一 最终是关于我们如何更好地治疗相当一部分人口的失眠。

Project Summary Studies have shown that women report more sleep difficulties and are more likely to be diagnosed with insomnia compared to men. Sleep disturbances are more likely to occur in women during times of hormonal fluctuations, including pregnancy and menopause, thus indicating that sex hormones play a role in the sleep-wake cycle. Understanding more about how sex hormones act to influence sleep can help us develop targeted treatments for women who suffer from sleep disorders. There are 2 major sleep centers in the brain, both located in the hypothalamus – the median preoptic nucleus (MnPO) and the ventrolateral preoptic nucleus (VLPO). There are estrogen receptors located in the MnPO, but not in the VLPO, suggesting that estrogen acts via the MnPO to regulate sleep-wake states. The MnPO is thought to promote sleep by inhibiting wake-promoting neurons in the brain. It has been found that estradiol (E2) infusion into the MnPO increases wake and decreases sleep in ovariectomized female rats, however the mechanism by which sleep is disrupted by E2 is largely unknown. During wakefulness, adenosine accumulates in the brain and increases sleep pressure, causing tiredness. The A1 and A2A receptors (A1R and A2AR) are expressed in the MnPO and play an important role in regulating the effects of adenosine in the brain. Infusion of an A1R agonist into the MnPO has been found to increase wake and decrease sleep in rats, while infusion of an A2AR agonist has been found to increase sleep and decrease wake. E2 has been hypothesized to influence the inhibitory/excitatory adenosinergic balance in the MnPO, as, in the presence of E2, the sleep-promoting effects of an A2AR agonist are blocked. One potential target of E2 is G protein-coupled receptor 37 (GPR37), as it has been shown to inhibit A2AR surface expression and function in the striatum. This project will test the hypothesis that E2 is decreasing NREM sleep and increasing wake by attenuating A2AR signaling through GPR37 modulation. To examine the effects of GPR37 in the MnPO, we are going to (1) Determine if E2 is sufficient for GPR37 upregulation in the MnPO, (2) Determine if A2AR and GPR37 form an interaction in the sleep active cells of the MnPO, and (3) Determine if GPR37 is necessary to cause E2-induced changes in sleep-wake states. Understanding estradiol’s role in the disruption of the sleep- wake cycle will help us gain greater insight into one of the unique mechanisms of insomnia in women and ultimately with how we can better treat insomnia in a substantial portion of the population.