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

孤儿受体 GPR37 在雌二醇诱导的睡眠-觉醒状态变化中的作用

• 批准号: 10677913
• 负责人: Katie Kruk
• 金额: $ 4.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-30 至 2026-08-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677913
• 关键词: ADORA2A gene; Adenosine; Adult; Affect; Agonist; Animals; Attenuated; Brain; Brain Stem; Cell Nucleus; Cells; Co-Immunoprecipitations; Corpus striatum structure; Coupled; Curiosities; Diagnosis; Equilibrium; Estradiol; Estrogen Receptors; Estrogens; Female; G-Protein-Coupled Receptors; GPR37 receptor; Gonadal Steroid Hormones; Hormonal; Hypothalamic structure; Infusion procedures; Lateral; Link; Measures; Mediating; Menopause; Messenger RNA; Modeling; Neuromodulator; Neurons; Orphan; Play; Population; Pregnancy; Proteins; Rat Transgene; Rattus; Receptor Signaling; Reporting; Role; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Sleeplessness; Surface; Techniques; Testing; Up-Regulation; Viral; Viral Vector; Wakefulness; Woman; experimental study; extracellular; falls; innovation; insight; mRNA Expression; men; non rapid eye movement; pharmacologic; preoptic nucleus; pressure; protein expression; receptor; receptor coupling; sleep difficulty

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.

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。女性在荷尔蒙波动期间更容易出现睡眠障碍， 包括怀孕和更年期，因此表明性激素在睡眠-觉醒周期中起作用。 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 帮助那些患有睡眠障碍的女性大脑中有两个主要的睡眠中心，它们都位于大脑中。 下丘脑-正中视前核（MnPO）和腹外侧视前核（VLPO）。有 雌激素受体位于MnPO中，但不在VLPO中，这表明雌激素通过MnPO起作用， 调节睡眠-觉醒状态。MnPO被认为是通过抑制大脑皮层中的促醒神经元来促进睡眠的。 个脑袋已经发现，雌二醇（E2）输注到MnPO中增加觉醒并减少睡眠， 卵巢切除的雌性大鼠，然而睡眠被E2破坏的机制在很大程度上是未知的。 在清醒时，腺苷在大脑中积累，增加睡眠压力，导致疲劳。的 A1和A2 A受体（A1 R和A2 AR）在MnPO中表达，并在调节MnPO中起重要作用。 腺苷对大脑的影响已发现将A1 R激动剂输注到MnPO中可增加觉醒 减少大鼠的睡眠，而A2 AR激动剂的输注已被发现增加睡眠， 醒来。假设E2影响MnPO中的抑制性/兴奋性腺苷能平衡，因为， 在E2的存在下，A2 AR激动剂的睡眠促进作用被阻断。E2的一个潜在目标是 G蛋白偶联受体37（GPR 37），因为它已被证明抑制A2 AR表面表达和功能， 纹状体这个项目将测试E2减少NREM睡眠和增加觉醒的假设。 通过GPR 37调节减弱A2 AR信号。为了检查GPR 37在MnPO中的作用， 我们将（1）确定E2是否足以上调MnPO中的GPR 37，（2）确定A2 AR和 GPR 37在MnPO的睡眠活性细胞中形成相互作用，和（3）确定GPR 37是否是必需的， 导致E2引起的睡眠-觉醒状态的变化。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， 最终我们如何更好地治疗大部分人的失眠症。