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.

项目概要 研究表明，女性睡眠困难较多，且更容易被诊断为失眠症 与男性相比。在荷尔蒙波动时期，女性更容易出现睡眠障碍， 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 对于患有睡眠障碍的女性。大脑中有两个主要的睡眠中枢，均位于 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，表明雌激素通过 MnPO 发挥作用 调节睡眠-觉醒状态。人们认为 MnPO 通过抑制大脑中促醒神经元来促进睡眠。 脑。研究发现，将雌二醇 (E2) 输注到 MnPO 中会增加觉醒并减少睡眠。 然而，E2 扰乱睡眠的机制在很大程度上尚不清楚。 清醒时，腺苷在大脑中积聚并增加睡眠压力，导致疲劳。这 A1 和 A2A 受体（A1R 和 A2AR）在 MnPO 中表达，在调节 腺苷对大脑的影响。已发现将 A1R 激动剂注入 MnPO 中可增加唤醒效果 并减少大鼠的睡眠，而输注 A2AR 激动剂被发现可以增加睡眠并减少睡眠 唤醒。假设 E2 会影响 MnPO 中的抑制/兴奋性腺苷能平衡，因为， 当 E2 存在时，A2AR 激动剂的促进睡眠作用被阻断。 E2 的一个潜在目标是 G 蛋白偶联受体 37 (GPR37)，已被证明可抑制 A2AR 表面表达和功能 纹状体。该项目将测试 E2 减少 NREM 睡眠并增加觉醒的假设 通过 GPR37 调制减弱 A2AR 信号传导。为了检查 GPR37 在 MnPO 中的影响， 我们将 (1) 确定 E2 是否足以上调 MnPO 中的 GPR37，(2) 确定 A2AR 和 GPR37 在 MnPO 的睡眠活跃细胞中形成相互作用，并且 (3) 确定 GPR37 是否是必要的 引起 E2 引起的睡眠-觉醒状态变化。了解雌二醇在扰乱睡眠中的作用 清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 最终我们如何才能更好地治疗大部分人口的失眠症。