Role of Melanin-concentrating Hormone in the Integration of Sleep and Reproductive Physiology

黑色素浓缩激素在睡眠和生殖生理整合中的作用

• 批准号: 10252769
• 负责人: Bethany Genelle Beekly
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252769
• 关键词: Adult; American; Anatomy; Area; Attention; Bilateral; Blood; Brain; Brain region; Cannulas; Chronic; Circadian Rhythms; Clozapine; Couples; Cytology; Data; Development; Electrodes; Electroencephalography; Environmental Exposure; Estradiol; Estrogens; Estrous Cycle; Estrus; Exposure to; Feedback; Female; Fertility; Follicle Stimulating Hormone; Frequencies; Gene Expression Profile; Genetic Transcription; Germ Cells; Gonadal Steroid Hormones; Gonadal structure; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Health; Heterogeneity; Hormone secretion; Human; Hypothalamic structure; Immunohistochemistry; Implant; In Situ Hybridization; Inadequate Sleep Hygiene; Individual; Infertility; Intervention; KISS1 gene; Knock-out; Knockout Mice; Lateral; Length; Link; Literature; Litter Size; Longevity; Luteinizing Hormone; Maps; Measures; Medial; Modeling; Monitor; Mus; Neurokinin B; Neuromedin K Receptor; Neurons; Neurosciences; Output; Ovulation; Oxides; Peptides; Physiologic pulse; Polysomnography; Pregnancy; Preoptic Areas; Production; Proestrus; Puberty; Public Health; Rattus; Reproduction; Reproductive Health; Reproductive Physiology; Reproductive system; Rodent; Role; Sex Differences; Sleep; Sleep Fragmentations; Structure of nucleus infundibularis hypothalami; System; Technology; Testing; Time; Tracer; Vagina; Viral; Work; awake; base; circadian; designer receptors exclusively activated by designer drugs; drinking water; effective intervention; effective therapy; experimental group; improved; male; melanin-concentrating hormone; mouse model; neural circuit; novel; pituitary gonadal axis; pup; reproductive; reproductive axis; reproductive function; reproductive success; response; sex; shift work; sleep pattern; sleep physiology

Project Summary/Abstract Reduced and fragmented sleep is associated with infertility in humans. Nearly one fifth of American couples struggle with infertility and, with increasing environmental exposure to sleep and circadian disruptors, deficiencies in pubertal development and fertility will likely continue to increase. At the apex of the hypothalamo- pituitary-gonadal (HPG) axis, central to reproductive physiology, are gonadotropin-releasing hormone (GnRH) neurons. Episodic release of GnRH drives pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn act on the gonads to promote maturation of gametes and production of sex steroids. A bout of high-frequency LH pulses is required for both pubertal onset and ovulation. Notably, the rise in LH pulse frequency that precipitates puberty occurs during sleep, while in adults, LH pulse frequency is reduced during sleep. However, the mechanisms linking sleep and reproduction represent a significant gap in the literature. We hypothesize that hypothalamic melanin-concentrating hormone (MCH) neurons temporally integrate the activity of the sleep and reproductive systems. MCH neurons are active during sleep and have projections to areas of reproductive control. Furthermore, administration of MCH to the medial preoptic area (mPOA), where GnRH neurons are abundant, is capable of both increasing and suppressing LH pulsatility. One possible explanation for this is that MCH neurons and their targets are more heterogeneous than previously thought, particularly between the sexes. Additionally, variability of sleep patterns and response to sex steroid feedback throughout the female estrous cycle are not accounted for in a consistent manner across studies. We aim to define the projection targets and co-expressed peptides of MCH neurons in the mouse brain to reveal distinct subpopulations and any differences therein defined by sex or the estrogen milieu. Further, we aim to systematically determine the effect of chemogenetically manipulating each of these subpopulations on cortical EEG and blood LH concentration as outputs of sleep and HPG axis activation, respectively. These studies will be performed in male and female mice in varied estrogen milieu and the results compared across groups. Finally, using the same experimental groups, we will measure LH secretion following manipulation of MCH neuronal subpopulations in both sleep and waking. This three-pronged approach will enable us to untangle the effects of MCH on both sleep and the reproductive axis and, importantly, the novel question of how these roles are related. Our attention to MCH neuronal subpopulations, sex differences, and the effects of the sex steroid milieu on both sleep and the HPG axis will define the transcriptional and functional heterogeneity of MCH neurons and contribute to a working model of how sleep and the HPG axis interact to result in normal pubertal development and reproduction.

项目摘要/摘要 睡眠减少和零碎与人类不孕不育有关。近五分之一的美国夫妇 与不孕不育作斗争，以及越来越多的环境暴露在睡眠和昼夜节律干扰物中， 青春期发育和生育方面的缺陷可能会继续增加。在下丘脑的顶端- 垂体-性腺轴(HPG)是促性腺激素释放激素(GnRH)，是生殖生理的中枢。 神经元。间歇性释放促性腺激素释放激素促进促黄体生成素和卵泡刺激素的搏动性分泌 激素(FSH)，它反过来作用于性腺，促进配子成熟和性生产 类固醇。青春期开始和排卵都需要一轮高频促黄体生成素脉冲。值得注意的是， 催产素的脉冲频率在睡眠中发生，而在成年人中，促黄体生成素的脉冲频率是 在睡眠中减少。然而，将睡眠和生殖联系起来的机制在 文学作品。我们假设下丘脑黑色素浓缩激素(MCH)神经元是临时性的 整合睡眠和生殖系统的活动。MCH神经元在睡眠期间活跃，并具有 对生殖控制领域的预测。此外，在内侧视前区注射MCH 促性腺激素释放激素(GnRH)神经元丰富的mPOA既有增强和抑制LH脉动性的作用。一 对此的可能解释是，MCH神经元和它们的靶点比以前更加不同 思想，尤其是在两性之间。此外，睡眠模式的变异性和对性激素的反应 在整个雌性发情周期中，反馈并不是在研究中以一致的方式解释的。我们 目的确定小鼠脑内MCH神经元的投射靶点和共表达的多肽，以揭示其在脑内的分布。 由性别或雌激素环境定义的不同的亚群和其中的任何差异。此外，我们的目标是 系统地确定化学遗传学操作这些亚群中的每一个对皮质的影响 脑电和血中黄体生成素浓度分别作为睡眠和HPG轴激活的输出。这些研究将 在不同的雌激素环境下对雄性和雌性小鼠进行实验，并对结果进行组间比较。最后， 使用相同的试验组，我们将测量操纵MCH神经元后的促黄体生成素分泌 睡眠和清醒状态下的亚群。这种三管齐下的方法将使我们能够理清 MCH对睡眠和生殖轴都有影响，重要的是，这两个角色是如何联系在一起的新问题。 我们对MCH神经元亚群、性别差异以及性激素环境对两者的影响的关注 睡眠和HPG轴将定义MCH神经元的转录和功能异质性和 为睡眠和HPG轴如何相互作用导致正常青春期发育的工作模型做出贡献 和繁衍。