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: 10430217
• 负责人: Bethany Genelle Beekly
• 金额: $ 3.53万
• 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 2023-04-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430217
• 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.

项目总结/摘要 睡眠减少和碎片化与人类不育有关。近五分之一的美国夫妇 与不孕不育作斗争，并且随着环境中睡眠和昼夜节律干扰因素的增加， 青春期发育和生育能力不足的情况可能会继续增加。在下丘脑的顶端- 垂体-性腺（HPG）轴是生殖生理的中心，是促性腺激素释放激素（GnRH） 神经元GnRH的间歇性释放驱动黄体生成素（LH）和卵泡刺激素（FSH）的脉冲式分泌。 一种激素（FSH），它反过来作用于性腺，促进配子成熟和性行为的产生 类固醇.青春期开始和排卵都需要一次高频LH脉冲。值得注意的是， 在LH脉冲频率，沉淀青春期发生在睡眠中，而在成人中，LH脉冲频率是 睡眠时减少。然而，睡眠和生殖之间的联系机制代表了一个重大的差距， 文学作品我们假设下丘脑黑色素浓集激素（MCH）神经元在时间上 整合睡眠和生殖系统的活动。MCH神经元在睡眠期间活跃， 对生殖控制领域的预测。此外，将MCH施用于内侧视前区 （mPOA），其中GnRH神经元丰富，能够增加和抑制LH脉动。一 对此的可能解释是MCH神经元及其靶点比以前更加异质 思想，尤其是两性之间。此外，睡眠模式的变化和对性类固醇的反应 整个雌性发情周期的反馈在各研究中没有以一致的方式进行解释。我们 目的明确小鼠脑内MCH神经元的投射靶点和共表达肽， 不同的亚群和其中由性别或雌激素环境定义的任何差异。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细胞的影响， EEG和血LH浓度分别作为睡眠和HPG轴激活的输出。这些研究将 在不同雌激素环境下的雄性和雌性小鼠中进行，并对各组结果进行比较。最后， 使用相同的实验组，我们将测量LH分泌后，操纵MCH神经元 亚群在睡眠和清醒时都是如此这种三管齐下的方法将使我们能够解决 MCH对睡眠和生殖轴的影响，以及重要的是，这些作用如何相关的新问题。 我们关注MCH神经元亚群、性别差异以及性类固醇环境对两者的影响， 睡眠和HPG轴将定义MCH神经元的转录和功能异质性， 有助于睡眠和HPG轴如何相互作用以导致正常青春期发育的工作模型 和繁殖。