Melanin-Concentrating Hormone: Ancestral Role in Feeding & Sleep Regulation

黑色素浓缩激素：在喂养中的祖先作用

• 批准号: 8116317
• 负责人: Philippe Mourrain
• 金额: $ 44.7万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116317
• 关键词: Adult; Animal Model; Anxiety; Behavior; Behavioral; Behavioral Model; Biological Assay; Body Weight; Brain; Bulimia; CASP6 gene; Caenorhabditis elegans; Calcium; Cells; Child; Complex; Consumption; Devices; Drosophila genome; Drosophila genus; Eating; Economic Burden; Exploratory Behavior; Fasting; Feeding behaviors; Fishes; Food; Food Intake Regulation; General Population; Generations; Genes; Genetic; Genetic Models; Genomics; Growth; Homeostasis; Human; Hypothalamic structure; Image; Individual; Investigation; Knowledge; Laboratories; Light; Link; Mammals; Medicine; Metabolic; Modeling; Molecular Biology; Monitor; Morbidity - disease rate; Neurons; Neurosciences; Neurotransmitters; Obesity; Orthologous Gene; Overweight; Pathway interactions; Patients; Pattern; Peptides; Phenotype; Population; Regulation; Research; Rewards; Role; Salmon; Skin; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Structure; Synteny; System; Therapeutic; Time; Vertebrates; Wakefulness; World Health Organization; Zebrafish; behavior influence; calcium indicator; cost; energy balance; feeding; food consumption; insight; melanin-concentrating hormone; mortality; neural circuit; novel; prevent; promoter; research study; sleep regulation; teleost; teleost fish

DESCRIPTION (provided by applicant): In mammals, melanin-concentrating hormone (hMCH) is a key regulator of feeding behavior, energy homeostasis, and sleep. MCH was first identified in salmon in 1983 as a peptide (sMCH) that induced skin lightening. Despite numerous studies in different fish species, however, no clear effect on feeding was shown for sMCH. Last year, we found, in zebrafish and four other teleost fishes, two MCH genes: mch1 and mch2. Whereas mch1 perfectly resembles salmon sMCH, the mch2 gene and MCH2 peptide share genomic structure, synteny, and high homology with mammalian hMCH. Zebrafish MCH2, like mammalian hMCH, is expressed in a distinct population of hypothalamic neurons and is up-regulated upon fasting, suggesting a conservation of MCH2/hMCH regulation and function across vertebrates. However, while mammalian hypothalamus harbors thousands of MCH cells, zebrafish larval and adult brains contain more compact networks of 50 and 150 MCH neurons respectively. As MCH is not found in non-vertebrate models like Drosophila and C. elegans, the discovery of mch2 offers us a unique opportunity to explore MCH function in a simple amenable genetic model, the zebrafish. We propose in a first specific aim to characterize the MCH2 neurocircuit and to relate its activity to behavioral states. To do so, we will (i) analyze MCH2 neurons identity and fast neurotransmitter phenotype, (ii) study their arborization and connections, and (iii) precisely monitor their pattern of activity with a calcium-imaging assay in different behavioral conditions. As feeding and sleep behaviors are exclusive in their timing, it is critical to follow the firing patterns of the totality of the MCH neurons to distinguish potential feeding- related and sleep-on subpopulations. In the second specific aim, we will precisely investigate the behavioral influence(s) of MCH2. To do so we will use both a classic genetic approach and state-of-the-art optogenetic manipulation of the mch2 circuit. We will first (i) study how the MCH2 peptide and circuit regulate food intake, growth, and body weight. Further, (ii) using a novel multi-behavioral tracking system we will analyze a large spectrum of behaviors associated with energy unbalance, food search and consumption, such as exploration, anxiety, aggressiveness, bulimic like behaviors versus slow eating, and the hedonistic influence of food. Finally, (iii) we will investigate the ancestral role for MCH in sleep- wake regulation by analyzing the sleep architecture during normal sleep, induced sleep, and after sleep deprivation. In conclusion, zebrafish offers a unique situation as a transparent vertebrate to perform non-invasive observation and manipulation of small but complete neuronal networks. It will bring major insight to our understanding of how a same hypothalamic circuit times and regulates behaviors so distinct in their timing and their functions. PUBLIC HEALTH RELEVANCE: In the zebrafish species, we have recently identified the equivalent of a major mammalian feeding and sleep hypothalamic actor called Melanin-Concentrating Hormone (MCH). The zebrafish will help us understand how MCH can regulate food consumption, energy balance, and sleep, and thus how MCH could be manipulated to prevent feeding or sleep disorders in the general public.

描述（由申请人提供）：在哺乳动物中，黑色素浓缩激素（hMCH）是摄食行为、能量稳态和睡眠的关键调节剂。 1983 年，MCH 首次在鲑鱼中被发现，是一种能够诱导皮肤美白的肽 (sMCH)。然而，尽管对不同鱼类进行了大量研究，但未发现 sMCH 对摄食有明显影响。去年，我们在斑马鱼和其他四种硬骨鱼中发现了两个 MCH 基因：mch1 和 mch2。 mch1 与鲑鱼 sMCH 非常相似，而 mch2 基因和 MCH2 肽与哺乳动物 hMCH 具有基因组结构、同线性和高度同源性。斑马鱼 MCH2 与哺乳动物 hMCH 一样，在不同的下丘脑神经元群体中表达，并且在禁食时上调，表明脊椎动物中 MCH2/hMCH 调节和功能的保守性。然而，哺乳动物的下丘脑含有数千个 MCH 细胞，而斑马鱼幼虫和成体的大脑则含有更紧凑的网络，分别由 50 个和 150 个 MCH 神经元组成。由于在果蝇和线虫等非脊椎动物模型中没有发现 MCH，因此 mch2 的发现为我们提供了一个独特的机会，可以在简单的遗传模型（斑马鱼）中探索 MCH 功能。我们提出的第一个具体目标是表征 MCH2 神经回路并将其活动与行为状态联系起来。为此，我们将 (i) 分析 MCH2 神经元的身份和快速神经递质表型，(ii) 研究它们的树枝化和连接，以及 (iii) 在不同行为条件下通过钙成像测定精确监测它们的活动模式。由于进食和睡眠行为在时间上是唯一的，因此跟踪整个 MCH 神经元的放电模式以区分潜在的进食相关亚群和睡眠亚群至关重要。在第二个具体目标中，我们将精确研究MCH2的行为影响。为此，我们将使用经典的遗传方法和最先进的 mch2 电路光遗传学操作。我们将首先 (i) 研究 MCH2 肽和电路如何调节食物摄入、生长和体重。此外，（ii）使用新颖的多行为跟踪系统，我们将分析与能量失衡、食物搜索和消费相关的大量行为，例如探索、焦虑、攻击性、贪食性行为与缓慢进食以及享乐主义影响食物。最后，(iii)我们将通过分析正常睡眠、诱导睡眠和睡眠剥夺后的睡眠结构来研究 MCH 在睡眠-觉醒调节中的祖先作用。总之，斑马鱼作为透明脊椎动物提供了独特的情况，可以对小型但完整的神经元网络进行非侵入性观察和操作。它将为我们理解相同的下丘脑回路如何计时和调节在时间和功能上如此不同的行为带来重要的见解。 公共健康相关性：在斑马鱼物种中，我们最近发现了一种相当于哺乳动物进食和睡眠下丘脑作用的物质，称为黑色素浓缩激素（MCH）。斑马鱼将帮助我们了解 MCH 如何调节食物消耗、能量平衡和睡眠，以及如何操纵 MCH 来预防公众的进食或睡眠障碍。