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因子。MCH于1983年首次在鲑鱼中被鉴定为诱导皮肤美白的肽（sMCH）。然而，尽管在不同鱼类中进行了大量研究，但sMCH对摄食没有明显影响。去年，我们在斑马鱼和其他四种硬骨鱼中发现了两种MCH基因：mch 1和mch 2。mch 1与鲑鱼sMCH非常相似，而mch 2基因和MCH 2肽与哺乳动物hMCH共享基因组结构、同线性和高度同源性。与哺乳动物hMCH一样，斑马鱼MCH 2在下丘脑神经元的不同群体中表达，并且在禁食时上调，这表明在脊椎动物中MCH 2/hMCH调节和功能是保守的。然而，虽然哺乳动物下丘脑含有数千个MCH细胞，但斑马鱼幼虫和成年大脑分别含有50和150个MCH神经元的更紧凑的网络。由于MCH在非脊椎动物模型如果蝇和C. mch 2的发现为我们提供了一个独特的机会，探索MCH功能在一个简单的顺从的遗传模型，斑马鱼。我们建议在第一个具体的目标，以表征MCH 2神经回路，并将其活动的行为状态。为此，我们将（i）分析MCH 2神经元的身份和快速神经递质表型，（ii）研究它们的分支和连接，（iii）在不同的行为条件下用钙成像检测精确监测它们的活动模式。由于进食和睡眠行为在其时间上是排他性的，因此遵循MCH神经元整体的放电模式以区分潜在的进食相关亚群和睡眠亚群是至关重要的。在第二个具体目标中，我们将精确地研究MCH 2的行为影响。为此，我们将使用经典的遗传学方法和最先进的mch 2电路光遗传学操作。我们将首先（i）研究MCH 2肽和回路如何调节食物摄入，生长和体重。此外，（ii）使用一种新的多行为跟踪系统，我们将分析与能量不平衡，食物搜索和消费，如探索，焦虑，侵略性，暴食样行为与慢吃，以及食物的享乐主义影响相关的行为的大范围。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，斑马鱼提供了一个独特的情况下，作为一个透明的脊椎动物进行非侵入性的观察和操作的小，但完整的神经元网络。它将为我们理解同一个下丘脑回路如何计时和调节行为带来重大的洞察力，这些行为在时间和功能上如此不同。 公共卫生相关性：在斑马鱼物种中，我们最近发现了一种相当于哺乳动物摄食和睡眠下丘脑的主要作用因子，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，从而了解如何操纵MCH来防止公众的进食或睡眠障碍。