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: 8258704
• 负责人: Philippe Mourrain
• 金额: $ 34.37万
• 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/8258704
• 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; optogenetics; prevent; promoter; public health relevance; 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）是喂养行为，能量稳态和睡眠的关键调节剂。 MCH于1983年首次在鲑鱼中被鉴定为诱导皮肤降低的肽（SMCH）。尽管在不同的鱼类中进行了许多研究，但对于SMCH尚未显示出对喂养的明显影响。去年，我们在斑马鱼和另外四个Teleost Fishes中发现了两个MCH基因：MCH1和MCH2。而MCH1非常类似于鲑鱼SMCH，而MCH2基因和MCH2肽具有基因组结构，同步和与哺乳动物HMCH的高同源性。斑马鱼MCH2与哺乳动物HMCH一样，在下丘脑神经元的不同种群中表达，并且在禁食时被上调，这表明对MCH2/HMCH的调节和跨脊椎动物的功能进行了保存。然而，尽管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包含50和150 MCH神经元的更紧凑的网络。由于MCH在果蝇和秀丽隐杆线虫等非魔力模型中找不到，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。我们提出了第一个特定的目的，以表征MCH2神经电路并将其活性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）研究其树博化和连接，以及（iii）在不同行为条件下使用钙成像测定法准确地监测其活性模式。由于喂养和睡眠行为在其时机上是独家的，因此遵循MCH神经元的整体发射模式以区分潜在的喂养相关和睡眠亚群，这一点至关重要。在第二个特定目标中，我们将精确研究MCH2的行为影响。为此，我们将同时使用经典的遗传方法和MCH2电路的最先进的光遗传操作。我们将首先研究MCH2肽和电路如何调节食物摄入，生长和体重。此外，（ii）使用新型的多行为跟踪系统，我们将分析与能源不平衡，食物搜索和消费相关的大量行为，例如探索，焦虑，侵略性，像行为相似的行为与缓慢的饮食以及食物的享乐主义影响。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在睡眠唤醒调节中的祖先作用。总之，斑马鱼提供了一种独特的情况，作为一种透明的脊椎动物，可以对小而完整的神经元网络进行非侵入性观察和操纵。这将使我们对同一个下丘脑电路时时间的理解给我们带来重大的见解，并调节其时间和功能如此不同的行为。 公共卫生相关性：在斑马鱼物种中，我们最近确定了相当于主要的哺乳动物喂养和睡眠下丘脑演员称为黑色素浓缩激素（MCH）。斑马鱼将帮助我们了解MCH如何调节食品消耗，能量平衡和睡眠，从而如何操纵MCH以防止公众的喂养或睡眠障碍。