Crosstalk of hypocretin and MCH in feeding regulation

下丘脑分泌素和 MCH 在摄食调节中的串扰

• 批准号: 7590483
• 负责人: XIAO-BING GAO
• 金额: $ 31.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590483
• 关键词: Action Potentials; Address; Amino Acids; Animals; Area; Behavior; Behavioral; Biological; Brain; Brain region; Calcium; Cardiovascular Diseases; Complement; Decision Making; Disease; Electrons; Emotions; Equilibrium; Food Intake Regulation; Gel; Generations; Genetic Transcription; Goals; Homeostasis; Hypothalamic structure; Image; Instinct; Lateral; Lead; Logic; Mammals; Methods; Microscopic; Molecular; Mus; Nerve Fibers; Neurons; Neuropeptides; Obesity; Obesity associated disease; Output; Peptides; Physiological; Play; Rattus; Regulation; Research; Risk Factors; Role; Shapes; Signal Transduction; Sleep; Slice; Source; Structure; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic Transmission; System; Testing; Transgenic Mice; depressed; digital; energy balance; feeding; hypocretin; melanin-concentrating hormone; mouse model; preprohormone; prevent

DESCRIPTION (provided by applicant): The lateral hypothalamus (LH) serves as a central hub, integrating a wide range of inputs from various brain regions and projecting neuropeptide-containing nerve fibers all over the brain. The LH has long been recognized as a feeding center. The regulation of food intake plays an important role in energy-balance homeostasis. Unbalanced energy accumulation leads to obesity, which has been recognized as a risk factor in many diseases and disorders. Despite the overwhelming importance of this structure, it remains poorly understood how the LH integrates different sources of signals and exerts its functions via hypocretin/orexin and melanin-concentrating hormone (MCH) systems in the LH. Both hypocretin and MCH have been implicated as orexigenic: Previous studies have suggested that hypocretin/orexin is an excitatory peptide while MCH is inhibitory. Given their opposite actions at the cellular level, it is intriguing to understand how these two systems interact dynamically to determine the final output and hence to determine the behavioral states of animals. The long-term goal of this project is to understand how these neurons interact with each other to form specific functional organizations for regulating different behaviors. In this proposal, we will use molecular biological, electrophysiological, immunocytochemical and electron microscopic methods as well as digital calcium imaging to address the interaction or hypocretin/orexin and MCH at the cellular level in both normal animals and transgenic mouse models. The chief hypothesis is that the excitatory role of hypocretin/orexin in the LH may serve as the engine to propel this brain region, while the inhibitory modulation induced by MCH may substantially adjust the tone of neuronal activity in the LH area and thus may shape the decision making of the LH and the arcuate nucleus. The following hypotheses will be examined: 1. Hypocretin/orexin serves as a major excitatory force to both hypocretin/orexin and MCH systems. 2. MCH modulates excitability in both hypocretin/orexin and MCH containing neurons. 3. Crosstalk of hypocretin and MCH underlies appropriate regulation of the melanocortin system in the arcuate nucleus. This proposal will begin to bridge the gap between studies at the molecular level and the systemic level on the role of the LH in regulation of food intake. We hope that results generated from this proposal will complement to the current framework in understanding energy homeostasis in mammals. Ultimately, we hope that our research will benefit those suffering from obesity and obesity-related diseases.

描述（由申请人提供）：外侧下丘脑（LH）充当中枢，整合来自不同大脑区域的广泛输入，并将含有神经肽的神经纤维投射到整个大脑。长期以来，LH 一直被认为是一个喂养中心。食物摄入的调节在能量平衡稳态中起着重要作用。不平衡的能量积累会导致肥胖，这已被认为是许多疾病和病症的危险因素。尽管这种结构极其重要，但人们对 LH 如何整合不同来源的信号并通过 LH 中的下丘脑分泌素/食欲素和黑色素浓缩激素 (MCH) 系统发挥其功能仍知之甚少。下丘脑分泌素和 MCH 都具有促进食欲的作用：之前的研究表明，下丘脑分泌素/食欲素是一种兴奋性肽，而 MCH 是抑制性肽。鉴于它们在细胞水平上的相反作用，了解这两个系统如何动态相互作用以确定最终输出并从而确定动物的行为状态是很有趣的。该项目的长期目标是了解这些神经元如何相互作用，形成特定的功能组织来调节不同的行为。在本提案中，我们将使用分子生物学、电生理学、免疫细胞化学和电子显微镜方法以及数字钙成像来解决正常动物和转基因小鼠模型中下丘脑分泌素/食欲素和 MCH 在细胞水平上的相互作用。主要假设是，LH 中下丘脑分泌素/食欲素的兴奋作用可能作为推动该大脑区域的引擎，而 MCH 诱导的抑制性调节可能会显着调整 LH 区域神经元活动的基调，从而可能塑造LH 和弓状核的决策。将检验以下假设： 1. 下丘脑分泌素/食欲素是下丘脑分泌素/食欲素和 MCH 系统的主要兴奋力。 2. MCH 调节下丘脑分泌素/食欲素和含有 MCH 的神经元的兴奋性。 3.下丘脑分泌素和MCH的串扰是弓状核中黑皮质素系统适当调节的基础。该提案将开始弥合关于 LH 在食物摄入调节中的作用的分子水平和系统水平研究之间的差距。我们希望该提案产生的结果将补充当前理解哺乳动物能量稳态的框架。最终，我们希望我们的研究能够造福那些患有肥胖症和肥胖相关疾病的人。