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）作为中枢，整合来自不同脑区的广泛输入，并将含神经肽的神经纤维投射到整个大脑。LH长期以来被认为是一个喂养中心。食物摄入的调节在能量平衡的稳态中起着重要的作用。不平衡的能量积累导致肥胖，这已被认为是许多疾病和障碍的危险因素。尽管这种结构的压倒性的重要性，它仍然知之甚少LH整合不同来源的信号，并通过LH下丘脑泌素/食欲素和黑色素浓缩激素（MCH）系统发挥其功能。下丘脑泌素和MCH都与食欲有关：以前的研究表明，下丘脑泌素/食欲素是一种兴奋性肽，而MCH是抑制性的。考虑到它们在细胞水平上的相反行为，理解这两个系统如何动态地相互作用以确定最终输出，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。在本研究中，我们将利用分子生物学、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技术，在正常动物和转基因小鼠模型中，在细胞水平上研究下丘脑分泌素/食欲素和MCH的相互作用。主要假设是下丘脑泌素/食欲素在LH中的兴奋作用可能是推动该脑区的引擎，而MCH诱导的抑制性调节可能实质上调节LH区神经元活动的音调，从而可能塑造LH和弓状核的决策。以下假设将被检验：1.下丘脑泌素/食欲素作为下丘脑泌素/食欲素和MCH系统的主要兴奋力。2. MCH调节下丘脑泌素/食欲素和MCH含有神经元的兴奋性。3.下丘脑泌素和MCH的相互作用是弓状核黑皮质素系统适当调节的基础。这一建议将开始弥合LH在调节食物摄入方面作用的分子水平和系统水平研究之间的差距。我们希望从这个提议中产生的结果将补充目前的框架，以了解哺乳动物的能量稳态。最终，我们希望我们的研究将有利于那些患有肥胖和肥胖相关疾病的人。