Crosstalk of hypocretin and MCH in feeding regulation

描述(申请人提供)：外侧下丘脑(LH)作为中央中枢，整合来自不同大脑区域的广泛输入，并在大脑各处投射含有神经肽的神经纤维。长期以来，黄体生成素一直被认为是一个喂养中心。食物摄入量的调节在能量平衡的动态平衡中起着重要作用。不平衡的能量积累导致肥胖，肥胖已被认为是许多疾病和障碍的危险因素。尽管这种结构具有压倒性的重要性，但人们仍然不清楚促黄体生成素是如何整合不同的信号源，并通过促黄体生成素/增食欲素和黑色素浓缩激素(MCH)系统发挥其功能的。下丘脑泌素和MCH都与食欲增加有关：以前的研究表明，下丘脑素/增食欲素是一种兴奋性多肽，而MCH是抑制性的。考虑到它们在细胞水平上的相反作用，理解这两个系统如何动态地相互作用来确定最终输出，从而确定动物的行为状态是很有趣的。这个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。在这个方案中，我们将使用分子生物学、电生理、免疫细胞化学和电子显微镜方法以及数字钙成像技术在细胞水平上研究正常动物和转基因小鼠模型中下丘脑/增食欲素和MCH的相互作用。主要的假说是，促黄体生成素/增食欲素的兴奋作用可能是推动这一脑区的引擎，而MCH诱导的抑制性调节可能实质上调节了促黄体生成素区神经元活动的音调，从而可能塑造促黄体生成素和弓状核的决策。我们将检验以下假设：1.下丘脑素/食欲素对下丘脑素/食欲素和MCH系统都是一种主要的兴奋力。2.MCH对下丘脑促性腺激素/食欲素神经元和含MCH神经元的兴奋性均有调节作用。3.在弓状核中，黑素皮质素系统的适当调节是下丘脑下丘脑与MCH相互作用的基础。这一建议将开始弥合分子水平和系统水平上关于黄体生成素在调节食物摄入中的作用的研究之间的差距。我们希望，这项提议产生的结果将补充目前的框架，了解哺乳动物的能量稳态。最终，我们希望我们的研究将造福于那些患有肥胖症和肥胖相关疾病的人。

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.