Crosstalk of hypocretin and MCH in feeding regulation

描述（由申请人提供）：外侧下丘脑（LH）作为一个中心枢纽，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。LH一直被认为是一个喂养中心。食物摄入的调节在人体能量平衡中起着重要的作用。能量积累不平衡导致肥胖，这已被认为是许多疾病和失调的危险因素。尽管这种结构非常重要，但人们对LH如何整合不同的信号来源并通过LH中的下丘脑分泌素/食欲素和黑色素浓缩激素（MCH）系统发挥其功能仍然知之甚少。下丘脑泌素和MCH都与增氧有关：先前的研究表明，下丘脑泌素/增氧素是一种兴奋性肽，而MCH是抑制性肽。考虑到它们在细胞水平上的相反作用，了解这两个系统如何动态地相互作用以决定最终输出，从而决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，我们将使用分子生物学、电生理学、免疫细胞化学和电镜以及数字钙成像等方法，在正常动物和转基因小鼠模型中研究下丘脑泌素/食欲素与MCH在细胞水平上的相互作用。主要的假设是，下丘脑分泌素/食欲素在LH中的兴奋作用可能是推动该脑区域的引擎，而MCH诱导的抑制调节可能会实质性地调节LH区域的神经元活动的基调，从而可能影响LH和弓状核的决策。以下假设将被检验：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的串扰是弓形核中黑素皮质素系统适当调节的基础。这一建议将开始弥合在分子水平和系统水平上对LH在调节食物摄入中的作用的研究之间的差距。我们希望从这一建议中产生的结果将补充目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将使那些患有肥胖和肥胖相关疾病的人受益。

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.