Role of the Central Amygdala in Ghrelin-Mediated Reward-Based Eating Behavior

描述(申请人提供)：Ghrelin是一种多肽激素，主要由排列在胃和肠道内的内分泌细胞分泌。Ghrelin最重要的作用包括刺激食物摄入、抑制能量消耗和促进肥胖。我们最近已经证明，Ghrelin调节了饮食的愉悦方面，特别是，提高了高脂肪食物的回报价值，并增加了获得美味、脂肪食物的动力。尽管有大量文献描述了Ghrelin在调节食物摄入量中的作用，但对Ghrelin在饮食享乐方面的作用机制知之甚少。在目前的资助中，我们建议更好地描述Ghrelin在基于奖励的进食行为中介导作用的神经元回路。特别是，我们将测试这一假设，即中央杏仁核(CEA)产生促肾上腺皮质激素释放因子(CRF)的神经元有助于Ghrelin在基于奖励的进食中的作用。我们将把这一假设作为三个独立但又相互关联的目标的一部分进行检验。我们将确定注射Ghrelin或限制热量自然增加的Ghrelin是否会激活CA CRF神经元。我们将确定Ghrelin提高高脂肪食物回报价值的能力是否需要CRF信号。此外，我们还将确定表达神经肽增食欲素的神经元是否介导了Ghrelin对CEA CRF神经元的影响。在这些研究中，我们将使用一种新开发的转基因小鼠品系，在该品系中，绿色荧光蛋白标记CRF神经元在大脑中的位置。这些小鼠将与其他小鼠模型一起使用，包括那些CRF或增食欲素缺失的小鼠，以阐明Ghrelin参与的感兴趣的神经元回路。我们还将使用药物管理的药物，包括Ghrelin、CRF和增食欲素受体的拮抗剂，以进一步表征这些途径。食物奖励行为将使用条件位置偏好行为任务来评估，该任务是我们为在小鼠模型中进行食物奖励行为的特定研究而改编和开发的。我们相信，这些实验将对与饮食相关的行为产生重要的见解，并最终可能导致肥胖的新疗法。这项研究将与Mario Perello合作进行，作为NIH补助金1R01DA024680-01、6-1-08至4-30-13的延伸。他们将在UTSW医学中心和位于阿根廷拉普拉塔市的多学科细胞生物学研究所(IMBICE-CONICET/PBA)的神经生理学实验室进行。它们旨在扩大和加强齐格曼博士和佩雷洛博士的研究兴趣，并将有助于建立佩雷罗博士和IMBICE的研究和研究能力。

DESCRIPTION (provided by applicant): Ghrelin is a peptide hormone secreted primarily by endocrine cells that line the stomach and intestine. The most important actions of ghrelin include stimulation of food intake, inhibition of energy expenditure and promotion of adiposity. We have recently shown that ghrelin mediates pleasurable aspects of eating, and in particular, enhances the rewarding value of foods high in fat and increases the motivation to obtain palatable, fatty foods. Despite a substantial literature characterizing ghrelin action in the regulation of the food intake, relatively little is known about the mechanisms responsible for ghrelin's action on hedonic aspects of eating. In the current grant, we propose to better characterize the neuronal circuits mediating ghrelin's action on reward- based eating behaviors. In particular, we will test the hypothesis that corticotrophin releasing factor (CRF)- producing neurons of the central amygdala (CeA) contribute to ghrelin's actions on reward-based eating. We will test this hypothesis as part of three independent, yet related aims. We will determine if rises in ghrelin that occur upon ghrelin injection or naturally upon caloric restriction activate CA CRF neurons. We will determine if ghrelin's ability to enhance the rewarding value of fatty food requires CRF signaling. Also, we will determine if neurons that express the neuropetide orexin mediate ghrelin's effects on CeA CRF neurons. For these studies, we will use a newly developed transgenic mouse line in which green fluorescent protein marks the location of CRF neurons within the brain. These mice will be used together with other mouse models, including those in which CRF or orexin are missing, to elucidate the ghrelin-engaged neuronal circuits of interest. We will also use pharmacologically administered agents, including antagonists to receptors for ghrelin, CRF and orexin, in order to further characterize these pathways. Food reward behaviors will be assessed using a conditioned place preference behavioral task that we have adapted and developed for the specific study of food reward behavior in mouse models. We believe these experiments will yield important insights about behaviors related to eating, and eventually may lead to new therapies for obesity. This research will be performed in collaboration with Mario Perello, as an extension of NIH grant 1R01DA024680-01, 6-1-08 to 4-30- 13. They will be performed both at UTSW Medical Center and in the laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (IMBICE-CONICET/PBA), located in the city of La Plata, Argentina. They are designed to extend and enhance the research interests of both Drs. Zigman and Perello, and will help build the research and research capabilities of Dr. Perello and the IMBICE.