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

中央杏仁核在胃饥饿素介导的基于奖励的饮食行为中的作用

基本信息

批准号：
8479265
负责人：
Jeffrey M Zigman
金额：
$ 5.4万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-05 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8479265
关键词：
Acute Amygdaloid structure Applications Grants Argentina Behavior Behavior Control Behavioral Body Weight Brain Brain region Caloric Restriction Cell Line Cellular biology Chronic Cities Cocaine Collaborations Complement Corticotropin-Releasing Hormone Data Diet Eating Eating Behavior Endocrine Energy Metabolism Exposure to FOS gene Fatty acid glycerol esters Food Food Intake Regulation Gastrointestinal tract structure Genetic Genetic Crosses Grant Green Fluorescent Proteins Homeostasis Hormones Infusion procedures Injection of therapeutic agent Institutes Institution Intestines Knockout Mice Laboratories Lead Literature Location Measures Mediating Medical center Methods Microinjections Midbrain structure Modeling Motivation Mus Neurons Obesity Pathway interactions Performance Play Psychosocial Stress Reporting Research Research Design Resistance Rewards Role Series Signal Transduction Stomach System Testing Transgenic Mice Tyrosine 3-Monooxygenase United States United States National Institutes of Health Ventral Tegmental Area addiction base design dopaminergic neuron ghrelin ghrelin receptor growth hormone secretagogue receptor hedonic hypocretin immunoreactivity insight interest motivated behavior mouse model multidisciplinary neuronal circuitry neurophysiology parent grant peptide hormone preference receptor receptor expression research study subcutaneous

项目摘要

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.

描述（由申请人提供）：Ghrelin是一种肽激素，主要由排列在胃和肠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。我们最近发现，ghrelin介导了进食的愉悦方面，特别是提高了高脂肪食物的奖励价值，并增加了获得美味脂肪食物的动机。尽管有大量的文献描述了生长激素释放肽在调节食物摄入方面的作用，但对生长激素释放肽对进食的享乐方面的作用机制知之甚少。在目前的拨款中，我们建议更好地描述神经元回路介导的胃饥饿素的行动奖励为基础的饮食行为。特别是，我们将测试的假设，促肾上腺皮质激素释放因子（CRF）产生的中央杏仁核（CeA）的神经元有助于饥饿素的行动奖励为基础的饮食。我们将测试这一假设的三个独立的，但相关的目标的一部分。我们将确定生长激素释放肽注射后或热量限制后自然发生的生长激素释放肽升高是否激活CA CRF神经元。我们将确定生长激素释放肽的能力，以提高高脂肪食物的奖励价值需要CRF信号。此外，我们将确定是否表达神经肽食欲素的神经元介导生长激素释放肽对CeA CRF神经元的影响。对于这些研究，我们将使用一种新开发的转基因小鼠系，其中绿色荧光蛋白标记CRF神经元在脑内的位置。这些小鼠将与其他小鼠模型一起使用，包括CRF或食欲素缺失的小鼠模型，以阐明感兴趣的ghrelin参与的神经元回路。我们还将使用重复给药的药物，包括生长激素释放肽、CRF和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性位置偏好行为任务进行评估，该任务是我们针对小鼠模型中食物奖励行为的具体研究而改编和开发的。我们相信，这些实验将产生与饮食相关的行为的重要见解，并最终可能导致肥胖的新疗法。本研究将与Mario Perello合作进行，作为NIH资助1 R 01 DA 024680 -01，6-1-08至4-30- 13的扩展。他们将在UTSW医学中心和位于阿根廷拉普拉塔市的细胞生物学多学科研究所（IMBICE-CONICET/PBA）的神经生理学实验室进行。他们的目的是扩大和提高博士的研究兴趣. Zigman和Perello，并将有助于建立博士的研究和研究能力. Perello和IMBICE.

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Constitutive and ghrelin-dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons.

DOI：
10.1085/jgp.201511383
发表时间：
2015-09
期刊：
The Journal of general physiology
影响因子：
0
作者：
López Soto EJ;Agosti F;Cabral A;Mustafa ER;Damonte VM;Gandini MA;Rodríguez S;Castrogiovanni D;Felix R;Perelló M;Raingo J
通讯作者：
Raingo J

Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: critical role of brain accessibility.