Alterations in Motivated Behavior in Rodent Models of Obesity

肥胖啮齿动物模型动机行为的改变

基本信息

批准号：
9053060
负责人：
Carrie Ferrario
金额：
$ 34.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-24 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9053060
关键词：
Address Adult Behavior Behavioral Behavioral Risk Factor Surveillance System Biochemical Blinking Body Weight decreased Brain Breeding Cardiovascular Diseases Cells Centers for Disease Control and Prevention (U.S.)Chemosensitization Communities Cues Data Development Diet Disease model Eating Epidemic Estrous Cycle Exposure to Female Food Functional Magnetic Resonance Imaging Functional disorder Future Glutamate Receptor Glutamates Goals Individual Learning Malignant Neoplasms Measures Mediating Metabolic Modeling Motivation Mus N-Methyl-D-Aspartate Receptors Neurobiology Non obese Non-Insulin-Dependent Diabetes Mellitus Nucleus Accumbens Obesity Phosphorylation Play Population Predisposition Prevalence Prevention strategy Psychological reinforcement Rat-1 Rattus Reporting Research Resistance Rewards Rodent Model Role Sex Characteristics Signal Transduction Slice Smell Perception Source Strategic Planning Sucrose Surface Synapses System Testing Therapeutic Training United States National Institutes of Health Weight Weight Gain Work approach behavior base behavior test craving evidence base feeding food craving healthy weight insight male motivated behavior neurobehavioral neurobiological mechanism neuromechanism novel strategies obesity prevention patch clamp pre-clinical public health relevance receptor function relating to nervous system response synaptic function trafficking transmission process treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Currently, 30% of adults in the U.S. are obese, with the prevalence of obesity rising each year (CDC BRFSS, 2012). Obesity contributes to type 2 diabetes, cardiovascular disease, and many cancers, but is very hard to treat clinically. In 2011, the NIH released its new strategic plan for NIH obesity research to provide a "blueprint that will encourage the research community to examine the epidemic of obesity from diverse perspectives...in order to develop and evaluate new prevention and treatment strategies". The proposed work directly addresses this need by using novel approaches to understand the neurobehavioral mechanisms that promote obesity. In people, exposure to cues associated with food (food-cues), like the smell of brownies or a blinking donuts sign, increases food craving and the amount of food consumed (Fedoroff et al. 1997, Soussignan et al. 2012). Obese people report stronger food craving and eat larger portions in response to food-cues. Further, increases in activity of the nucleus accumbens (NAc) triggered by food-cues predict future weight gain in normal weight people and future inability to lose weight after obesity (Murdaugh et al. 2011; Demos et al. 2012). Thus in people, enhanced neurobehavioral responses to food-cues contribute to obesity. But, the mechanism underlying this enhanced neurobehavioral reactivity in obese and obesity-susceptible individuals is unknown. Our long-term goal is to understand the neurobiological mechanisms underlying enhanced cue- triggered 'craving' in obesity-susceptible and obese individuals. AMPA type glutamate receptors (AMPAR) provide the main source of excitation to the NAc. The NAc plays a critical role in food-cue triggered motivation in non-obese rats (Cardinal et al. 2002; Kelley, 2004; Everitt & Robbins, 2005). Disruption of AMPAR synaptic trafficking blocks the expression of cue-triggered motivation for sucrose in non-obese mice (Crombag et al. 2008a,b). These data suggest that enhancement of AMPAR function in the NAc may contribute to enhanced food-cue triggered motivation in obesity. However, no studies have examined NAc glutamate transmission or mechanisms of food-cue motivation in any rodent model of obesity. Our preliminary data show that obesity- prone are more motivated by "food-cues" and have increased NAc surface levels of AMPARs compared to obesity-resistant. We will combine rodent models of obesity with behavioral, electrophysiological and biochemical measures to determine the contribution of obesity, diet, and NAc glutamate transmission to enhanced motivation for food-cues. This work will have significant translational relevance given that modulation of glutamate transmission is a viable therapeutic approach in other disease models (Sidorov et al., 2013; Kreitzer and Malenka 2007; Loweth et al., 2013; Schwendt et al., 2012). Modulation of glutamate transmission will help those struggling with obesity to maintain a healthy weight by dampening the ability of food-cues to influence their behavior. We strongly believe this work will open new avenues for treatment by providing a better understanding of the behavioral and neural differences underlying enhanced motivation triggered by food-cues in obesity.

描述（由申请人提供）：目前，美国 30% 的成年人肥胖，肥胖患病率逐年上升（CDC BRFSS，2012）。肥胖会导致 2 型糖尿病、心血管疾病和许多癌症，但2011 年，NIH 发布了 NIH 肥胖研究的新战略计划，以提供“鼓励研究界研究肥胖流行病的蓝图”。从不同的角度......以便制定和评估新的预防和治疗策略”。拟议的工作通过使用新方法来了解促进肥胖的神经行为机制，直接解决了这一需求。在人们中，暴露于与食物（食物）相关的线索- 提示），例如布朗尼蛋糕的气味或闪烁的甜甜圈标志，会增加对食物的渴望和消耗的食物量（Fedoroff 等人，1997 年；Soussignan 等人，2012 年）。此外，由食物提示引发的伏隔核 (NAc) 活动增加可预测正常体重人群未来体重增加以及肥胖后未来无法减肥的部分（Murdaugh 等人，2011 年；Demos）。等人，2012）。因此，在人类中，对食物线索的神经行为反应增强会导致肥胖。但是，肥胖和肥胖易感人群的神经行为反应增强的机制。我们的长期目标是了解肥胖易感人群和肥胖人群中增强的线索触发“渴望”的神经生物学机制，AMPA 型谷氨酸受体（AMPAR）为 NAc 提供了主要的兴奋来源。食物提示触发非肥胖大鼠动机的关键作用（Cardinal et al. 2002；Kelley，2004；Everitt & Robbins， AMPAR 突触运输的破坏会阻止非肥胖小鼠中线索触发的蔗糖动机的表达（Crombag 等人，2008a，b）。这些数据表明，NAc 中 AMPAR 功能的增强可能有助于增强食物-然而，没有研究在任何肥胖啮齿类动物模型中检验 NAc 谷氨酸的传递或食物提示动机的机制。与肥胖抗性相比，肥胖倾向更容易受到“食物线索”的激励，并且 AMPAR 的 NAc 表面水平有所增加。我们将把肥胖的啮齿动物模型与行为、电生理和生化测量相结合，以确定肥胖、饮食和 NAc 谷氨酸的贡献。鉴于谷氨酸传输的调节是其他疾病模型中可行的治疗方法，这项工作将具有重要的转化意义（Sidorov 等，2013；Kreitzer 和Malenka 2007；Loweth 等人，2013 年；Schwendt 等人，2012 年）。我们相信，调节谷氨酸传输将有助于那些与肥胖作斗争的人保持健康的体重。这项工作将通过更好地了解肥胖症中食物线索引发的增强动机背后的行为和神经差异，为治疗开辟新的途径。