Alterations in Motivated Behavior in Rodent Models of Obesity

肥胖啮齿动物模型动机行为的改变

• 批准号: 9244247
• 负责人: Carrie Ferrario
• 金额: $ 6.94万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/9244247
• 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; Electrophysiology (science); Epidemic; Estrous Cycle; Exposure to; Female; Food; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glutamate Receptor; Glutamates; Goals; Health; 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; receptor function; relating to nervous system; response; synaptic function; trafficking; transmission process; treatment strategy

 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(申请人提供)：目前，美国30%的成年人患有肥胖症，肥胖率每年都在上升(CDC BRFSS，2012)。肥胖会导致2型糖尿病、心血管疾病和许多癌症，但在临床上很难治疗。2011年，美国国立卫生研究院发布了NIH肥胖症研究的新战略计划，提供了一份“蓝图，鼓励研究界从不同的角度审视肥胖症的流行……以便开发和评估新的预防和治疗策略”。这项拟议的工作通过使用新的方法来了解促进肥胖的神经行为机制，直接满足了这一需求。在人类中，接触到与食物有关的线索(食物线索)，如巧克力饼的气味或闪烁的甜甜圈标志，会增加食物渴望和食物消耗量(Fedoroff等人。1997年，Soussignan等人。2012年)。肥胖者对食物的渴望更强烈，他们会根据食物提示吃更多的食物。此外，食物提示引发的伏隔核(NAC)活动的增加预测了正常体重人群未来的体重增加和肥胖后未来无法减肥(Murdaugh等人)。2011年；Demos et al.2012年)。因此，在人类中，对食物暗示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神经行为反应增强的机制尚不清楚。我们的长期目标是了解在肥胖易感和肥胖个体中，由增强的线索触发的“渴望”背后的神经生物学机制。AMPA型谷氨酸受体(AMPAR)是NAC的主要兴奋源。NAC在非肥胖大鼠的食物提示触发的动机中发挥着关键作用(Cardinal等人)。2002年；凯利，2004年；Everitt&Robbins，2005年)。AMPAR突触运输的中断阻止了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线索触发的肥胖动机。然而，还没有研究在任何肥胖的啮齿动物模型中检查NAC谷氨酸的传递或食物线索动机的机制。我们的初步数据显示，容易肥胖的人更多地受到“食物暗示”的推动，与肥胖抵抗者相比，他们的AMPAR在NAC表面的水平更高。我们将结合肥胖的啮齿动物模型和行为、电生理和生化指标来确定肥胖、饮食和NAC谷氨酸传递对增强食物提示动机的贡献。鉴于调节谷氨酸传递在其他疾病模型中是一种可行的治疗方法，这项工作将具有重要的翻译意义(Sidorov等人，2013年；Kreitzer和Malenka，2007年；Loweth等人，2013年；Schwendt等人，2012年)。谷氨酸传递的调节将通过抑制食物暗示影响他们行为的能力，帮助那些与肥胖作斗争的人保持健康的体重。我们坚信，这项工作将为肥胖的治疗开辟新的途径，因为它可以更好地理解肥胖中食物提示引发的动机增强背后的行为和神经差异。