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: 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
• 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

 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（由适用提供）：目前，美国有30％的成年人是肥胖，每年肥胖症的流行率上升（CDC BRFSS，2012年）。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。 NIH在2011年发布了新的NIH肥胖研究战略计划，以提供“蓝图，鼓励研究界从多样化的角度研究肥胖的流行……以制定和评估新的预防和治疗策略。拟议的工作直接通过使用新颖的方法来理解这种需求，以促进肥料，以促进饲料，以促进人们（企业），以促进人们，以促进人们（企业），以促进人们，企业，以促进人们，企业，企业，企业，企业。布朗尼蛋糕或闪烁的甜甜圈迹象，增加了食物的渴望和消耗的食物量（Fedoroff等，1997年，Soussignan等人，肥胖者报告强烈的食物，并响应食物的响应，以增加对食物的活力（NAC）的体重（NAC）的体重， Et。2012年。但是，这种增强的神经行为反应性的机制尚不清楚。我们的长期目标是了解增强的提示的神经生物学机制在肥胖症和肥胖个体中“渴望”。 AMPA型谷氨酸受体（AMPAR）为NAC提供了兴奋的主要来源。 NAC在食品库中起着至关重要的作用，引发了非肥胖大鼠的动机（Cardinal等，2002； Kelley，2004； Everitt＆Robbins，2005）。 AMPAR突触运输的破坏阻碍了非肥胖小鼠蔗糖的提示触发动机的表达（Crombag etal。2008a，b）。这些数据表明，NAC中AMPAR功能的增强可能有助于增强肥胖的动机。然而，在任何啮齿动物中，我们的初步数据表明，与肥胖相比，尚无研究检查的NAC谷氨酸传播或食物-CUE动机的机制，即我们的初步数据表明，与肥胖症相比，NAC表面水平的水平更高，并且具有NAC表面水平的提高。我们将肥胖模型与行为，电生理和生化措施相结合，以确定肥胖，饮食和NAC谷氨酸传播的贡献，以增强食品库的动机。鉴于在其他疾病模型中，谷氨酸传播的调节是一种可行的治疗方法，这项工作将具有显着的转化相关性（Sidorov等，2013； Kreitzer和Malenka 2007； Loweth等，2013； Schwendt等，2012）。谷氨酸传播的调节将有助于那些苦苦挣扎的肥胖者来维持健康的体重来维持健康的体重来影响食物的行为。我们坚信，这项工作将通过更好地理解肥胖症中食物库引发的增强动机的行为和神经差异来开辟新的治疗途径。