Alterations in Motivated Behavior in Rodent Models of Obesity

 描述（由申请人提供）：目前，美国30%的成年人肥胖，肥胖的患病率每年都在上升（CDC BRFSS，2012）。肥胖导致2型糖尿病，心血管疾病和许多癌症，但很难在临床上治疗。2011年，美国国立卫生研究院发布了其新的战略计划，为美国国立卫生研究院肥胖研究提供了一个“蓝图，将鼓励研究界从不同的角度研究肥胖的流行......以便制定和评估新的预防和治疗战略”。这项工作通过使用新的方法来理解促进肥胖的神经行为机制，直接解决了这一需求。在人类中，暴露于与食物相关的线索（食物线索），如布朗尼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 et al. 1997，Soussignan et al. 2012）。肥胖的人报告更强烈的食物渴望和吃更大的部分，以回应食物线索。此外，由食物线索触发的丘脑核（NAc）活性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 et al. 2011; Demos et al. 2012）。因此，在人类中，对食物线索的增强的神经行为反应有助于肥胖。但是，肥胖和肥胖易感个体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者和肥胖个体中增强的线索触发的“渴望”的神经生物学机制。AMPA型谷氨酸受体（AMPAR）提供NAc的主要兴奋源。NAc在非肥胖大鼠的食物线索触发的动机中起关键作用（Cardinal等人，2002; Kelley，2004; Everitt & Robbins，2005）。AMPAR突触运输的破坏阻断了非肥胖小鼠中蔗糖的线索触发动机的表达（Crombag等人，2008 a，B）。这些数据表明，NAc中AMPAR功能的增强可能有助于增强肥胖症中食物线索触发的动机。然而，还没有研究在任何啮齿动物肥胖模型中检查NAc谷氨酸传输或食物提示动机的机制。我们的初步数据显示，与抗肥胖者相比，肥胖倾向者更受“食物线索”的激励，并且增加了AMPAR的NAc表面水平。我们将结合联合收割机啮齿动物模型的肥胖行为，电生理和生化措施，以确定肥胖，饮食和NAc谷氨酸传输的贡献，以增强动机的食物线索。鉴于谷氨酸传递的调节在其他疾病模型中是可行的治疗方法，这项工作将具有显著的翻译相关性（Sidorov et al.，2013; Kreitzer和Malenka 2007; Loweth等人，2013;施温特等人，2012年）。调节谷氨酸传输将通过抑制食物线索影响其行为的能力，帮助那些与肥胖作斗争的人保持健康的体重。我们坚信，这项工作将通过更好地理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。

 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.