Cafeteria diet-induced dysregulation of food seeking: neurochemical bases

描述（由申请人提供）：肥胖在西方世界已经达到了一个危机点，特别是在美国，三分之一的人口肥胖，还有更多的人被归类为超重。肥胖的一个主要原因是暴饮暴食，其中大部分是针对能量密集，非常美味的食物。摄食是体液、代谢、生理和心理过程复杂相互作用的产物。关于后者，动机行为和成瘾的神经生物学进展表明，内源性阿片肽和多巴胺是奖励刺激（尤其是食物）的情感加工的核心，也是学习奖励和奖励相关刺激的相关性的核心，这使它们成为肥胖病因学中重点研究的逻辑怀疑对象。在这个项目的第一部分，我们将测试一个假设，即长期食用能量密集的高美味食物会破坏阿片类药物依赖的工具激励学习过程，导致美味食物消费的愉悦体验与指导食物寻找行为的食物的激励价值之间的不一致，最终导致强迫性食物寻找。将通过药理学和遗传干预的结合以及脑啡肽释放的测量来测试内源性阿片样物质在基底外侧杏仁核中传递中断的假设作用。由于环境刺激，如精心设计的广告、包装和产品植入，可以有效地影响进食，该项目的第二部分将测试一个假设，即长期食用美味食物会加剧线索诱导的寻食，这一过程涉及中枢多巴胺和/或阿片类物质传递的可塑性。因此，我们将把饮食引起的肥胖的临床前模型与先进的行为、神经化学和遗传方法相结合，以获得有望对指导公共政策和治疗暴饮暴食和肥胖具有重要意义的数据。

DESCRIPTION (provided by applicant): Obesity has reached a crisis point in the Western world, especially in the US where one third of the population is obese, and many more are classified as overweight. A major cause of obesity is overeating, the majority of which is targeted to energy-dense, highly palatable foods. Feeding is the product of a complex interaction between humoral, metabolic, physiological and psychological processes. Regarding the latter, advances in the neurobiology of motivated behavior and addiction demonstrate that endogenous opioid peptides and dopamine are central to affective processing of rewarding stimuli, especially food, and to learning about rewards and the relevance of reward-related stimuli, making them logical suspects for focused investigation in the etiology of obesity. In the first part of this project, we will test the hypothesis that chronic consumption of energy-dense highly palatable foods disrupts opioid-dependent instrumental incentive learning processes, resulting in discordance between the pleasurable experience of palatable food consumption and the incentive value assigned to the food that guides food-seeking behavior, leading ultimately to compulsive food-seeking. The hypothesized role of disruption in endogenous opioid transmission in the basolateral amygdala will be tested using a combination of pharmacological and genetic interventions and by measurement of enkephalin release. As environmental stimuli, such as carefully engineered advertising, packaging and product placement can potently influence feeding, the second part of the project will test the hypothesis that chronic consumption of highly palatable foods accentuates cue-induced food-seeking, and that this process involves plasticity in central dopamine and/or opioid transmission. Thus, we will combine a preclinical model of diet-induced obesity with a combination of advanced behavioral, neurochemical and genetic methodologies to yield data that promise to have important implications for guiding public policy and treating overeating and obesity.