Cafeteria diet-induced dysregulation of food seeking: neurochemical bases

描述(申请人提供)：在西方世界，肥胖已经达到了危机的临界点，特别是在美国，三分之一的人口肥胖，更多的人被归类为超重。肥胖的一个主要原因是暴饮暴食，其中大部分是高能量、高口感的食物。喂食是体液、代谢、生理和心理过程之间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的进展表明，内源性阿片肽和多巴胺是奖励刺激，特别是食物的情感处理的核心，并有助于了解奖励和与奖励相关的刺激的相关性，使它们成为肥胖症病因学重点研究的合理嫌疑人。在这个项目的第一部分，我们将测试一种假设，即长期摄入高能量密度的高口感食物会扰乱阿片类药物依赖的工具性激励学习过程，导致美味食物的愉快消费体验与引导食物寻找行为的食物的激励价值之间的不协调，最终导致强迫性食物寻找。中断在杏仁基底外侧核内源性阿片传递中的假设作用将通过药理学和遗传学干预的组合以及脑啡肽释放的测量来测试。由于精心设计的广告、包装和产品植入等环境刺激可能会对喂养产生巨大影响，该项目的第二部分将测试一种假设，即长期食用高度美味的食物会加剧线索诱导的食物寻找，并且这一过程涉及中枢多巴胺和/或阿片类药物传输的可塑性。因此，我们将把饮食诱导肥胖的临床前模型与先进的行为、神经化学和遗传学方法相结合，以产生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.