The dark side of preferred food addiction: role of CRF systems

该建议假设，扩展杏仁核的CRF系统中的神经适应性介导了美味食物戒断的负面情感后果，从而通过负强化机制迫使美味食物摄入。研究使用了一种新的动物模型，该模型基于“间歇性但扩展的，美味食物的获取”，与药物依赖模型共享概念基础，并强调食物成瘾的“阴暗面”，这是一个未被充分研究的创新研究领域。该模型的初步研究发现，对美味食物的完善性和情感依赖性随着间歇性获取而发展，并表明美味食物可能会因为获得负强化特性而被强迫食用，就像滥用药物一样。此外，申请人在K99阶段进行的行为、分子和电生理初步研究表明，在该模型中，CRFl受体在从首选食物中退出时观察到的变化中发挥了关键作用。具体目标1和2结合了复杂的行为技术（渐进式比例强化计划，颅内自我刺激，升高+迷宫）与互补的神经药理学和脑部位特异性慢病毒siRNA敲低方法，以确定CRFl受体在少食，动机缺陷和焦虑样行为中的作用，这些行为是在从美味食物中戒断时看到的。特异性目标3鉴定了中央延伸杏仁核离散区域中CRF/CRFl系统mRNA和蛋白质表达的分子变化，这些变化是在慢性、间歇性美味食物获取的戒断过程中观察到的。

The proposal hypothesizes that neuroadaptations in CRF systems ofthe extended amygdala mediate negative affective consequences of palatable food withdrawal and thereby come to compel palatable food intake via a negative reinforcement mechanism. Studies use a novel animal model based on "intermittent, but extended, access to palatable food that shares conceptual underpinnings with drug dependence-models and which emphasizes the "dark side" of food addiction, an understudied, innovative area of research. Preliminary studies with the model found that consummatory and affective dependence on palatable food develop with intermittent access and suggest that palatable food may come to be eaten compulsively for acquired negative reinforcing properties, as has been proposed for abused drugs. In addition, behavioral, molecular and electrophysiological preliminary studies, generated by the applicant during the K99 pahse ofthe award, suggest a key role for CRFl receptor in the alterations observed during withdrawal from preferred food in this model. Specific Aims 1 and 2 combine sophisticated behavioral techniques (progressive ratio reinforcement schedules, intracranial selfstimulation, elevated plus maze) with complementary neuropharmacologic and brain site-specific lentiviral siRNA knockdown approaches to determine the role of CRFl receptors in the hypophagia, motivational deficits, and anxiogenic-like behavior that is seen upon withdrawal from palatable food. Specific Aim 3 identifies molecular changes in mRNA and protein expression of CRF/CRFl systems in discrete regions ofthe central extended amygdala that are observed during withdrawal from chronic, intermittent palatable food access.