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

该提议假设，杏仁核扩展的CRF系统中的神经适应调节调节了美味食物退出的负面情感后果，从而通过负面强化机制迫使美味食物摄取。研究使用了一种新的动物模型，该模型基于“间歇性但延长的可口食物的获取”，该模型与药物依赖模型具有共同的概念基础，并强调了食物成瘾的“黑暗面”，这是一个研究较少的创新研究领域。该模型的初步研究发现，对美味食物的消耗性和情感性依赖是以断断续续的方式发展起来的，并表明人们可能会因为后天获得的负面强化特性而强制食用美味食物，就像滥用药物所提出的那样。此外，由申请人在K99过程中产生的行为、分子和电生理初步研究表明，在这个模型中，CRF1受体在退出首选食物时观察到的变化中发挥了关键作用。特定的目标1和2结合了复杂的行为技术(进行性比率强化计划、颅内自我刺激、升高+迷宫)与补充的神经药理学和脑部位特异性慢病毒siRNA敲除方法，以确定CRF1受体在低噬食症、动机缺陷和退出美味食物时出现的类似焦虑行为中的作用。特定目标3确定中央杏仁核中央延伸区域CRF/CRF1系统的mRNA和蛋白表达的分子变化，这些变化是在从慢性、间歇性美味食物中撤退时观察到的。

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.