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

该提案假设，在CRF系统的扩展杏仁核的神经适应介导的美味的食物撤回的负面情感后果，从而迫使美味的食物摄入通过负强化机制。研究使用了一种新的动物模型，该模型基于“间歇性但延长的对可口食物的获取，与药物依赖模型共享概念基础，并强调食物成瘾的“黑暗面”，这是一个研究不足的创新研究领域。该模型的初步研究发现，对可口食物的消费性和情感依赖是随着间歇性的接触而发展的，并表明可口食物可能会被强迫性地食用，以获得负面的强化特性，就像滥用药物一样。此外，由申请人在该奖项的K99阶段期间产生的行为、分子和电生理学初步研究表明，CRF 1受体在该模型中从优选食物戒断期间观察到的改变中起关键作用。特定目的1和2联合收割机将复杂的行为技术（渐进比率强化时间表、颅内自我刺激、高架十字迷宫）与互补的神经药理学和脑位点特异性慢病毒siRNA敲低方法组合，以确定CRF 1受体在食欲减退、动机缺陷和从可口食物戒断后观察到的致焦虑样行为中的作用。具体目标3鉴定了在从慢性间歇性可口食物获取中戒断期间观察到的中央延伸杏仁核的离散区域中CRF/CRF 1系统的mRNA和蛋白质表达的分子变化。

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.