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

描述(由申请人提供)：该申请为皮埃特罗·科托内博士提出了一份职业发展计划，他是一名受过药理学训练的博士后研究员，致力于了解食物和药物成瘾的分子基础的研究生涯。申请者将接受George Koob博士在行为神经科学方法和依赖和药物戒断的动物模型方面的指导，并由Eric Zorrilla博士在与进食、应激神经化学和焦虑样行为有关的问题上联合指导，并由Pietro Sanna博士在生化和神经解剖学技术方面联合指导。该项目将在圣地亚哥富裕的神经科学社区的斯克里普斯研究所进行。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。另外，行为学和电生理学的初步研究表明，CRF1受体在该模型中从偏爱食物中撤除时观察到的变化中起着关键作用。特定目标1和2结合了复杂的行为技术(渐进比率强化计划、颅内自我刺激、提升+迷宫)与补充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、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过程中观察到的。相关性：该项目寻求确定与压力相关的CRF系统在食物成瘾方面的作用和潜在的治疗相关性。

DESCRIPTION (provided by applicant): The application proposes a career development plan for Dr. Pietro Cottone, a pharmacologically trained post-doctoral fellow committed to a research career in understanding the molecular bases of food and drug addiction. The applicant will be mentored by Dr. George Koob in behavioral neuroscience methods and animal models of dependence and drug withdrawal and co-mentored by Dr. Eric Zorrilla in issues related to feeding, stress neurochemistry, and anxiety-like behavior and by Dr. Pietro Sanna in biochemical and neuroanatomical techniques. The project will be conducted at The Scripps Research Institute in the rich neuroscience community of San Diego. The proposal hypothesizes that neuroadaptations in CRF systems of the 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. Additional behavioral and electrophysiological preliminary studies suggest a key role for CRF1 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 self-stimulation, elevated plus maze) with complementary neuropharmacologic and brain site-specific lentiviral siRNA knockdown approaches to determine the role of CRF1 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/CRF1 systems in discrete regions of the central extended amygdala that are observed during withdrawal from chronic, intermittent palatable food access. Relevance: The project seeks to define the role and potential therapeutic relevance of stress-related CRF systems on food addiction.