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

描述（由申请人提供）：该申请为Pietro Cottone博士提出了一项职业发展计划，Pietro Cottone博士是一名经过严格培训的博士后研究员，致力于了解食物和药物成瘾的分子基础。申请人将由乔治Koob博士指导行为神经科学方法和依赖性和药物戒断的动物模型，由Eric Zorrilla博士共同指导喂养、应激神经化学和焦虑样行为相关问题，由Pietro Sanna博士指导生物化学和神经解剖学技术。该项目将在圣地亚哥丰富的神经科学社区的斯克里普斯研究所进行。该提案假设，在CRF系统的扩展杏仁核的神经适应介导可口的食物撤回的负面情感后果，从而迫使可口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。额外的行为和电生理学的初步研究表明，CRF 1受体在该模型中从首选食物戒断期间观察到的改变中起关键作用。特定目标1和2联合收割机将复杂的行为技术（渐进比例强化计划、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敲除方法相结合，以确定CRF 1受体在食欲减退、动机缺陷和从可口食物中戒断后观察到的致焦虑样行为中的作用。具体目标3确定了在慢性间歇性美味食物获取过程中观察到的中央延伸杏仁核离散区域中CRF/CRF 1系统mRNA和蛋白质表达的分子变化。相关性：该项目旨在确定与压力相关的CRF系统对食物成瘾的作用和潜在治疗相关性。

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.