Epigenetic Mechanisms in the Perpetuation of Anorexia Nervosa-like Behavior

描述(申请人提供：神经性厌食症(AN)是一种严重的饮食障碍，复发率和死亡率都很高。除了身体形象扭曲、自我节制饮食、严重减肥以及害怕肥胖/体重增加外，高达80%的患者患有 在饮食失调的发展过程中从事高水平的体力活动。一种模拟AN的几个方面的动物模型是“活动型厌食症”(ABA)，包括多动症和自愿减少进食量。在这个大鼠模型中，动物可以自由地使用滚轮，每天有1小时的限制获取食物。在这个自由奔跑和限制进食的时间表中，大鼠变得过度活跃和厌食，体重大幅下降，如果不终止时间表，最终将死于饥饿。青春期服用ABA的经历增加了焦虑样行为，并促进了成年后的食物厌恶学习。这些数据表明，青少年多动症和食物限制的经历会产生长期的行为后果。提出的神经生物学机制涉及调节压力和奖励过程的大脑区域。我们假设，在青春期经历类似AN的行为可能会导致大脑中持续的表观遗传变化，从而增加复发的易感性 行为紊乱，并导致住院患者的永久化。结合ABA动物模型和一个新的全基因组表观遗传平台--全面高通量相对甲基化阵列(“Charm”)，这项建议旨在确定青春期ABA经历对DNA甲基化和大脑重要应激和奖励区域基因表达的急性和长期影响。这项建议中的实验将提供关于青少年经历类似AN行为的表观遗传后果的新信息，并可能促进开发更有效的临床治疗AN及相关饮食障碍的方法。

DESCRIPTION (provided by applicant: Anorexia nervosa (AN) is a severe eating disorder with a very high relapse rate and mortality. In addition to body image distortion, self-imposed eating restraint, serious weight loss, and fear of "fat"/weight gain, up to 80% of patients with AN are engaged in high levels of physical activity during the development of their eating disorders. One animal model that mimics several aspects of AN, including hyperactivity and voluntary reductions on food intake, is "activity-based anorexia" (ABA). In this rat model, animals have free access to running wheels and 1 h restricted access to food each day. During this free running and restricted food access schedule, rats become hyperactive and anorexic, and lose a significant amount of weight, and will eventually die of starvation if the scheduled is not terminated. Experience with ABA during adolescence increases anxiety-like behavior and facilitates food aversion learning in adulthood. These data suggest that adolescent experience with hyperactivity and food restriction has long- term behavioral consequences. The neurobiological mechanisms proposed involve brain regions that mediate stress and reward processes. We hypothesize that experience with AN-like behavior during adolescence could result in persistent epigenetic alterations in the brain that increase susceptibility to relapse of disordered behavior and contributes to the perpetuation of AN in patients. Combining the ABA animal model with a novel genome-wide epigenetic platform, Comprehensive High-throughput Array for Relative Methylation ("CHARM"), this proposal aims to determine the acute and long term consequences of ABA experience during adolescence on DNA methylation and gene expression in brain regions important to stress and reward. The experiments in this proposal will provide new information about the epigenetic consequences of adolescent experience with AN-like behavior and may facilitate development of more effective clinical therapy for AN and related eating disorders.