Epigenetic Mechanisms in the Perpetuation of Anorexia Nervosa-like Behavior

描述（由申请人提供：神经性厌食症（AN）是一种严重的进食障碍，复发率和死亡率非常高。除了身体形象扭曲、自我约束饮食、体重严重下降以及害怕“胖”/体重增加外，高达80%的AN患者 在他们的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（包括多动和食物摄入的自愿减少）的动物模型是“基于活动的厌食症”（阿坝）。在该大鼠模型中，动物可以自由接近转轮，每天1小时限制进食。在这种自由奔跑和限制食物获取的时间表期间，大鼠变得过度活跃和过度活跃，并且体重显著减轻，并且如果时间表不终止，最终将死于饥饿。青春期阿坝的经验增加了焦虑样行为，并促进了成年后的食物厌恶学习。这些数据表明，青少年的经验与多动症和食物限制有长期的行为后果。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，青春期AN样行为的经历可能导致大脑中持续的表观遗传改变，增加了AN复发的易感性。 行为障碍，并有助于患者的AN的延续。将阿坝动物模型与新的全基因组表观遗传平台，相对甲基化综合高通量阵列（“CHARM”）相结合，该提议旨在确定青春期阿坝经历对DNA甲基化和对压力和奖励重要的大脑区域中的基因表达的急性和长期后果。本提案中的实验将提供有关青少年AN样行为经验的表观遗传后果的新信息，并可能促进AN和相关饮食失调的更有效临床治疗的发展。 神经性厌食症（Anorexia Nervosa，AN）是一种严重的进食障碍，目前尚无有效的治疗方法。青春期是发育过程中的一个关键时期，许多生物变化发生，并可能持续到成年。我们将使用AN的动物模型，“基于活动的厌食症”（阿坝），以确定阿坝对大脑中表观遗传标记的青少年经历的短期和长期后果。这些实验的结果将提供有关AN如何发展以及疾病如何维持的新信息，以确定大脑中的新靶点，这些靶点可用于为AN和相关饮食失调制定更有效的治疗策略。

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. PUBLIC HEALTH RELEVANCE: Anorexia Nervosa (AN) is a severe eating disorder for which there are no effective treatments. Adolescence is a critical period during development when many biological changes occur and can persist through adulthood. We will use an animal model of AN, "activity-based anorexia" (ABA), to determine the short- and long-term consequences of adolescent experience with ABA on epigenetic marks in the brain. The results of these experiments will provide new information about how AN develops and how the disease is maintained to identify novel targets in the brain that may be used to develop more effective treatment strategies for AN and related eating disorders.