Epigenetic Mechanisms in the Perpetuation of Anorexia Nervosa-like Behavior

神经性厌食症样行为持续的表观遗传机制

基本信息

批准号：
8281794
负责人：
KELLIE L. K. TAMASHIRO
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8281794
关键词：
Acute Adolescence Adolescent Adult Animal Model Animals Anorexia Anorexia Nervosa Anxiety Behavior Behavior Disorders Behavioral Biological Biological Assay Biology Body Image Body Weight decreased Brain Brain region Characteristics Clinical Coupled CpG Islands DNA Methylation Data Development Diet Disease Eating Eating Disorders Emaciation Epigenetic Process Exercise Family Study Fatty acid glycerol esters Female Food Food Access Food Aversion Fright Gene Expression Genes Genetic Genome Glucocorticoids Homeostasis Human Hyperactive behavior Individual Learning Life Experience Long-Term Effects Malnutrition Mediating Mental disorders Methylation Modeling Mood Disorders National Institute of Mental Health Neurobiology Nutritional Patients Personality Personality Traits Physical activity Play Predisposition Prevalence Probability Promoter Regions Protocols documentation Psychosocial Influences Rattus Recovery Relapse Relative (related person)Reporting Resistance Rewards Risk Rodent Role Running Schedule Secondary to Starvation Stress Testing Thinness Time Twin Studies Weight Weight Gain base biological adaptation to stress critical developmental period critical period effective therapy excessive exercise experience food restriction genetic linkage genome-wide male mortality neural circuit neurobiological mechanism novel relating to nervous system research study restraint reward processing treatment strategy

项目摘要

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.

描述（申请人提供：神经性厌食症（Anorexia nervosa，AN）是一种严重的饮食失调症，复发率和死亡率非常高。除了身体形象扭曲外，自我控制饮食、体重严重下降、对“脂肪”/体重的恐惧高达 80% 的 AN 患者获益在饮食失调的过程中从事高水平的体力活动。一种模仿 AN 多个方面的动物模型，包括多动症和自愿减少食物摄入量，是“活动性厌食症”(ABA)。在该大鼠模型中，动物可以自由使用跑轮，并且每天有 1 小时的限制时间获取食物。在这个自由奔跑和限制食物获取的时间表中，老鼠变得过度活跃和厌食，并且体重显着下降，如果不终止时间表，最终将死于饥饿。青少年时期的 ABA 体验会增加类似焦虑的行为，并促进成年后的食物厌恶学习。这些数据表明，青少年多动和食物限制的经历会产生长期的行为后果。所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，青春期期间经历过类似 AN 的行为可能会导致大脑中持续的表观遗传改变，从而增加复发的可能性。行为紊乱并导致患者 AN 持续存在。该提案将 ABA 动物模型与新型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，旨在确定青春期 ABA 经历对 DNA 甲基化和基因表达的急性和长期影响对压力和奖励很重要的大脑区域。本提案中的实验将提供有关青少年经历 AN 样行为的表观遗传后果的新信息，并可能促进针对 AN 和相关饮食失调的更有效的临床治疗的开发。公共卫生相关性：神经性厌食症 (AN) 是一种严重的饮食失调症，目前尚无有效的治疗方法。青春期是发育过程中的关键时期，此时会发生许多生物学变化，并且可以持续到成年期。我们将使用 AN 动物模型，即“基于活动的厌食症”(ABA)，来确定青少年 ABA 经历对大脑表观遗传标记的短期和长期影响。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，这些靶点可用于开发针对 AN 和相关饮食失调的更有效的治疗策略。