Epigenetic Mechanisms in the Perpetuation of Anorexia Nervosa-like Behavior

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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.