The grant being proposed "Mechanisms behind long-term and transgenerational effects of adolescent behavior" will address the Challenge Area (15) Translational Science, and the Specific Challenge Topic 15-AA-101* Determining If and How Adolescent Behaviors Affect Connections in the Developing Brain. A large body of both human and animal data support the idea that adolescent behaviors can have life-long effects on an individual. This sensitivity may derive, in part, from the dramatic developmental changes in brain function that are taking place at this time to generate skills for independence. Compounding this phenomenon is the adolescent-associated increase in risk-taking that predisposes them to initiate the use of addictive drugs. In addition, brain plasticity during adolescence may also contribute to heightened sensitivity to the long-term negative consequences of stress. Even more dramatic are new studies demonstrating that certain qualities acquired during youth in response to their environment may be passed on to future offspring, potentially magnifying the consequences of negative (or positive) adolescent behaviors. Many studies have begun to reveal how negative (and positive) experiences during adolescence, such as the ill-effects on adolescent exposure to nicotine or social stress, or the positive effects of an enriched environment, have long-term effects on life-long health and well being. However, they have focused on gene products involved in particular biochemical pathways and physiological processes of interest to individual investigators. In most cases molecular mechanisms underlying these effects have not been revealed, preventing rigorous test of whether they are physiologically relevant to long-lasting vulnerability to health problems that occurs in response to these specific adolescent behaviors. Thus, in this proposal, which is a joint effort by the Feig lab at Tufts University School of Medicine and the Meissner Lab at Harvard University and the Broad Institute, we will perform unbiased genome-wide screens to detect all genes in appropriate regions of the brain that display experience-induced, long-term changes in DNA methylation and/or histone modification that could that could account for long-term negative or positive consequences on health. Moreover, we will investigate whether any epigenetic-induced effects of these adolescent experiences are transmitted to the next generation It is anticipated that by identifying new long-lasting and/or transgenerational effectors of specific "negative" and "positive" adolescent behaviors, this study will generate new hypotheses that begin to answer the question proposed in this Challenge Area of how adolescent behavior "rewire(s) the developing brain thereby creating vulnerability for a number of persistent health problems including mental health disorders.....and addiction." This study will also suggest epigenetic mechanisms by which long-term and/or transgenerational changes in the expression of these effectors are regulated. As such, it will suggest strategies to specifically block their response to adolescent behaviors in mice to test their role in how "behaviors exhibited during this period can influence lifetime (and/or transgenerational) health and well-being. PUBLIC HEALTH RELEVANCE: Although a person's genetic blueprint strongly contributes to his/her susceptibility to disease, it is clear that the environment in which one lives influences how that blueprint is read. This appears to be particularly important during adolescent years where substantial evidence implies that some experiences during adolescence, such as exposure to nicotine or social stress have negative consequences on life-long health and well being. Our new data even suggest that these adolescent behaviors may influence future offspring when they are adolescents. This proposal will take advantage of state of the art tools to identify how these adolescent experiences have their effect through long-term structural modifications of genes that changes the way they are read. It is anticipated that this information will generate new hypotheses for how to reverse the long-lasting consequences of poor adolescent behaviors.