This is an application for support from the Recovery Act Limited Competition for NIH Grants: Research to Address the Heterogeneity in Autism Spectrum Disorders (R01) RFA-MH-09-170. We propose to leverage ongoing collaboration among faculty at Duke University, Yale University, and the University of Puerto Rico to develop a model of heterogeneity in social behavior in a nonhuman primate model in an ethologically natural context, identify genetic variation associated with this variability in social behavior, and determine the underlying mechanism using a combination of genetic, behavioral, and pharmacological techniques in the laboratory. One of the hallmark features of autism spectrum disorders (ASD) is dysfunction in social perception, attention, and interaction. Nonetheless, significant individual variation in these features frustrates diagnosis and challenges the development of effective treatments. Evidence suggests that individual variation in social behavior in ASD arises from a combination of genetic predispositions and individual experience, yet the underlying biological mechanisms remain poorly understood, in part due to the lack of a suitable animal model in which natural variation in both underlying genetics and individual experience generates heterogeneity in social behavior that is qualitatively similar, if not homologous, to that seen in humans. To address this gap, we propose to develop a model for studying the genetic, contextual, and neurobiological contributions to social behavior phenotype in rhesus macaques. We have previously demonstrated that these animals show hallmark social perception, attention, and reward behaviors that are qualitatively similar to those shown by typically developing humans;that individual variation in key genes impairs these behaviors in humans and rhesus in similar ways;and the same underlying neural pathways mediate the extraction of social information from the environment, translation of that information into reward and punishment signals, and ultimate expression of this information in attention to others that promotes or inhibits further interaction. Our proposed research will first characterize variability in social reward, social attention, and social aggression in a natural population of rhesus macaques living in large groups on Cayo Santiago Island in Puerto Rico, then assay key genes thought to contribute to social behavior and its dysfunction in humans including ASD, a finally test the impact of potential therapeutic interventions in the laboratory in macaques of known genotype. Our start-up has been catalyzed by support from the Duke University Institute for Brain Sciences, which has been renewed through the end of 2009, as well as support from the Duke Primate Genomics Initiative, in order to provide a seamless transition to ARRA stimulus grant support. Our project can be scaled up NOW by hiring new staff, paying extra technician and bench fees, and purchasing supplies and minor equipment with ARRA funds. Specifically, we will generate 7 new jobs and support salary for 7 faculty. Notably, we already have the research architecture in place to do high-throughput phenotyping and genetic analyses in monkeys, with targeted pharmacological studies in genetically-identified subgroups of animals. By integrating these methods we will develop a biologically predictive model of heterogeneity in primate social behavior that will inform our understanding of the basic genetic, developmental, and neurobiological causes of phenotypic heterogeneity in autism. PUBLIC HEALTH RELEVANCE: One of the hallmark features of autism spectrum disorders (ASD) is dysfunction in social perception, attention, and interaction. Nonetheless, significant individual variation in these features frustrates diagnosis and challenges the development of effective treatments. To address this gap, we will determine the genetic, developmental, and neurobiological contributions to social behavior phenotype in rhesus macaques.