PROJECT SUMMARY Social attachments form the basis of human relationships at every level of social organization, from relationships between parents and children, romantic partners, to peers and group affiliation. Disruptions in attachment occur across the spectrum of mental illness, and severe neuropsychiatric disorders often manifest with a dramatic collapse of social attachment and cognition. Despite this critical role of social attachment, little is known regarding the neural and genetic mechanisms underlying attachment. Mice and other genetic model organisms do not exhibit enduring social attachments, precluding genetic analysis of these behaviors. Prairie voles are small rodents that display social monogamy, or pair bonds, between mates. Pair bond formation results in dramatic changes to many other innate social behaviors. Thus, prairie voles engage in a rich repertoire of social behaviors that strikingly mirror attachment in humans. Pioneering work identified the peptide hormones vasopressin (Avp) and oxytocin (Oxt), as critical mediators of pair bonding in voles and social cognition and behaviors in humans. These findings suggest that the genetics and neural control of social attachment may be conserved, and indeed, have inspired clinical trials seeking to use these hormones to ameliorate disruptions in social cognition due to neuropsychiatric conditions. Nevertheless, how these pathways and other genes function to control specific aspects of complex social behaviors remains unknown. Until now, we have been unable to understand how OxtR and V1aR function to control patterns of neural activity in response to partners or strangers. We have generated prairie voles bearing mutations in OxtR and V1aR that completely eliminate the function of these receptors, and developed approaches for optical recording of neural activity in freely moving animals during behavior and profiling of gene expression in prairie voles. Using this powerful system, we can now test the hypothesis that OxtR and V1aR control distinct aspects of 1) pair bonding and adult social attachment behaviors, 2) partner- or stranger-specific patterns of neural activity in specific regions of the vole brain during social interactions, and 3) changes in gene expression underlying social attachment in these neural populations. Our preliminary work suggests that OxtR signaling is not required genetically for pair bonding in prairie voles, and, thus, that a more refined understanding of the neural and molecular pathways underlying social attachment may provide new insights into the pathways that mediate the formation of such long term social memory and affiliation. These studies will elucidate the mechanisms by which OxtR and V1aR facilitate attachment and, eventually, inform new therapeutic approaches across the spectrum of mental illness.