Oxytocin (OT) regulates many aspects of social behavior, including parental nurturing, individual discrimination and social attachment. OT is hypothesized to influence social behaviors by enhancing the salience and reinforcing value of social stimuli. Building on this hypothesis, rodent research has provided a compelling rationale for targeting the OT system to improve social cognition in psychiatric disorders such as autism spectrum disorders (ASD). Indeed, intranasal administration of OT enhances some aspects of social functioning in individuals with autism spectrum disorder (ASD), and the OT system is a leading pharmacological target for enhancing social function in ASD. Single nucleotide polymorphisms (SNPs) in noncoding regions of the human OT receptor gene (OXTR) are associated with core symptoms of ASD, altered brain activity patterns, and ASD diagnosis. However, human gene association studies do not provide insights about the exact mechanisms by which polymorphisms in OXTR lead to variation in brain function or social behavior. The socially monogamous prairie vole is an ideal model organism to explore the molecular processes by which variation in the OT system can lead to alterations in brain phenotype, and downstream social behaviors. OT receptor (OXTR) signaling in the nucleus accumbens (NAcc) is critically involved in alloparental nurturing and social bond formation in prairie voles. There is remarkable individual variation in the density of OXTR in the NAcc of prairie voles that is associated with variation in social behavior and resilience to early life social neglect. A set of 9 SNPs in the prairie vole OXTR gene (Oxtr) explains more than 70% of the variation in OXTR density in the NAcc, but not in other brain areas. These 9 SNPs are all equally strongly associated with OXTR density in the NAcc, due to fact that they are all perfectly correlated with each other in our colony. In this case, when multiple correlated SNPs are driving the association, genotype-phenotype association study design is not useful to disentangle the individual SNP?s contribution to variation in the phenotype. The goal of this proposal is to develop a state-of-the- art genome editing technique combining viral vector procedures with the novel CRIPSR-Cas9 genome editing method to enable targeting of Oxtr SNPs in the NAcc in adult prairie voles. The viral vector mediated CRISPR- Cas9 method will introduce small mutations hypothesized to alter the function of the genomic region including the targeted SNP and will result in changed NAcc OXTR expression when functional SNPs are investigated. Hence, the functional role of the individual SNPs in the prairie vole Oxtr can be explored using this method. In addition, this approach, for the first time developed in prairie voles, will be useful for future experiments for example identifying the functional roles of specific OXTR neuronal populations in social behavior and will give insights with important implications for human genetic studies investigating the potential influence of OXTR SNPs on brain phenotype, social cognition and psychopathology.
Genetic variation in the oxytocin receptor gene is associated with variation in social cognition and psychiatric disorders such as autism spectrum disorders, but the molecular mechanisms underlying these associations are largely unknown. This proposal uses the prairie vole model to understand how variation in the oxytocin receptor gene leads to an alteration in brain function by utilizing a state-of-the-art gene editing technique allowing brain region specific manipulation of genomic regions in adult animals. This proposal is the first to develop this novel method in a non-traditional animal model proven to be well suited for studying the neuro-genetics of social cognition and may inform treatment strategies for autism and other psychiatric disorders.