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Abstract The formation of enduring relationships dramatically influences future behavior, promoting affiliation between familiar individuals. How such attachments are encoded to elicit and reinforce specific social behaviors in distinct ethological contexts remains unknown. Signaling via the oxytocin receptor (Oxtr) in the nucleus accumbens (NAc) facilitates social reward as well as pair bond formation between mates in socially monogamous prairie voles^1–9. How Oxtr function influences activity in the NAc during pair bonding to promote affiliative behavior with partners and rejection of other potential mates has not been determined. Using longitudinalin vivofiber photometry in wild-type prairie voles and those lacking Oxtr, we demonstrate that Oxtr function sex-specifically regulates pair bonding behaviors and associated activity in the NAc. Oxtr function influences prosocial behavior in females in a state-dependent manner. Females lacking Oxtr demonstrate reduced prosocial behaviors and lower activity in the NAc during initial chemosensory investigation of novel males. Upon pair bonding, affiliative behavior with partners and neural activity in the NAc during these interactions increase, but these changes do not require Oxtr function. Conversely, males lacking Oxtr display increased prosocial investigation of novel females. Using the altered patterns of behavior and activity in the NAc of males lacking Oxtr during their first interactions with a female, we can predict their future preference for a partner or stranger days later. These results demonstrate that Oxtr function sex-specifically influences the early development of pair bonds by modulating prosociality and the neural processing of sensory cues and social interactions with novel individuals, unmasking underlying sex differences in the neural pathways regulating the formation of long-term relationships. 

Prairie voles (Microtus ochrogaster) are a powerful model for studying the neurobiology of social bonding, yet tools for region- and cell type-specific gene regulation remain underdeveloped in this species. Here, we present a lentivirus-mediated CRISPR activation and interference (CRISPRa/i) platform for somatic gene modulation in the prairie vole brain. This system enables non-mutagenic, titratable regulation of gene expression in the adult brain without germline modification. Our dual-vector system includes one construct expressing dCas9-VPR (VP64-p65-Rta) referred to as CRISPRa or dCas9-KRAB-MeCP2 (Kruppel-associated box-methyl CpG binding protein 2), referred to as CRISPRi under a neuron-specific promoter, and a second construct delivering a U6-driven sgRNA (single guide RNA) alongside an elongation factor 1 alpha (EF1α)-driven mCherry reporter. We detail the design, production, and stereotaxic delivery of these tools and demonstrate their application by targeting four genes implicated in social behavior (Oxtr, Avpr1a, Drd1,andDrd2) across two mesolimbic brain regions: the nucleus accumbens and ventral pallidum. Gene expression analyses confirmed robust, bidirectional transcriptional modulation for selected targets, establishing a proof of concept for CRISPRa/i in this non-traditional model. The dual-vector design is readily adaptable to other gene targets, cell types, and brain regions, and can be multiplexed to provide a flexible and scalable framework for investigating gene function in behaviorally relevant circuits. These advances represent the first successful implementation of somatic CRISPRa/i in prairie voles and expand the genetic toolkit available for this species.