Microparticle-based delivery of oxytocin receptor antisense DNA in the medial amygdala blocks social recognition in female mice

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Abstract
Social recognition constitutes the basis of social life. In male mice and rats, social recognition is known to be governed by the neuropeptide oxytocin (OT) through its action on OT receptors (OTRs) in the medial amygdala. In female rats and mice, which have sociosexual behaviors controlling substantial investment in reproduction, an important role for OT in sociosexual behaviors has also been shown. However, the site in the female brain for OT action on social recognition is still unknown. Here we used a customized, controlled release system of biodegradable polymeric microparticles to deliver, in the medial amygdala of female mice, “locked nucleic acid” antisense (AS) oligonucleotides with sequences specific for the mRNA of the OTR gene. We found that single bilateral intraamygdala injections of OTR AS locked nucleic acid oligonucleotides several days before behavioral testing reduced social recognition. Thus, we showed that gene expression for OTR specifically in the amygdala is required for normal social recognition in female mice. Importantly, during the same experiment, we performed a detailed ethological analysis of mouse behavior revealing that OTR AS-treated mice underwent an initial increase in ambivalent risk-assessment behavior. Other behaviors were not affected, thus revealing specific roles for amygdala OTR in female social recognition potentially mediated by anxiety in a social context. Understanding the functional genomics of OT and OTR in social recognition should help elucidate the neurobiological bases of human disorders of social behavior (e.g., autism).