Role of oxytocin receptors in modulation of fear by social memory

Oxytocin receptors (Oxtr) are important mediators of social learning and emotion, with bidirectional effects on fear and anxiety. Contrary to the anxiolytic actions of Oxtr in the amygdala, we recently showed that Oxtr in the lateral septum mediate the enhancement of fear conditioning by social defeat in mice. Using positive social interactions, which impair fear conditioning, here we attempted to delineate whether the role of septal Oxtr in fear regulation depends on the valence of the social memory. Pharmacological and genetic manipulations of lateral septal Oxtr were combined with the social buffering of fear paradigm, in which pre-exposure to nonfearful conspecifics reduces subsequent contextual fear conditioning, as revealed by decreased freezing behavior. Antagonism and down-regulation of Oxtr in the lateral septum abolished, while oxytocin (Oxt) administration before pre-exposure to nonfearful conspecifics facilitated the decrease of freezing behavior. The septal oxytocin system enhances memory of social interactions regardless of their valence, reducing fear after positive and enhancing fear after negative social encounters. These findings explain, at least in part, the seemingly bidirectional role of Oxt in fear regulation.