Functional Involvement of Septal miR-132 in Extinction and Oxytocin-mediated Reversal of Social Fear

Social interactions are critical components for the survival of mammalian biology and evolution. Dysregulation of social behavior often leads to psychopathologies such as social anxiety disorder, which is characterized by an intense fear and avoidance of social situations. Using the social fear conditioning (SFC) paradigm, we analyzed expression levels of miR-132-3p and miR-124-3p within the septum, a brain region essential for social behavior and fear, after acquisition and extinction of social fear. Functional in vivo approaches using pharmacology, functional inhibition of miR-132-3p, viral miR-132 overexpression and shRNA-mediated knockdown of miR-132-3p within oxytocin receptor positive neurons confirmed septal miR-132-3p to be involved in social fear extinction and the oxytocin-mediated reversal of social fear. Moreover, Argonaute-RNA-co-immunoprecipitation-microarray analysis and further target mRNA quantification, depicted growth differentiation factor-5 (GDF-5) to be involved in miR-132-3p-mediated regulation of social fear extinction. Local application of GDF-5 resulted in impaired social fear extinction, an effect which seems to be mediated by miR-132-3p. In summary, we show that septal miR-132-3p is functionally involved in social fear extinction learning and oxytocin-mediated reversal of social fear. Septal Ago2 was pulled down by means of Argonaute-co-immunoprecipitation (6F4). To determine a target of miR-132-3p, miR-132-3p inhibitor (Inh) or scrambled LNA (Scr) was infused into the septum of male mice and tissue was punched 2 days thereafter. IPs were performed in duplicates and for each condition one Input sample was analysed.