Abstract Social phobia is highly detrimental for social behavior, mental health, and productivity. Despite much previous research, the behavioral and neurobiological mechanisms associated with the development of social phobia remain elusive. To investigate these issues, the present study implemented a mouse model of social threat conditioning in which mice received electric shock punishment upon interactions with unfamiliar conspecifics. This resulted in immediate reductions in social behavior and robust increases in defensive mechanisms such as avoidance, freezing, darting, and ambivalent stretched posture. Furthermore, social deficits lasted for prolonged periods and were independent of contextual settings, sex variables, or particular identity of the social stimuli. Shedding new light into the neurobiological factors contributing to this phenomenon, we found that optogenetic silencing of the prelimbic (PL), but not the infralimbic (IL), subregion of the medial prefrontal cortex (mPFC) during training led to subsequent forgetting and development of lasting social phobia. Similarly, pharmacological inhibition of NMDARs in PL also impaired the development of social phobia. These findings are consistent with the notion that social-related trauma is a prominent risk factor for the development of social phobia, and that this phenomenon engages learning-related mechanisms within the prelimbic prefrontal cortex to promote prolonged representations of social threat. Abstract Figure

The prelimbic prefrontal cortex mediates the development of lasting social phobia as a consequence of social threat conditioning.