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

Social avoidance is highly detrimental for natural behavior. Despite much research on this topic, the mechanisms underlying the development of social avoidance as a consequence of social-related traumatic experiences remain highly elusive. To investigate this issue, we adapted a mouse model of social threat conditioning in which mice received shock punishment during exploration of an unfamiliar conspecific. This resulted in prominent and lasting reductions in social behavior, effects that were not observed in mice that received shock punishment in the absence of a social stimulus. Furthermore, the effects of social threat conditioning were independent of contextual settings, sex variables, and particular identity of the unfamiliar conspecifics that predicted shock punishment. Shedding new light into the neurobiological bases for this phenomenon, we found that optogenetic silencing of the prelimbic (PL), but not infralimbic (IL), prefrontal cortex during social threat conditioning produced profound forgetting and restoration of social behavior during subsequent sociability tests. Significant forgetting and recovery of social behavior was also observed with prelimbic inhibition of NMDARs. Collectively, these findings are consistent with the notion that social-related trauma is a prominent risk factor for social avoidance, and that traumatic experiences that involve social elements engage learning-related mechanisms in corticolimbic networks to promote long-term representations of social threat.