A prefrontal–habenular circuitry regulates social fear behaviour

Abstract The medial prefrontal cortex (mPFC) has been implicated in the pathophysiology of social impairments, including social fear. However, the precise subcortical partners that mediate mPFC dysfunction on social fear behaviour have not been identified. Using a social fear conditioning paradigm, we induced robust social fear in mice and found that the lateral habenula (LHb) neurons and LHb-projecting mPFC neurons are activated synchronously during social fear expression. Moreover, optogenetic inhibition of the mPFC–LHb projection significantly reduced social fear responses. Importantly, consistent with animal studies, we observed an elevated prefrontal–habenular functional connectivity in subclinical individuals with higher social anxiety characterized by heightened social fear. These results unravel a crucial role of the prefrontal–habenular circuitry in social fear regulation and suggest that this pathway could serve as a potential target for the treatment of social fear symptoms often observed in many psychiatric disorders.