Explaining gender differences in anxiety.

Li et al. find that a set of oxytocin-responsive neurons in the medial prefrontal cortex (mPFC) look similar in both sexes, but in males they secrete a protein (CRHBP) that antagonizes the effect of the corticotropin-releasing hormone (CRH) associated with stress, thus causing an anti-anxiety effect with males that is not seen in females. This suggests the possibility of developing gender specific therapies for anxiety.

Highlights

•Activation of OxtrINs (oxytocin receptor interneurons) is anxiolytic in males and prosocial in females 

•OxtrINs specifically express CRHBP, an inhibitor of the stress hormone CRH 

•CRHBP blocks activation of layer 2/3 pyramidal cells by CRH only in males 

•OxtrINs in the mPFC (medial prefrontal cortex) coordinate sexually dimorphic social/emotional behaviors

Summary

The frequency of human social and emotional disorders varies significantly between males and females. We have recently reported that oxytocin receptor interneurons (OxtrINs) modulate female sociosexual behavior. Here, we show that, in male mice, OxtrINs regulate anxiety-related behaviors. We demonstrate that corticotropin-releasing-hormone-binding protein (CRHBP), an antagonist of the stress hormone CRH, is specifically expressed in OxtrINs. Production of CRHBP blocks the CRH-induced potentiation of postsynaptic layer 2/3 pyramidal cell activity of male, but not female, mice, thus producing an anxiolytic effect. Our data identify OxtrINs as critical for modulation of social and emotional behaviors in both females and males and reveal a molecular mechanism that acts on local medial prefrontal cortex (mPFC) circuits to coordinate responses to OXT and CRH. They suggest that additional studies of the impact of the OXT/OXTR and CRHBP/CRH pathways in males and females will be important in development of gender-specific therapies.