Cholecystokinin A receptor in the medial preoptic area GABAergic cells modulate male-specific anxiety-like behaviors

Anxiety disorders frequently accompanies aggression and their co-occurrence predicts worse functional impairment and poor prognosis. Nevertheless, the underlying neural mechanisms for co-occurring anxiety disorders and aggression remains elusive mostly due to the lack of appropriate animal models. Here, we designed a chronic coveted stress (CCS) male mouse model in which a pair of male mouse (owner) and a female mouse (partner) are physically separated from a peer conspecific male mouse (single) that poses a chronic emotional stress. After 7-day modeling, mice exposure to CCS exhibited anxiety-related behaviors involving anxiety-like and aggressive behaviors. Then we identified the cellular and molecular mediator underlying the co-occurring behaviors. Activation and inhibition of GABAergic neurons in the medial preoptic area (mPOA) or the cholecystokinin A receptor (CCKAR) expressed on these cells promoted and rescued the behavioral abnormality in CCS mice, respectively. Whereas the excitability of mPOA GABAergic neurons was increased by CCS modeling, it was bi-directionally regulated by CCKAR. This study established a novel mouse model of anxiety disorders accompanied with aggression and the revealed mechanism provides promising therapeutic targets for co-occurring anxiety and aggression disorders.