Medial preoptic CCKAR mediates anxiety and aggression induced by chronic emotional stress in male mice.

Anxiety disorders frequently accompany aggression, with their co-occurrence predicting greater functional impairment and poor prognosis. Nevertheless, the underlying neural mechanisms remain elusive, primarily due to a lack of appropriate animal models. Here, we designed a chronic conspecific outsider stress (CCS) model in which male mice underwent perceived social threats and exhibited increased anxiety-like behaviors accompanied by aggression. CCS led to activation and hyperexcitability of GABAergic neurons in the medial preoptic area (mPOA). Inhibition of mPOA GABAergic (mPOA) neurons rescued CCS-induced anxiety-like and aggressive behaviors, whereas activating these cells induced susceptibility to CCS. Moreover, CCS upregulated the mRNA and protein expression of the sexual-dimorphic gene, cholecystokinin A receptor (CCKAR)-encoding gene in the mPOA. Importantly, the knock-down and overexpression of CCKAR in the mPOA neurons had alleviating and promoting effects on anxiety-like and aggressive behaviors, aligning with decreased and increased excitability by the anxiolytic CCKAR antagonist MK-329 and the anxiogenic CCKAR agonist A71623 in mPOA neurons, respectively. Overall, our study characterizes a novel mouse model of anxiety disorders accompanied by aggression and the neuronal subpopulation and molecular mediator of the aberrant behaviors provide potential targets of intervention for anxiety disorders with aggression.