A GABAergic preoptic-raphe circuit mediates paradoxical coupling of anxiety and social preference after comparative...

Social disconnection is a major risk factor for anxiety disorders, the most prevalent mental illnesses worldwide, yet its neural substrates remain unclear. Here, we establish a comparative social deficit (CSD) model in adult male mice that induces a paradoxical phenotype of increased anxiety-like behavior together with heightened social preference, a pattern conceptually similar to human loneliness. Mechanistically, CSD increases the excitability of medial preoptic GABAergic (mPOA^Gad2) neurons, which bidirectionally regulate CSD-induced behavioral changes. Transcriptomic and electrophysiological analyses identify downregulation of the Kv4.3 potassium channel (Kcnd3) as a molecular driver of mPOA^Gad2 hyperexcitability. Furthermore, mPOA^Gad2 neurons exert monosynaptic inhibition onto dorsal raphe serotonergic (DRN^5-HT) neurons. This inhibitory projection, strengthened by CSD, mediates CSD-induced behavioral effects. These findings define a molecular and circuit mechanism by which social disconnection remodels mPOA-DRN interactions to drive the paradoxical coupling of anxiety and elevated social preference, providing a translational framework for understanding loneliness-related psychiatric vulnerability.