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

A GABAergic preoptic-raphe circuit links social deficit to increased anxiety and social preference in male mice, with 50% of mPOA Gad2 neurons showing hyperexcitability.

• Why it matters: Understanding the neural basis of social disconnection is crucial because it is a major risk factor for anxiety disorders, yet its underlying mechanisms are not well understood.
• What they did: The study used a comparative social deficit model in adult male mice, combined with transcriptomic and electrophysiological analyses, to identify downregulation of Kcnd3 and its role in mPOA Gad2 neuron hyperexcitability, and mapped their inhibitory projections to dorsal raphe serotonergic neurons.
• The result: Findings reveal that social deficit-induced hyperexcitability of mPOA Gad2 neurons enhances inhibition of DRN 5-HT neurons, mediating the paradoxical increase in anxiety and social preference, offering a framework for loneliness-related psychiatric vulnerability.