ARNT2 Controls Prefrontal Somatostatin Interneurons Mediating Affective Empathy

Empathy is crucial for our social lives, and its disruption is a prominent characteristic of various psychiatric conditions. However, the specific genes and neurobiological mechanisms underlying empathy deficits remain elusive. By combining forward genetic mapping with transcriptome analysis, we discovered that the Arnt2 gene encoding a basic-helix-loop-helix (bHLH)-PAS transcription factor is a key driver of significant alteration in observational fear, a basic form of affective empathy. Selective deletion of Arnt2 in somatostatin (SST)-expressing inhibitory neurons resulted in reduced excitability of pyramidal cells, an increase in spontaneous firing, and alteration in in vivo Ca2+ dynamics in SST neurons in the anterior cingulate cortex (ACC), leading to deficits in observational fear and affective state discrimination. Together, our findings provide the first direct evidence that ARNT2 regulates emotion recognition and affect sharing through its functional actions in the cortical inhibitory circuit and highlight the neural substrates underlying social affective dysfunctions in psychiatric disorders.