S)-ketamine (esketamine), one of ketamine enantiomers, has been approved for treatment-resistant depression. Although several preclinical studies have shown that another enantiomer (R)-ketamine (arketamine) has greater potency antidepressant-like effects than esketamine, the antidepressant mechanism of ketamine enantiomers is not fully understood. Here, we aimed to identify brain regions that contribute to the difference in antidepressant action between ketamine enantiomers using isolation-reared mouse model of depression. We found that lower doses of arketamine than esketamine had antidepressant-like effects in isolation-reared mice in the forced swim test. Then, the machine learning classifiers with brain-wide activation mapping in isolation-reared Arc-dVenus reporter mice revealed that the agranular insular cortex (aIC) may contribute to the antidepressant-like effect of arketamine and discrimination between the effects of ketamine enantiomers. Furthermore, a temporary suppression of neuronal activity in the aIC blocked the antidepressant-like effect of arketamine, but not of esketamine, and conversely activation of neurons in the aIC induced antidepressant-like effects in isolation-reared mice. These findings suggest that activation of the aIC is involved at least partly in the antidepressant-like effects of arketamine.
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