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While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (<jats:italic>R<\/jats:italic>)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (<jats:italic>R<\/jats:italic>)-ketamine, but not (<jats:italic>S<\/jats:italic>)-ketamine, is able to counteracts this reduction. (<jats:italic>R<\/jats:italic>)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (<jats:italic>R<\/jats:italic>)-ketamine on social memory. 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KH has also received speakers\u2019 honoraria, consultant fees, or research support from Abbott, Boehringer Ingelheim, Daiichi-Sankyo, Meiji Seika Pharma, Seikagaku Corporation, Dainippon-Sumitomo, Taisho, Otsuka, Murakami Farm and Perception Neuroscience. All other authors declare they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}