286. Restoration by ketamine metabolites of cognitive and affective prosocial behaviors in a mouse model of depression

Abstract Background The execution of prosocial behaviors requires the ability to accurately understand and infer others’ affective states. Impairments in prosocial functioning have been shown to be associated with the pathology of several psychiatric disorders. In particular, individuals with depression exhibit reduced cognitive and affective responses to others’ emotions. These impairments may exacerbate feelings of social isolation and hinder successful reintegration into society. Aims & Objectives In this study, we analyzed changes in prosocial behaviors and the associated neural activity in mice before and after the induction of a depression-like state. We also examined the effects of ketamine metabolites on the prosocial behavioral deficits.

Method: All animal procedures were approved by the Animal Care and Use Committee of Hiroshima University. We used chronic corticosterone-treated male C57BL/6J mice as a model of depression. We assessed the cognitive components of prosocial functioning using the three-chamber test, which involved presenting a cage mate that had been injected with complete Freund’s adjuvant (CFA; CFA mouse) alongside an untreated cage mate (non-CFA mouse). Then, we analyzed the social preference of the experimental mouse for the CFA mouse. We also assessed emotional components by measuring the mechanical allodynia transferred socially after interaction with a CFA mouse. Furthermore, to elucidate the neural mechanisms underlying prosocial deficits in corticosterone-treated mice, we analyzed c-Fos expression in relevant brain regions following social interaction with a CFA mouse and performed fiber photometry recordings in the anterior insular cortex during social interaction.

Results: A significant preference for the CFA-injected cage mate and socially transferred allodynia were observed in naïve mice. However, both of these prosocial responses were abolished after the depression model was induced by chronic corticosterone administration. Furthermore, the acute administration of either (2R,6R)-hydroxynorketamine (HNK) or (2S,6S)-HNK to mice treated with corticosterone restored prosocial behaviors. Our analysis of the neural mechanisms underlying prosocial behaviors revealed that social interaction with a CFA mouse significantly activated the anterior cingulate cortex and the insular cortex (IC) in naïve mice, compared with interaction with a non-CFA mouse. In contrast, activation of the anterior IC (aIC) was not observed in corticosterone-treated mice, suggesting that reduced aIC activity may contribute to prosocial behavioral deficits. Discussion & Conclusions The aIC is a pain-associated brain region that contributes to the representation of bodily states. It is also known that its activity increases in response to observed pain in close social relationships. In our previous study, a whole-brain analysis of neuronal activation patterns following ketamine administration revealed that the aIC was particularly activated in brains treated with the (R)-enantiomer of ketamine in a mouse model of depression. Furthermore, we demonstrated that aIC activation contributes to the improvement of social cognitive behaviors induced by (R)-ketamine (Yokoyama et al., Mol Psychiatry 2024). Together with our present findings, impaired prosocial behaviors in the mouse model of depression and their recovery by HNKs may be linked to changes in aIC function, highlighting the importance of this region as a potential therapeutic target.