Oxytocin attenuates isolation-evoked emotional and social behavioral dysregulation through neural, immune, and microbiota mechanisms

Chronic social isolation (SI) beginning in adolescence can lead to serious mental health problems and social skill deficits, potentially linked to altered development and function of the prefrontal cortex (PFC), a brain region frequently implicated in neuropsychiatric disorders. Oxytocin (OXT), a neuropeptide renowned for its prosocial effects, holds significant potential as an intervention for neuropsychiatric disorders. However, the efficacy of OXT in ameliorating mental disorders induced by adolescent-onset chronic SI remains uncertain. In this work, four-week-old C57BL/6 J mice were subjected to three months of SI, and subsequent alterations in their emotional and social behaviors were assessed. Thereafter, OXT was administered intranasally to SI mice to evaluate the effects of the intervention. The results show that exposure to SI leads to anxiety- and depression-like behaviors, deficits in social novelty recognition, and long-term impairments in social memory. OXT intervention effectively reversed the damage caused by SI, including improvements in behavioral deficits, increased expression of MAP-2 and PSD-95 in PFC, downregulation of abnormally elevated OXT receptor levels, reduction of neuroinflammation, and modulation of gut microbiota homeostasis. Our study confirms the therapeutic effects of OXT in reversing isolation-induced neuropsychiatric disorders and elucidates its potential regulatory mechanisms, offering important implications for clinical interventions.