In this study, the authors show that subjecting adult animals to prolonged social isolation results in impaired heterochromatin formation in oligodendrocytes and decreased myelin thickness, specifically in the prefrontal cortex. This suggests that social experience can regulate myelin plasticity in the adult via an epigenetic program. Protracted social isolation of adult mice induced behavioral, transcriptional and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC) and impaired adult myelination. Social re-integration was sufficient to normalize behavioral and transcriptional changes. Short periods of isolation affected chromatin and myelin, but did not induce behavioral changes. Thus, myelinating oligodendrocytes in the adult PFC respond to social interaction with chromatin changes, suggesting that myelination acts as a form of adult plasticity.