Cell Type-Specific Downregulation of Dnmt3a in Nucleus Accumbens Oligodendrocytes Prevents Myelin Damage and Reduces Susceptibility to Social Stress in Male Mice.

Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in stress-related neurobiological adaptations. In this study, we employed a well-established mouse model of chronic social defeat stress (CSDS) to investigate the functional role of Dnmt3a in modulating individual susceptibility to social stress. Male C57BL/6J mice were exposed to chronic/submaximal social defeat stress (CSDS/SSDS). AAV vectors were used to achieve Dnmt3a overexpression or global and oligodendrocyte-specific knockdown in the nucleus accumbens (NAc). Behavioral tests, including social interaction, open field, and elevated zero maze, were conducted alongside Western blotting and immunofluorescence assays. CSDS selectively increased Dnmt3a expression in NAc oligodendrocytes of stress-susceptible mice. Overexpression of Dnmt3a in the NAc enhanced susceptibility to stress, whereas its knockdown conferred resilience, without affecting baseline behaviors. Dnmt3a negatively regulated myelin basic protein (MBP) and dopamine D1 receptor expression. Stress-susceptible mice exhibited shortened myelinated segments and reduced D1 receptor levels, while D2 receptor expression remained unchanged. Dnmt3a in NAc oligodendrocytes modulates susceptibility to social stress through a Dnmt3a-MBP/D1 receptor-NAc pathway, highlighting a critical glia-neuron interaction. This mechanism extends our understanding of the neurobiological basis of stress-related disorders and positions Dnmt3a as a promising therapeutic target for developing precision interventions or biomarkers.