CHEMOGENETIC ACTIVATION OF MATURE OLIGODENDROCYTES REVEALS A ROLE FOR MYELIN PLASTICITY IN EMOTIONAL CIRCUITS

Experience and neuronal activity can induce dynamic changes in myelination throughout development and adulthood, suggesting a form of plasticity that enables the brain to adapt to environmental demands. While myelin remodeling is classically attributed to newly generated oligodendrocytes derived from precursor cells, the contribution of mature oligodendrocytes to activity-dependent myelin plasticity remains poorly understood. To investigate this, we used inducible transgenic mice expressing the DREADD receptor hM3Dq selectively in PLP⁺ oligodendrocytes. Chemogenetic activation of mature oligodendrocytes increased myelin thickness and shortened nodes of Ranvier, consistent with adaptive changes in existing myelin rather than the formation of new myelin sheaths. Beyond structural effects, sustained mature oligodendrocytes activation led to alterations in physiological and behavioral responses, including increased anxiety-like behavior and impaired extinction of fear memories, particularly in female mice. These changes were associated with altered neuronal activity in brain regions involved in emotional processing, suggesting that myelin remodeling by mature oligodendrocytes can influence circuit function and behavior. To test the converse hypothesis—that stress itself can induce myelin remodeling—we subjected mice to immobilization stress, a well-established model of post-traumatic stress disorder. Stress exposure induced comparable myelin remodeling, notably affecting nodes of Ranvier in cortical and limbic regions, again with a stronger impact in female mice. Together, these findings demonstrate that mature oligodendrocytes actively contribute to myelin plasticity and that both stress-induced and experimentally driven myelin remodeling can modulate neuronal circuits and innate emotional behavior.