Remodeling of pre-existing myelinated axons and oligodendrocytes is stimulated by environmental enrichment in the young adult brain

Oligodendrocyte production and central nervous system (CNS) myelination is a protracted process, extending into adulthood. While stimulation of neuronal circuits has been shown to enhance oligodendrocyte production and myelination during development, the extent to which physiological stimuli induces activity-dependent plasticity within oligodendrocytes and myelin is unclear, particularly in the adult CNS. Here, we find that using environmental enrichment (EE) to physiologically stimulate neuronal activity for 6-weeks during young adulthood in C57Bl/6 mice results in an enlargement of callosal axon diameters, with a corresponding increase in thickness of pre-existing myelin sheaths. Additionally, EE uniformly promotes the direct differentiation of pre-existing oligodendroglia in both corpus callosum and somatosensory cortex, while differentially impeding OPC homeostasis in these regions. Furthermore, results of this study indicate that physiologically relevant stimulation in young adulthood exerts little influence upon the de novo generation of new myelin sheaths on previously unmyelinated segments and does not enhance OPC proliferation. Rather in this context, activity-dependent plasticity involves the coincident structural remodeling of axons and pre-existing myelin sheaths and increases the direct differentiation of pre-existing oligodendroglia, implying constraints on maximal de novo production in the adult CNS. Together, our findings of myelinated axon remodeling and increased pre-existing oligodendroglial differentiation constitute a previously undescribed form of adaptive myelination that likely contributes to neuronal circuit maturation and the maintenance of optimum cognitive function in the young adult CNS. Main pointsO_LIEnvironmental enrichment induces the plasticity of myelinated axons, resulting in axon caliber enlargement and increased thickness of pre-existing myelin sheaths C_LIO_LIEnvironmental enrichment increases the direct differentiation of pre-existing oligodendroglia C_LIO_LIEnvironmental enrichment alters OPC homeostasis C_LI