Remyelination restores myelin content on distinct neuronal subtypes in the cerebral cortex

ABSTRACTAxons in the cerebral cortex exhibit diverse patterns of myelination, with some axons devoid of myelin, some exhibiting discontinuous patches of myelin, and others continuous myelin that is interrupted only by nodes of Ranvier. Oligodendrocytes establish this pattern by sorting through a high density of potential targets to select a small cohort of axons for myelination; however, the myelination patterns established on distinct excitatory and inhibitory neurons within the cortex remain to be fully defined and little is known about the extent to which these patterns are restored after oligodendrocyte regeneration. Here we show that axons in layer I of the somatosensory cortex, a key region for integration of input from local and distant sources, exhibit an extraordinarily diverse range of myelination patterns, even among distinct neuronal subtypes. Although larger axons were more often selected for myelination, neuronal identity profoundly influenced the probability of myelination. The relative differences in myelination among neuron subtypes were preserved between cortical areas with widely varying myelin density, suggesting that regional differences in myelin abundance arises through local control of oligodendrogenesis, rather than selective reduction of myelin on distinct neuron subtypes. By following the loss and regeneration of myelin sheaths along defined neurons in vivo we show that even though the distribution of myelin on individual PV and VM neuron axons was altered following remyelination, the overall myelin content on these neurons was restored. The findings suggest that local changes in myelin can be tolerated, allowing opportunistic selection of available targets by newly formed oligodendrocytes to restore relative differences in myelin content between functionally distinct neurons.