Focal-White Matter Lesions Stimulate Circuit Wide Myelinogenesis to Facilitate Myelin Repair

Focal demyelination results in conduction block along neural circuits, leading to functional deficits in diseases such as multiple sclerosis (MS). As demyelination disrupts circuit function, could oligodendroglia in non-lesioned regions compensate for circuit dysfunction and contribute to lesion repair? To address this possibility, lysolecithin-induced demyelination in the corpus callosum was performed concomitantly with neuron-specific AAV labeling and cell-lineage tracing of new myelin. We demonstrate non-lesioned regions of the contralateral and ipsilateral cortex display enhanced myelinogenesis, preceding lesion remyelination. By labeling nascent and pre-existing myelin using dual-inducible reporters, we find that myelinogenesis is significantly enhanced in the ipsilateral non-lesioned cortex and corpus callosum, without alteration to pre-existing myelin. Selectively ablating the newly formed oligodendrocytes outside of the lesion impairs remyelination, while enhancing myelination in non-lesioned regions accelerates lesion repair. Collectively, our results establish that focal lesions induce compensatory myelinogenesis to promote remyelination, highlighting the therapeutic potential of early pro-myelinating interventions.