Figure 3. Myelin dysregulation can arise from different stages of oligodendroglial lineage and myelin adaptation.

A variety disease states can influence different stages of myelin formation or adaptation and contribute to myelin dysregulation. 1. Oligodendroglial lineage dynamics: Pathologies affecting OPC populations and their dynamics can generate a knock-on effect on the rest of the lineage. These can vary from OPC population alterations in particular brain regions to differentiation blocks, and to overall reduction in the survival of oligodendroglial cells. For example, certain cancer therapies induce disruptions in white matter oligodendroglial cells, which also affects activity-regulated myelin plasticity and cognition. 2. Myelin integrity, axonal support: several debilitating diseases and conditions are characterized by demyelination, which leads to deterioration of neuronal functions. In addition to demyelinating disorders, neurodegenerative and neuropsychiatric diseases also exhibit white matter disruption. Microenvironmental toxicity or neuronal pathology can contribute to the decline of myelin and oligodendrocytes. 3. Circuit level myelin adaptations: neuronal-activity regulated myelination is adaptive in the healthy brain, and contributes to cognitive functions by fine-tuning neuronal network coordination. Abnormal patterns of neuronal activity might cause maladaptative myelination, which in turn could promote pathological neuronal network function, particularly in neuropsychiatric diseases. Cellular level disruptions in oligodendroglial cells (1) or abnormal myelination (2) can cause circuit level (3) myelin dysregulation, which can alter circuit function and cognition. Figure created in BioRender.