Brain-wide mapping of oligodendrocyte organization, oligodendrogenesis, and myelin injury

• Brain-wide atlases map oligodendrocyte distribution in aging, injury, and disease • Regionally diverse oligodendrocyte patterns are conserved across the lifespan • Acute demyelination and recovery reflect region-specific resilience and vulnerability • Amyloidosis causes severe myelin loss and distinct plaque pathology in white matter Brain-wide atlases map oligodendrocyte distribution in aging, injury, and disease Regionally diverse oligodendrocyte patterns are conserved across the lifespan Acute demyelination and recovery reflect region-specific resilience and vulnerability Amyloidosis causes severe myelin loss and distinct plaque pathology in white matter Insulating sheaths of myelin accelerate neuronal communication in the mammalian brain. Oligodendrocytes that produce myelin are generated throughout life to gradually increase myelin coverage, but these dynamics have not been defined brain-wide across the lifespan. We developed a cellular mapping pipeline involving tissue clearing, lightsheet microscopy, and AI-assisted analysis to identify the precise location of millions of oligodendrocytes and assess regional myelin density in the mouse brain. These atlases revealed the diversity of oligodendrocyte patterning, which was consistent between brain hemispheres, individuals, and sexes but displayed both age- and region-specific differences. Integration of these atlases with transcriptomic and ultrastructural datasets highlighted underlying mechanisms that may control this patterning. In models of demyelination and disease, we identified regions of enhanced oligodendrocyte resilience and vulnerability and white matter injury near β-amyloid plaques, demonstrating the utility of this pipeline for defining brain-wide oligodendrocyte dynamics in both health and disease.