Brain-wide mapping of oligodendrocyte organization and oligodendrogenesis across the murine lifespan

Abstract

SUMMARYInsulating sheaths of myelin accelerate neuronal signaling in complex networks of the mammalian brain. In the CNS, myelin sheaths are exclusively produced by oligodendrocytes, which continue to be generated throughout life to change patterns of myelination. However, a brain-wide analysis of oligodendrocyte dynamics across the lifespan has not been performed. We developed a rapid, robust cellular mapping pipeline involving tissue clearing, lightsheet microscopy, atlas alignment, and automated segmentation to define the location of all oligodendrocytes in the mouse brain. This analysis demonstrated the remarkable consistency of oligodendrocyte patterns between hemispheres, individuals, and sexes, and established that oligodendrocyte maps estimate myelin coverage. We trained a vision transformer to identify newly generated oligodendrocytes from millions of mature cells, highlighting age- and region-specific differences in oligodendrogenesis, and revealing areas of enhanced oligodendrocyte resilience and regenerative capacity following demyelination, demonstrating the utility of this pipeline for uncovering brain-wide oligodendrocyte dynamics in health and disease.