Abstract Myelin formation by oligodendrocytes regulates conduction velocity and functional integrity of neuronal axons. While individual oligodendrocytes form myelin sheaths around multiple axons and control the functions of neural circuits in the brains, it remains unclear if oligodendrocytes selectively form myelin sheaths around the specific types of axons. In this study, we developed a method for observing a single oligodendrocyte and its myelin sheaths around different types of axons in the mouse cerebellar white matter. This was achieved by combining sparse fluorescent labeling of oligodendrocytes by attenuated rabies virus and subsequent immunostaining for axonal markers along with tissue clearing. We revealed that approximately half of the oligodendrocytes showed a preferential myelination of axons originating from Purkinje cells in the adult mice. The preference for Purkinje cell axons was more pronounced during development, when the process of myelination within cerebellar white matter was initiated; over 90% of oligodendrocytes preferentially myelinated the Purkinje cell axons. The transgenic mice that label early born oligodendrocytes showed that their myelin sheaths were predominantly formed around Purkinje cell axons in the adult cerebellar white matter. These results suggest that a significant proportion of oligodendrocytes preferentially myelinate functionally distinct axons in the cerebellar white matter, and the axonal preference of myelination is established during development.

Axonal selectivity of myelination by single oligodendrocytes established during development in mouse cerebellar white matter