Adult differentiating oligodendrocytes remain in the premyelinating stage for ~2 days [9], during which they integrate as mature oligodendrocytes (top) or degenerate (bottom). High axonal activity (top) increases vesicular release [4,5], and the release of growth factors [132,133] to facilitate the initiation of myelination and integration into neuronal circuits. During the later stages of mature oligodendrocyte integration (top right), sustained axonal activity may upregulate local myelin protein translation [96,165,185] and drive actin depolymerization-driven myelin wrapping [95,96]. Decreasing axonal activity (bottom, left) reduces vesicular release [4,5,90] and the release of growth factors [131], which limits myelin initiation and integration. If appropriate myelination cues are not received during this short period (bottom, right), programmed cell death pathways are activated [153,186] and oligodendroglia degenerate and are phagocytocized by microglia (red, [145]).