Local demyelination rekindles oligodendrocyte precursor dynamics and remyelination in old age

Abstract Cortical myelination is critical for circuit function, plasticity, and long-term stability in the adult brain. With age and disease, the capacity to restore myelin after oligodendrocyte (OL) loss declines, and this failure is thought to reflect intrinsic limitations of OL precursor cells (OPCs) and a loss of permissive cues within the cortical environment. Here, using single-OL ablations and intravital imaging in mice, we show that as cortical remyelination efficiency declines, OPC motility declines, a phenomenon that can be mimicked by blocking CXCL12/CXCR4 signaling. Counter to prevailing notions, however, we find that even in aging, OPCs retain the capacity to generate new OLs and sheath axons, which can be rekindled by a graded demyelinating stimulus, inducing a more juvenile OPC motile state. This reveals an unrecognized remyelination potential in aging and identifies OPC dynamics as a key determinant of cortical remyelination, a property that could be targeted to improve myelin repair.