Cortical demyelination plays a critical role in the pathogenesis of progressive multiple sclerosis (MS), leading to physical and cognitive disability and brain atrophy. It is not known whether the pattern of cortical myelination is re-established following injury.

MOBP-EGFP transgenic mice aged 8-10 weeks old were fed the oligodendrocyte toxin, cuprizone (0.2%), for three weeks and resulting changes in myelination were followed by repeated two-photon imaging through chronic cranial windows implanted over the somatosensory cortex.

Cuprizone exposure induced near complete oligodendrocyte loss and demyelination in the upper layers of the cortex within five weeks. Newly formed oligodendrocytes appeared at a much higher rate than the generation of new oligodendrocytes in control mice. Oligodendrocyte cell bodies appeared in locations distinct from those occupied prior to cuprizone exposure, demonstrating that the global pattern of oligodendrocytes is not maintained after injury. Remyelinating oligodendrocytes formed new internodes that, after an initial period of remodeling, remained remarkably stable. Single remyelinating oligodendrocytes replaced sheaths and formed sheaths around axons that were previously unmyelinated, thereby generating a novel myelination pattern. In cases of internode replacement, nodes of Ranvier often appeared in a similar location, suggesting that key molecular cues that define the placement of myelin are preserved after myelin is lost. Sensory enrichment after demyelination appeared to prevent the loss of some oligodendrocytes, helping to preserve the pattern of myelination formed prior to injury.

The ability to monitor remyelination of individual axons in living animals offers new opportunities for defining the mechanisms of oligodendrogenesis and axon recognition, as well as evaluating the effectiveness of potential therapeutics in vivo.