Rapid production of new oligodendrocytes is required in the earliest stages of motor skill learning

We identified a novel marker of newly-forming oligodendrocytes – the ecto-enzyme Enpp6 – and used this to track oligodendrocyte differentiation in adult mice as they learned a motor skill (running on a wheel with unevenly spaced rungs). Production of Enpp6 - expressing immature oligodendrocytes was accelerated within just 2.5 hours exposure to the complex wheel in subcortical white matter and within 4 hours in motor cortex. Conditional deletion of Myelin regulatory factor (Myrf) in oligodendrocyte precursors blocked formation of new Enpp6(+) oligodendrocytes and impaired learning within the same ~2-3 hour time frame. This very early requirement for oligodendrocytes suggests a direct and active role in learning, closely linked to synaptic strengthening. Running performance of normal mice continued to improve over the following week accompanied by secondary waves of oligodendrocyte precursor proliferation and differentiation. We conclude that new oligodendrocytes contribute to both early and late stages of motor skill learning.