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

The acquisition of a new skill or motor program is thought to be mediated by changes in neuronal plasticity at early stages of learning, which is later stabilized by new myelin generated by oligodendrocytes. In this study, the authors show that oligodendrocyte precursors exist in a ‘primed’ state, which allows them to contribute to early stages of motor learning. We identified mRNA encoding the ecto-enzyme Enpp6 as a marker of newly forming oligodendrocytes, and used Enpp6 in situ hybridization to track oligodendrocyte differentiation in adult mice as they learned a motor skill (running on a wheel with unevenly spaced rungs). Within just 2.5 h of exposure to the complex wheel, production of Enpp6 -expressing immature oligodendrocytes was accelerated in subcortical white matter; within 4 h, it was accelerated 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 h 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 concluded that new oligodendrocytes contribute to both early and late stages of motor skill learning.