Abstract

Motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursors (OLPs). We asked whether OL production is also required for non-motor learning and cognition, using T-maze and radial arm maze tasks that tax spatial working memory. Maze training stimulated OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation; myelin sheath formation was also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impaired training-induced improvements in maze performance. Remarkably, there was a strong positive correlation between working memory performance of individual mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+ neurons in the mPFC, underscoring the key role of OL lineage cells in cognitive performance.