Abstract The current studies are based on unexpected data from early brain development in mice establishing that reduced neuronal activity results in premature oligodendrocyte progenitor cell differentiation. These data contrast with the extensive data in the literature that axonal activity increases myelination. The fundamental hypothesis under investigation is that during early development, neuronal activity initially allows and/or enhances OPC proliferation but inhibits premature differentiation. The current studies will use Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-expression in cortical neurons to investigate the impact of decreased or increased neuronal activity on oligodendrocyte progenitor cell proliferation, survival and differentiation in corpus callosum and cortex. scRNASeq studies will characterize the transcriptome changes in oligodendrocyte progenitor cells when cortical neuronal activity is reduced or increased. Our data establishing that reduced neuronal activity induces premature oligodendrocyte differentiation in young mice are unexpected given the significant data in the literature establishing that neuronal activity enhances oligodendrocyte progenitor cell differentiation and myelination later in development. We will therefore investigate when during development the impact of neuronal activity shifts from blocking differentiation to enhancing differentiation.