Della Flora Nunes, G. | Search bioRxiv

bioRxiv2026

Premyelinating Oligodendrocyte Survival Governs CNS Remyelination

Myelinating oligodendrocytes are produced throughout life by the constitutive differentiation of oligodendrocyte precursor cells (OPCs). However, the rate of oligodendrocyte generation changes with age and after a demyelinating injury. Here, we report that variation in premyelinating oligodendrocyte (preOL) survival modulates the rate of oligodendrocyte production. PreOL survival increased to drive the regeneration of oligodendrocytes after demyelination and decreased in middle-aged mice to contribute to age-related decline in oligodendrocyte production. Furthermore, we demonstrate that treatment with a GPR17 antagonist, Myro-02, increases oligodendrocyte replacement by promoting preOL survival after demyelination. Together, our findings demonstrate that increased survival of preOLs governs the regeneration of oligodendrocytes following demyelinating injury and suggest that modulating preOL survival may be an alternative therapeutic avenue to promote oligodendrocyte regeneration.

neuroscience↗

bioRxiv2025

Myelin Supports Cortical Circuit Function Underlying Skilled Movement

Primary motor cortex (M1) is among the most heavily myelinated cortical regions and generates tightly coordinated neuronal activity patterns that drive skilled movement. Activity-dependent myelination is required for motor skill acquisition, and myelin loss in demyelinating diseases such as multiple sclerosis leads to motor impairment. Yet how myelination influences neuronal activity underlying skilled behavior remains unclear. By combining in vivo imaging of oligodendrocytes with high density Neuropixels recordings during dexterous reaching, we demonstrate that cuprizone-induced demyelination impairs movement efficiency, and alters cell-type-specific neuronal activity and synchrony in a manner that predicts motor output. Using a computational model constrained by these data, we identify inhibitory axonal propagation failures as a mechanistic link between myelin loss and altered circuit function. Partial remyelination normalizes cortical network-level metrics and reach consistency but leaves smooth movement impaired, revealing a selective vulnerability in inhibitory circuits. These findings close a critical gap between cellular models of demyelination and clinical motor impairment by demonstrating how myelin supports cortical circuit dynamics driving skilled behavior.

neuroscience↗