BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep
Daniela Rojo, Louisa Dal Cengio, Anna Badner, Samuel Kim, Noriaki Sakai, Jacob J. Greene, Tess Dierckx, Lindsey Catherine Mehl, Ella Eisinger, Julia Ransom, Caroline Arellano-Garcia, Mohammad E. Gumma, Rebecca L. Soyk, Cheyanne M. Lewis, Mable Lam, Maya K. Weigel, Valentina Martínez Damonte, Belgin Yalçın, Samuel E. Jones, Hanna M. Ollila, Seiji Nishino, Erin M. Gibson
Abstract
Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.