Demyelination regulates BMAL1 to signal adult neural stem cells to initiate oligodendrogenesis

Circadian clocks, endogenous oscillators generating cell-autonomous rhythms, are intrinsic in most cells, including neural cells. Under physiological conditions, they are synchronized to local macro- and micro-environments by the action of external cues and regulate various cellular processes like metabolism, proliferation, and differentiation. Demyelination is a common form of central nervous system pathology that has variable degrees of recovery. Demyelination changes the surrounding microenvironment via damaged myelin and activation of glial cells. How these microenvironmental changes affect circadian clocks in the lesions, and their consequences are mostly unknown. Here, we show that circadian clocks are altered in demyelinating lesions. This initiates molecular signals that induce adult neural stem cells (NSCs) in the subventricular zone (SVZ) to produce oligodendrocyte lineage cells (OLCs) to enhance restoring myelin. Circadian clocks in demyelinating lesions shortened the period to transcribe more clock target genes, including the Wnt inhibitors SFRP1 and SFRP5. Unexpectedly, SFRP1 and SFRP5 signaled to the SVZ to reduce the circadian transcription factor BMAL1, causing more SVZ NSCs to differentiate into OLCs. We further found that inhibition of Bmal1 expression in astrocytes, the signal-producing cells in the lesions, prevented the migration of OLCs from the SVZ to demyelinating lesions. Thus, our findings show that communication between demyelinating lesions and the SVZ via local circadian clocks enhances the remyelination process by supplying OLCs from the SVZ to the lesions.