Circadian Clock-mediated Brain Repair System: Circadian Clocks Respond to Brain Damage to Recruit Adult Neural Stem Cells for Repair

The brain has the most complicated structure with diverse microenvironments, tightly controlled for brain functions. Circadian clocks are endogenous oscillators generating cell-autonomous rhythms in cellular processes. They are distributed across the brain and synchronized to the local macro- and micro-environments by the action of external cues. Circadian clocks in different brain regions also communicate by neuro-circuits and paracrine/humoral cues to coordinate physiological processes. Therefore, once insults to the brain change microenvironments, this affects local circadian clocks. This suggests that altered circadian clocks in the lesions may signal other brain regions for further processes. However, how these microenvironmental changes affect local circadian clocks, and with what consequences, is mostly unknown. Here, we show that within demyelinating lesions, a common brain pathology with variable degrees of recovery, astrocyte circadian clocks produce the Wnt inhibitor SFRP1 and SFRP5. Unexpectedly, SFRP1 and SFRP5 signal to the subventricular zone (SVZ) to reduce the circadian transcription factor BMAL1. This sequence of events causes adult neural stem cells in the SVZ to differentiate into oligodendrocyte lineage cells which are then supplied to demyelinated lesions. Our findings show that circadian clocks in demyelinating lesions respond to microenvironmental changes and communicate with the SVZ to enhance a natural repair system, spontaneous remyelination.