TIMING NEUROGENESIS: CIRCADIAN REGULATION OF ADULT NEURAL STEM CELLS IN THE MOUSE SUBVENTRICULAR ZONE

The ability to track circadian fluctuations has evolved as an adaptation in organisms, enabling them to anticipate predictable environmental changes. This temporal awareness is also observed at the cellular level, where a self-sustained molecular clock composed of transcription–translational feedback loops drives daily rhythmic gene expression. One context in which 24-hour rhythmicity is relevant is the regulation of adult neural stem cells (aNSCs) in the mouse brain, which reside in two neurogenic niches: the dentate gyrus of the hippocampus and the subventricular zone (SVZ). The existence of a functional circadian clock regulating rhythmic activation in the aNSCs of the SVZ has not yet been investigated. Therefore, we investigated whether SVZ aNSCs proliferate in a time-of-day-dependent manner in vivo and whether such rhythmicity is driven by an endogenous molecular circadian clock. Immunohistochemistry on brain sections from PER2::VENUS mice on a 4h sampling scheme revealed a higher number of proliferating and S-phase cells during the dark phase, which was abolished in Per2^-/- mice. Moreover, anti-phase cycling of PER2 and BMAL1 in aNSCs across the day suggested the existence of a circadian TTFL within these cells. To investigate circadian regulation of molecular pathways in aNSCs, we performed time-series bulk RNA sequencing on in vitro aNSCs, which revealed several, but distinct rhythmic pathways in active aNSCs versus quiescent aNSCs. Together, these findings suggest that SVZ aNSC proliferation is likely regulated by their endogenous circadian clock, underscoring circadian control as an additional layer of neural stem cell regulation.