Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics

Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca²⁺ dynamics and promoted NSC activation. We further discovered a Ca²⁺ signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca²⁺ pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca²⁺ fluxes to mimic quiescent-state-like Ca²⁺ dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.