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

Cell. 2021 Feb 4;184(3):709-722.e13. doi: 10.1016/j.cell.2020.12.026. Epub 2021 Jan 21.


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.

Keywords: CRISPR-Cas9; Ca(2+) signaling; G-proteins; NSCs; circadian rhythm; in vivo imaging; melatonin; mini-endoscopes; neural stem cells; subventricular zone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / drug effects
  • Adult Stem Cells / metabolism*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Behavior, Animal / drug effects
  • Calcium / metabolism*
  • Cell Division / drug effects
  • Cell Proliferation / drug effects
  • Circadian Rhythm* / drug effects
  • Cytosol / metabolism
  • Epidermal Growth Factor / pharmacology
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Intracellular Space / metabolism*
  • Melatonin / metabolism
  • Mice
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism*
  • Optogenetics
  • Signal Transduction / drug effects
  • Tryptamines / pharmacology


  • Inositol 1,4,5-Trisphosphate Receptors
  • Tryptamines
  • luzindole
  • Epidermal Growth Factor
  • Melatonin
  • Calcium

Grants and funding