부산대학교 도서관

Keywords neural stem cells; NSCs; subventricular zone; in vivo imaging; mini-endoscopes; circadian rhythm; melatonin; CRISPR-Cas9; Ca2+ signaling; G-proteins Highlights * Adult neural stem cell (NSC) activation is regulated by the day/night cycle * NSC states differ in Ca.sup.2+ dynamics and steady-state levels * Darkness-induced melatonin signaling modulates NSC states via calcium * Mimicking quiescent-state Ca.sup.2+ entry reverses switch to NSC proliferative state Summary 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 Ca.sup.2+ dynamics and promoted NSC activation. We further discovered a Ca.sup.2+ signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca.sup.2+ pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca.sup.2+ fluxes to mimic quiescent-state-like Ca.sup.2+ dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals. Author Affiliation: (1) CERVO Brain Research Center, Quebec City, QC G1J 2G3, Canada (2) Universite Laval, Quebec City, QC G1V 0A6, Canada (3) Division of Physiological Genomics, BioMedical Center, Ludwig-Maximilians-Universitat Munchen, Munich, Germany (4) Institute of Stem Cell Research, Helmholtz Center, Munich, Germany (5) Department of Cell Biology and Anatomy, Ludwig-Maximilians-Universitat Munchen, Munich, Germany (6) Munich Cluster for Systems Neurology (SyNergy), Munich, Germany * Corresponding author Article History: Received 8 May 2020; Revised 25 August 2020; Accepted 15 December 2020 (miscellaneous) Published: January 21, 2021 (footnote)7 Lead contact Byline: Archana Gengatharan (1,2), Sarah Malvaut (1,2), Alina Marymonchyk (1,2), Majid Ghareghani (1,2), Marina Snapyan (1,2), Judith Fischer-Sternjak (3,4), Jovica Ninkovic (4,5), Magdalena Gotz (3,4,6), Armen Saghatelyan [armen.saghatelyan@fmed.ulaval.ca] (1,2,7,*)