Talks:
Systems Biology of Mammalian Sleep/Wake Cycles/Toward Molecular definition of NREM and REM sleeps
Name:
Hiroki Ueda
Position:
Professor
Affiliation:
Synthetic Biology/ Systems Pharmacology
RIKEN(BDR)/ The University of Tokyo
Email:
Photo:
Research Interests:
chronobiology by investigating mammalian circadian clocks and sleep/wake cycles
Selected Publications:
Abstract:
The detailed molecular and cellular mechanisms underlying NREM sleep (slow-wave sleep) and REM sleep (paradoxical sleep) in mammals are still elusive. To address these challenges, we first constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep. Comprehensive bifurcation analysis predicted that a Ca2+-dependent hyperpolarization pathway may play a role in slow-wave sleep. To experimentally validate this prediction, we generate and analyze 26 KO mice, and found that impaired Ca2+-dependent K+ channels (Kcnn2 and Kcnn3), voltage-gated Ca2+ channels (Cacna1g and Cacna1h), or Ca2+/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca2+ ATPase (Atp2b3) increases sleep duration. Genetical (Nr3a) and pharmacological intervention (PCP, MK-801 for Nr1/Nr2b) and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Based on these results, we propose a hypothesis that a Ca2+-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals. In this talk, I will also describe how we identify essential genes (Chrm1 and Chrm3) in REM sleep regulation, and propose a plausible molecular definition of a paradoxical state of REM sleep.