The molecular circadian clock as a causal mediator of sleep-regulated neurophysiology and cognition

Sleep deprivation disrupts memory consolidation, and alters gene transcription in the cortex and hippocampus. We hypothesize that sleep deprivation-induced deficits in memory processes are caused in part by misregulation of the molecular circadian (~24hr) clock. Until now, experimentally testing this hypothesis has been a major challenge. Specifically, the molecular clock controls sleep and wake behavior through effects on the suprachiasmatic nucleus and other sleep-regulatory circuits. Furthermore, sleep and wake cause widespread, simultaneous changes in transcription, translation, neural activity, neuromodulation, and hormone release. Thus ascribing functional causality to one specific state-dependent variable (and in particular, clock gene expression) has proven difficult. Here, we propose to develop and use novel optogenetic tools to rapidly up- or downregulate individual clock genes in vivo, in a circuit-specific manner, independent of the animal’s behavioral state. We will use cutting-edge computational models and bioinformatic analyses to optimize optogenetic regulation of clock genes in the brain. We will test our hypotheses using both traditional and novel optogenetic tools, computational modeling, bioinformatics, behavioral analysis and electrophysiology. This can only be achieved by a synergistic collaborative intercontinental, interdisciplinary research team: a group at the University of Düsseldorf (Germany) will develop optogenetic tools, a group at the Korea Advanced Institute of Science and Technology (South Korea) will carry out mathematical modeling and bioinformatics analyses of CCGs, and groups at the University of Michigan (United States) will study effects on cortical plasticity, and a group at the University of Groningen (Netherlands) will examine effects on hippocampus-mediated memory.