Circadian regulation of brain and body in larval zebrafish

PROJECT SUMMARY Circadian rhythms drastically alter animal behavior through diverse actions on cellular targets throughout the body. Disruptions of sleep-activity cycles account for a wide range of diseases affecting behavior, neurology, metabolism, and muscle physiology. This proposal presents a set of studies designed to understand the mechanisms and interactions of circadian effects on cells and systems spanning the body. Circadian rhythms manifest downstream of pacemakers via signaling molecules that act directly on targets to regulate physiology. Understanding how distinct targets are modified to achieve a constellation of physiological and behavioral rhythms is a major goal in chronobiological research. We study how neurons, muscles, and biomechanics interact in larval zebrafish, a tractable diurnal vertebrate, and our preliminary experiments suggest these animals experience a breadth of circadian changes far more diverse than previously known. Although the zebrafish is an imperfect model of sleep behavior, its clear circadian rhythms combined with its tractability for physiological, behavioral, and genetic approaches make it an ideal system for understanding how circadian rhythms organize and interact across cells and organs. We propose to define how diverse circadian effects on nervous system output and muscle physiology amount to complex behavioral output, by tracking and modeling zebrafish behavior and arousal across the diel cycle. We will manipulate light exposure to disentangle circadian and photic effects on target systems, and we will use computational models to understand how circadian effects interact to shape behavioral output. Furthermore, we will evaluate the breadth of circadian regulation of physiology across cellular targets by performing in vivo electrophysiology and functional imaging. Combining this approach with cellular- resolution transcriptional profiling enables us to define how circadian effector molecules signal divergently across targets. Finally, we will test for interactions across circadian targets by examining rhythms following focal lesions throughout the nervous system. Together these experiments will provide detailed information and models regarding the interaction of circadian effects across cells and systems.