Cross-Species Analyses of the Molecular and Circuit Basis ofSleep

Summary Sleep is an enigmatic behavior that is conserved across the animal kingdom. The mechanisms underlying the regulation of sleep remain poorly understood, and the function of sleep is even more elusive. Yet, dysregulation of sleep is a major cause of human morbidity, and understanding why we sleep is a fundamental question in neuroscience research. We propose that gaining a deep understanding of sleep requires studying this process across molecular, circuit, neurophysiological, and behavioral levels. To accomplish this, our group has been using a multidisciplinary, cross-species approach (Drosophila and mice) to study sleep. The recent work of our group has coalesced around two main themes: how circadian time organizes sleep and arousal and how dedicated neural circuits encode homeostatic drive. Our investigations into these processes have led to new insights into 1) the conserved molecular mechanisms mediating the circadian regulation of sleep and arousal; 2) how different types of neural codes impact plasticity and behavior; and 3) how sleep drive is generated, released, and persists in time. In this research program project, we will build upon our prior studies of the circadian and homeostatic regulation of sleep and develop new approaches to investigate the neurophysiology and function of sleep. First, we will address whether the temporal coding mechanisms found in Drosophila clock neurons are also conserved in the mammalian suprachiasmatic nucleus. Compared to our understanding of the circadian clock, much less is known about the homeostatic regulation of sleep. Nevertheless, we predict that the nature of neural circuits underlying sleep homeostasis will be conserved, and we will seek to identify a sleep homeostatic integrator circuit in mice. Our studies of the cellular mechanisms mediating sleep homeostasis have led us to examine the role of astrocytes in sleep behavior. We plan to determine whether sleep-regulating molecular pathways in these cells are conserved and will perform systematic investigations into the role of astrocytes in regulating neuronal physiology and behavior. To fully exploit the power of the Drosophila model for studying sleep, we will develop a new multimodal imaging method for characterizing and quantifying sleep. Our research has largely focused on how sleep is regulated, but in the future will also address the function of sleep in neural plasticity using a simple, defined circuit and new electrophysiological methods. Finally, we are extending our studies into human disorders, including studying the genetic basis of familial sleepwalking. Our goal is to not only delineate conserved mechanisms underlying sleep and its function, but also to uncover fundamental neurobiological principles governing these processes.