Functional and Developmental Analysis of Sleep Drive Circuitry

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1. Abstract Sleep is a behavior that is critical for maintaining human health, and its importance is underscored by its conservation across phylogeny. Much of the research on the neural mechanisms underlying sleep has been performed in adults. However, sleep is distinctly different in young animals and may play a key role in proper development of the nervous system. Not only do young animals of nearly all species sleep more than mature adults, this sleep is deeper and more consolidated. It is thought that this longer and deeper sleep may either be a consequence of and/or contribute to the greater developmental and plastic processes occurring in the brains of young animals. However, how this sleep of young animals is regulated is poorly understood, and how it contributes to the proper development of neural circuits remains understudied. Our lab recently discovered a group of neurons that control homeostatic sleep drive in mature animals. These neurons become highly active after sleep deprivation to trigger homeostatic rebound sleep in mature animals and are both necessary and sufficient for sleep drive. Intriguingly, we also found that these sleep drive neurons are highly active at baseline in young animals. These data, along with additional preliminary findings, have led me to hypothesize that this sleep drive circuit is responsible for inducing high baseline sleep in young animals and that this circuit undergoes a developmental switch to only control homeostatic sleep rebound in adults. My additional preliminary data also suggest that loss of sleep in young animals impairs normal sleep patterns in adults. Thus, I also hypothesize that ontogenetic sleep (sleep during development) plays an important role in proper development of sleep drive circuitry. In Aim 1, I propose to study this sleep drive circuit to address the molecular, cellular, and physiological mechanisms regulating sleep in young animals. In Aim 2, I will investigate the role of putative downstream sleep effector neurons in ontogenetic sleep and also ask whether ontogenetic sleep, in turn, affects the development of this sleep drive circuit. The experiments proposed in the above aims will help fill a significant gap in our knowledge about the neural circuitry controlling sleep throughout development. In addition, the resulting findings may deepen our understanding of the molecular and circuit principles governing generation of sleep drive more broadly. Importantly, performing this work will provide me with a strong conceptual and technical training in sleep and neural circuit analyses underlying behavior. With the support of my proposed mentorship team and the outstanding training environment, the research and training activities proposed here will ideally position me for a future career in academic neuroscience research.