Metabolic, Genetic and Neurological Control of Sleep Behavior

Abstract

Sleep is a ubiquitous behavior that presents itself in unique ways throughout the animal kingdom and has proven to be necessary for their health. Underlying that behavior are conserved characteristics that prevail over many adaptations that have evolved in different organisms as few animals, if any, have dispensed with sleeping behavior altogether. The conserved nature of the behavior suggests that this behavior is genetically encoded in all animals. A genetic basis would suggest conserved mechanisms of control and shared function across the animal kingdom. However, despite its conserved nature, the precise function of sleep has eluded scientists for centuries. Here, we hope to elucidate some aspects of sleep regulation from an evolutionary as and functional standpoint. In Chapter 1, the basics of sleep are introduced including its neuronal control with a focus on micro-circuits that manage sleep. Additionally, we cover the genetic basis of sleep across the animal kingdom looking at human inheritance of sleep disorders and traits. We also examine Drosophila studies that establish clear genetic control of sleep behavior. Finally, we introduce the relationship between metabolism and sleep with a focus on the interplay between the endocrine system and sleep behavior. This thesis presents work that elucidates the genetic basis of sleep both in the fruit fly as well as in humans. Findings regarding the relationship between disrupting metabolism and sleep are presented in Chapter 2. Specifically, activating insulin signaling in specific brain regions in Drosophila affects metabolism as well as sleep and feeding behavior. Chapter 3 discusses the genetic basis of sleep in humans by following up on an advanced genomic technique that identifies genes causal of insomnia disorder believed to occur in neurons. Knockdowns of the conserved orthologs of these candidates were tested in Drosophila for aberrations in sleep behavior uncovering several possible conserved genes that affect sleep. Finally, Chapter 4 examines insomnia-linked genes that are purported to be localized in human glia by the same methods used in Chapter 3. Leveraging the Drosophila genetic tools, we localize knockdown of orthologs to the glial cells in the fly and examine sleep behavior identifying several conserved genes that regulate sleep in glia. Chapter 5 provides a discussion on the significance of being able to validate genomic studies in humans with the versatile Drosophila model in addition to the implications of connecting sleep and metabolism.