Sleep and Circadian Rhythm Disorders After Traumatic Brain Injury

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PROJECT SUMMARY/ABSTRACT Almost two million people sustain a traumatic brain injury (TBI) in the United States every year. TBI is a contributing factor to one-third of all injury-related deaths, and more than 40% of survivors suffer long-term impairments, including sleep and circadian rhythm disorders (SCRDs). These disorders may underlie or exacerbate the lifetime elevated risks of metabolic disorders, mood disorders, and neurodegenerative disease found in TBI patients. While the prevalence of SCRDs has long been recognized in TBI patients and recapitulated in animal models, the mechanisms underlying these disorders at the molecular and circuit levels are unknown. This proposal exploits the Drosophila melanogaster genetic model to identify genes that contribute to TBI-induced SCRDs and to determine the role of sleep in mediating molecular and physiological outcomes of TBI. Based on published and preliminary data, we hypothesize that TBI-induced inflammatory responses disrupt the circadian and sleep regulatory systems in the brain, forming a positive feedback loop that prolongs inflammation. We have established a tunable, head-specific Drosophila TBI paradigm that results in chronic sleep reduction and reduced circadian rhythmicity of locomotor behavior after injury. In this model, mild injury induces SCRD without affecting mortality. We seek to answer two key questions: (Aim 1) What are the genetic drivers of sleep and circadian remodeling at various phases after TBI? (Aim 2) Can interventions that target sleep and circadian disruption after injury improve TBI outcomes? In Aim 1 we will conduct a candidate knockdown/knockout screen of proinflammatory genes to identify genes that contribute to aspects of sleep and circadian disruption after injury. In Aim 2 we will conduct the first comprehensive analysis of sleep architecture changes after TBI in both sexes of flies. We will use this data to design a paradigm of sleep manipulation at various phases after TBI to examine how sleep changes after TBI affect longevity, locomotor function, and neuronal and glial health. To pursue these aims, I will combine genetic tools for physiological characterization and for sleep manipulation as well a behavioral assays available in the fly model. Use of a novel Drosophila TBI model will allow unparalleled temporally and spatially controlled genetic manipulations to identify not only which genes are important in SCRDs, but in what tissue(s) they act. The proposed study will be impactful as it will define genetic pathways that link fundamental brain processes to TBI and provide the foundation for future investigation with translational implications.