Genetic, molecular, and neural mechanisms of alcohol-induced effects on sleep

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–––– Project Summary/Abstract ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– Alcohol use and abuse affect millions of people, exacting immense tolls on personal and public health and the economy. One of the most reported consequences of active alcohol use and recovery from alcohol use disorder is insomnia, which includes difficulties falling asleep (increased sleep latency), staying asleep, or achieving high- quality sleep. Alcohol-induced insomnia is highly predictive of relapse, making it an important driver of persistent alcohol abuse. For improved treatment of alcohol use disorder and prevention of relapse, we need to understand the mechanisms of alcohol-associated sleep problems, which are currently unknown. Drosophila offer a valuable approach to unraveling these mechanisms thanks to their translational relevance for sleep and alcohol responses and their high economy of scale. My preliminary data show that a single, high-dose alcohol exposure robustly increases sleep latency, the time it takes to fall asleep, for at least six nights. Based on these findings, in Aim 1, I propose determining the genetic contributions to alcohol-induced sleep delays. I will do so by examining human genes, identified with Genome-Wide Association Studies, that are linked to alcohol and sleep phenotypes. I will test these candidate genes in the Drosophila nervous system, examining their necessity for alcohol-induced sleep effects. In Aim 2, I will determine the roles of neurons and conserved neurotransmitter systems in alcohol- induced sleep disruptions. I will utilize a subset of a few hundred uncharacterized neurons that our lab has found to affect both sleep latency and alcohol responses. I will examine the role of these in alcohol-induced sleep delays and determine the neurotransmitters required for regulating sleep, alcohol responses, and their interaction in these neurons. Together, these experiments will identify potential genetic and molecular targets for treating alcohol use disorders and their associated sleep disturbances. While I have a strong academic background and laboratory experience focused on rodent addiction, I require additional training to develop as an independent researcher. My goals as a graduate student are to build strength in neurogenetics, Drosophila model systems, the neurobiological mechanisms of alcohol abuse, behavioral analysis, and tools for studying these topics. This foundation will prepare me to pursue my long-term career goal of obtaining a tenured faculty position. I anticipate that my preliminary data plus the aims described here will produce at least one scientific manuscript each while also supplying preliminary data for future grant applications. Under the training provided by this fellowship, I will refine technical skills, deepen my expertise in alcohol research, and become independent in experimental choice, design, analysis, and communication. These skills will propel me on my trajectory towards a career as an independent researcher and educator. While facilitating these goals, the proposed project will also shed necessary first mechanistic light on the phenomenon of alcohol-induced sleep loss, which is a critical contributor to persistent human alcohol use.