Sleep Deficits induced by Alcohol

––– PROJECT SUMMARY / ABSTRACT –––––––––––––––––––––––––– Sleep Deficits Induced by Alcohol –––– Alcohol use disorders (AUD) are a public health problem for which few effective treatments exist. Alcohol drinking causes sleep disturbances, both acutely, as well as with chronic use. These long-lasting sleep deficits are often ‘alleviated’ by drinking yet more alcohol, thus reinforcing a vicious negative cycle. A large fraction of AUD patients in recovery will continue to experience sleep deficits, even after other physical withdrawal symptoms have subsided. That fraction of abstainers is most at risk for relapse. Despite its obvious clinical significance, very little is understood about the mechanistic links between alcohol consumption and the development of long-lasting sleep deficits, and how these sleep deficits might be addressed to reduce continued or relapsing alcohol use. This proposal aims to undertake a mechanistic investigation into the genes and neurons that regulate alcohol-induced sleep deficits, with the long-term goal of finding interventions to ameliorate these deficits. We use Drosophila as a model organism because of its economy of scale and face- valid behaviors, i.e. alcohol responses that ‘look like’ those in humans. We propose to build on our substantial foundational data showing that sedating alcohol exposures lead to long-lasting sleep deficits for days after alcohol exposure and clearance. This includes loss of total sleep amount, especially at night, an increase in sleep latency, which means that it takes flies longer to fall asleep after lights out, and poor sleep quality — all recapitulating human phenotypes. In Aim1 we will investigate behavioral correlates and predictors of alcohol- induced sleep deficits. In Aim2 we will investigate the genetic mechanisms of ethanol-induced sleep deficits based on our preliminary data from three genes, generated using three orthogonal approaches. We will investigate the role of the insulin receptor signaling pathway, which we have previously shown to regulate behavioral responses to alcohol. We will also test 216 candidate genes associated with sleep phenotypes in humans for their role in alcohol-induced sleep deficits. In Aim3 we will determine neurons and circuits that mediate ethanol-induced sleep deficits, based on our preliminary findings that different neurons have distinct effects on ethanol-induced sleep deficits. This necessary step will allow us to address mutants’ pleiotropy, affecting multiple alcohol responses, and it also paves the way to investigate the molecular changes induced by alcohol that might mediate persistent sleep deficits. Together, these data will provide first mechanistic insights into the long-lasting sleep deficits that are induced by alcohol. Because these deficits pose a significant risk factor for continued and relapsing alcohol use, our mechanistic investigation will also suggest potential interventional strategies.