Alcohol tolerance encoding in sleep and memory circuits

Project Summary / Abstract A single acute ethanol exposure causes lasting changes in behavior and brain function. Acute changes may form a basis for progressive changes with subsequent ethanol exposures, incrementally increasing the risk of alcohol use disorder. Studies from humans to Drosophila have uncovered strong behavioral and neural links

between the development of ethanol tolerance, an early form of ethanol-induced plasticity, and changes in sleep. We recently discovered in Drosophila that a small group of circadian clock neurons that regulate sleep also encode rapid ethanol tolerance, the form of tolerance that is closely associated with proximal changes in

sleep. Whereas prior work in Drosophila implicated clock pacemaker genes and a potential relationship between sleep and rapid tolerance, our new data provides an anatomical locus and a focus on the specific aspects of the tolerance/sleep interaction. The long-term goal is to determine how ethanol causes changes in

sleep. The expected long-term impact is a better understanding of the relation between addiction and sleep. Because rapid ethanol tolerance appears to map to some but not all sleep regulatory neurons, we hypothesize that ethanol may ‘misuse’ sleep circuitry. Circadian rhythms and sleep are extensively studied in Drosophila. While our understanding of rapid ethanol

tolerance is less complete, it is easy to study and intriguing underlying mechanisms are beginning to emerge. The density of data on sleep mechanisms in Drosophila and mammals creates an opportunity to better understand tolerance and its relation to longer term effects of ethanol. The plan for this proposal is to determine the extent of co-encoding of rapid ethanol tolerance and sleep in

Drosophila. To do this, we propose three experiments. First, we plan to map rapid ethanol tolerance in sleep circuitry. Second, we discovered that rapid ethanol tolerance is composed of a labile and a consolidated memory-like states. We plan to map these and also evolutionarily conserved tolerance genes in the sleep

circuitry. Third, We plan to survey the function of the approximately 50 known sleep genes in rapid ethanol tolerance. The majority of these genes have not yet been tested for their role in tolerance. The expected outcome of the proposed research is a genetic and circuit map of rapid tolerance with respect to

sleep.