Drug naïve animals given a single dose of ethanol show changed responses to subsequent doses, including the development of ethanol tolerance and ethanol preference. These simple forms of behavioral plasticity are due in part to changes in gene expression and neuronal properties. Surprisingly little is known about how ethanol initiates changes in gene expression or what the changes do. Here we demonstrate a role in ethanol plasticity for Hr38, the sole Drosophila homolog of the mammalian Nr4a1/2/3 class of immediate early response transcription factors. Acute ethanol exposure induces transient expression of Hr38 and other immediate early neuronal activity genes. Ethanol activates the Mef2 transcriptional activator to induce Hr38, and the Sirt1 histone/protein deacetylase is required to terminate Hr38 induction. Loss of Hr38 decreases ethanol tolerance and causes precocious but short-lasting ethanol preference. Similarly, reduced Mef2 activity in all neurons or specifically in the mushroom body α/β neurons decreases ethanol tolerance; Sirt1 promotes ethanol tolerance in these same neurons. Genetically decreasing Hr38 expression levels in Sirt1 null mutants restores ethanol tolerance, demonstrating that both induction and termination of Hr38 expression are important for behavioral plasticity to proceed. These data demonstrate that Hr38 functions as an immediate early transcription factor that promotes ethanol behavioral plasticity.

Drug naïve animals given a single dose of ethanol show changed responses to subsequent doses, including the development of ethanol tolerance and ethanol preference. These simple forms of behavioral plasticity are due in part to changes in gene expression and neuronal properties. Surprisingly little is known about how ethanol initiates changes in gene expression or what the changes do. Here we demonstrate a role in ethanol plasticity for Hr38, the sole Drosophila homolog of the mammalian Nr4a1/2/3 class of immediate early response transcription factors. Acute ethanol exposure induces transient expression of Hr38 and other immediate early neuronal activity genes. Ethanol activates the Mef2 transcriptional activator to induce Hr38, and the Sirt1 histone/protein deacetylase terminates Hr38 induction. Loss of Hr38 decreases ethanol tolerance and causes precocious but shortlasting ethanol preference. Similarly, reduced Mef2 activity in all neurons or specifically in the mushroom body α/β neurons decreases ethanol tolerance; Sirt1 promotes ethanol tolerance in these same neurons. Genetically decreasing Hr38 expression levels in Sirt1 null mutants restores ethanol tolerance, demonstrating that both induction and termination of Hr38 expression are important for behavioral plasticity to proceed. These data demonstrate that Hr38 functions as an immediate early transcription factor that promotes ethanol behavioral plasticity. IntroductionEthanol, one of the most widely used and frequently abused addictive drugs, is a small molecule that diffuses rapidly throughout the body and that binds to an as yet incompletely defined spectrum of molecules. Its effects vary based on dose, exposure time and pattern, an individuals' history of intake, and their genetic makeup. This complexity of action has hampered progress in reducing the prevalence of alcohol use disorders through rational interventions (Edenberg & Foroud 2013).One approach forward is to define, in detail, the stimulusresponse relationship for ethanol in ethanol naïve animals. While the first ethanol exposure rarely leads directly to alcoholism, it does cause changes in behavior that reflect changes in brain function; these changes provide an altered substrate for subsequent intake and promote addiction risk. Furthermore, many genes are oppositely regulated by acute ethanol exposure and in ethanol withdrawal (Palmisano & Pandey 2017). Practically, this suggests that detailed mechanistic understanding of acute ethanol exposure action, especially when coupled to measures of behavioral plasticity, will provide insight into the more complex mechanisms underlying addiction. One form of ethanolinduced behavioral plasticity is tolerance, the acquired resistance to the inebriating and sedating properties of ethanol (Fadda & Rossetti 1998). Ethanol tolerance facilitates increased intake, a risk factor for later developing alcohol use disorders.Drugs of abuse, including ethanol, cause changes in gene expression in the brain that can alter the properties of the brain. Drosophila me...