Mef2 induction of the immediate early gene Hr38/Nr4a is terminated by Sirt1 to promote ethanol tolerance.

Adhikari, P; Orozco, D; Randhawa, H; Wolf, F W

Adhikari, P; Orozco, D; Randhawa, H; Wolf, F W.

Afiliación

Adhikari P; Quantitative and Systems Biology, University of California, Merced, California.
Orozco D; Molecular Cell Biology, University of California, Merced, California.
Randhawa H; Molecular Cell Biology, University of California, Merced, California.
Wolf FW; Quantitative and Systems Biology, University of California, Merced, California.

Genes Brain Behav ; 18(3): e12486, 2019 03.

Article en En | MEDLINE | ID: mdl-29726098

RESUMEN

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/ß 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.

Asunto(s)

Consumo de Bebidas Alcohólicas/genética; Depresores del Sistema Nervioso Central/farmacología; Proteínas de Drosophila/genética; Etanol/farmacología; Factores Reguladores Miogénicos/genética; Neuronas/efectos de los fármacos; Sirtuina 1/genética; Animales; Proteínas de Drosophila/metabolismo; Drosophila melanogaster; Mutación con Pérdida de Función; Cuerpos Pedunculados/citología; Cuerpos Pedunculados/efectos de los fármacos; Cuerpos Pedunculados/metabolismo; Factores Reguladores Miogénicos/metabolismo; Plasticidad Neuronal; Neuronas/metabolismo; Receptores Citoplasmáticos y Nucleares/genética; Receptores Citoplasmáticos y Nucleares/metabolismo; Sirtuina 1/metabolismo

Palabras clave

Drosophila; Hr38; Mef2; Sirt1; behavioral plasticity; ethanol tolerance; immediate early gene; mushroom bodies

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Consumo de Bebidas Alcohólicas / Depresores del Sistema Nervioso Central / Factores Reguladores Miogénicos / Proteínas de Drosophila / Etanol / Sirtuina 1 / Neuronas Límite: Animals Idioma: En Revista: Genes Brain Behav Asunto de la revista: CIENCIAS DO COMPORTAMENTO / GENETICA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido

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