Adhikari P, Orozco D, Randhawa H, Wolf F W
Quantitative and Systems Biology, University of California, Merced, California.
Molecular Cell Biology, University of California, Merced, California.
Genes Brain Behav. 2019 Mar;18(3):e12486. doi: 10.1111/gbb.12486. Epub 2018 May 28.
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.
未接触过药物的动物单次给予乙醇后，对后续剂量的反应会发生变化，包括产生乙醇耐受性和乙醇偏好。这些简单形式的行为可塑性部分归因于基因表达和神经元特性的改变。令人惊讶的是，对于乙醇如何启动基因表达变化或这些变化有何作用，人们知之甚少。在这里，我们证明了Hr38在乙醇可塑性中的作用，Hr38是哺乳动物Nr4a1/2/3类即刻早期反应转录因子在果蝇中的唯一同源物。急性乙醇暴露会诱导Hr38和其他即刻早期神经元活动基因的瞬时表达。乙醇激活Mef2转录激活因子以诱导Hr38，而Sirt1组蛋白/蛋白质脱乙酰酶是终止Hr38诱导所必需的。Hr38缺失会降低乙醇耐受性，并导致早熟但持续时间短的乙醇偏好。同样，所有神经元或特定蘑菇体α/β神经元中Mef2活性降低会降低乙醇耐受性；Sirt1在这些相同的神经元中促进乙醇耐受性。在Sirt1基因敲除突变体中通过基因手段降低Hr38表达水平可恢复乙醇耐受性，这表明Hr38表达的诱导和终止对于行为可塑性的发生都很重要。这些数据表明，Hr38作为一种即刻早期转录因子，促进乙醇行为可塑性。
