Department of Anatomy and Program in Neuroscience, University of California, San Francisco, California 94158, USA.
J Neurosci. 2013 May 8;33(19):8134-43. doi: 10.1523/JNEUROSCI.3695-12.2013.
In both mammalian and insect models of ethanol intoxication, high doses of ethanol induce motor impairment and eventually sedation. Sensitivity to the sedative effects of ethanol is inversely correlated with risk for alcoholism. However, the genes regulating ethanol sensitivity are largely unknown. Based on a previous genetic screen in Drosophila for ethanol sedation mutants, we identified a novel gene, tank (CG15626), the homolog of the mammalian tumor suppressor EI24/PIG8, which has a strong role in regulating ethanol sedation sensitivity. Genetic and behavioral analyses revealed that tank acts in the adult nervous system to promote ethanol sensitivity. We localized the function of tank in regulating ethanol sensitivity to neurons within the pars intercerebralis that have not been implicated previously in ethanol responses. We show that acutely manipulating the activity of all tank-expressing neurons, or of pars intercerebralis neurons in particular, alters ethanol sensitivity in a sexually dimorphic manner, since neuronal activation enhanced ethanol sedation in males, but not females. Finally, we provide anatomical evidence that tank-expressing neurons form likely synaptic connections with neurons expressing the neural sex determination factor fruitless (fru), which have been implicated recently in the regulation of ethanol sensitivity. We suggest that a functional interaction with fru neurons, many of which are sexually dimorphic, may account for the sex-specific effect induced by activating tank neurons. Overall, we have characterized a novel gene and corresponding set of neurons that regulate ethanol sensitivity in Drosophila.
在哺乳动物和昆虫的乙醇中毒模型中，高剂量的乙醇会导致运动障碍，最终导致镇静。对乙醇镇静作用的敏感性与酗酒的风险成反比。然而，调节乙醇敏感性的基因在很大程度上是未知的。基于先前在果蝇中进行的乙醇镇静突变体的遗传筛选，我们鉴定了一个新基因 tank（CG15626），它是哺乳动物肿瘤抑制因子 EI24/PIG8 的同源物，在调节乙醇镇静敏感性方面具有重要作用。遗传和行为分析表明，tank 在成年神经系统中发挥作用，促进乙醇敏感性。我们将 tank 调节乙醇敏感性的功能定位到尚未涉及乙醇反应的脑间部神经元中。我们表明，急性操纵所有表达 tank 的神经元的活性，或特别是脑间部神经元的活性，以性别二态的方式改变乙醇敏感性，因为神经元的激活增强了雄性而不是雌性的乙醇镇静作用。最后，我们提供了解剖学证据表明，表达 tank 的神经元与表达神经性别决定因子 fruitless（fru）的神经元形成可能的突触连接，fru 最近被牵连到调节乙醇敏感性。我们认为，与 fru 神经元的功能相互作用，其中许多是性别二态的，可能解释了激活 tank 神经元所诱导的性别特异性效应。总的来说，我们已经描述了一个调节果蝇乙醇敏感性的新基因和相应的神经元集。
