Lange Anthony P, Wolf Fred W
Quantitative and Systems Biology Graduate Program, University of California, Merced, CA 95343.
Department of Molecular and Cell Biology, University of California, Merced, CA 95343.
bioRxiv. 2023 Feb 2:2023.01.30.526363. doi: 10.1101/2023.01.30.526363.
Alcohol tolerance is a simple form of behavioral and neural plasticity that occurs with the first drink. Neural plasticity in tolerance is likely a substrate for longer term adaptations that can lead to alcohol use disorder. Drosophila develop tolerance with characteristics similar to vertebrates, and it is useful model for determining the molecular and circuit encoding mechanisms in detail. Rapid tolerance, measured after the first alcohol exposure is completely metabolized, is localized to specific brain regions that are not interconnected in an obvious way. We used a forward neuroanatomical screen to identify three new neural sites for rapid tolerance encoding. One of these was comprised of two groups of neurons, the DN1a and DN1p glutamatergic neurons, that are part of the Drosophila circadian clock. We localized rapid tolerance to the two DN1a neurons that regulate arousal by light at night, temperature-dependent sleep timing, and night-time sleep. Two clock neurons that regulate evening activity, LNd6 and the 5th LNv, are postsynaptic to the DN1as and they promote rapid tolerance via the metabotropic glutamate receptor. Thus, rapid tolerance to alcohol overlaps with sleep regulatory neural circuitry, suggesting a mechanistic link.
酒精耐受性是一种在首次饮酒时就会出现的简单行为和神经可塑性形式。耐受性中的神经可塑性可能是导致酒精使用障碍的长期适应性变化的基础。果蝇产生的耐受性具有与脊椎动物相似的特征，是详细确定分子和神经回路编码机制的有用模型。在首次酒精暴露完全代谢后测量的快速耐受性，定位于以一种不明显方式相互连接的特定脑区。我们使用正向神经解剖学筛选来确定三个新的快速耐受性编码神经位点。其中一个位点由两组神经元组成，即DN1a和DN1p谷氨酸能神经元，它们是果蝇生物钟的一部分。我们将快速耐受性定位于两个在夜间通过光调节觉醒、温度依赖性睡眠时间和夜间睡眠的DN1a神经元。调节夜间活动的两个生物钟神经元LNd6和第五个LNv，是DN1a神经元的突触后神经元，它们通过代谢型谷氨酸受体促进快速耐受性。因此，对酒精的快速耐受性与睡眠调节神经回路重叠，这表明存在一种机制联系。
