Department of General Psychiatry, Heidelberg University Hospital, 69120 Heidelberg, Germany.
Functional Neuroanatomy, Heidelberg University, 69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2022 Jun 21;119(25):e2122477119. doi: 10.1073/pnas.2122477119. Epub 2022 Jun 14.
Alcohol intoxication at early ages is a risk factor for the development of addictive behavior. To uncover neuronal molecular correlates of acute ethanol intoxication, we used stable-isotope-labeled mice combined with quantitative mass spectrometry to screen more than 2,000 hippocampal proteins, of which 72 changed synaptic abundance up to twofold after ethanol exposure. Among those were mitochondrial proteins and proteins important for neuronal morphology, including MAP6 and ankyrin-G. Based on these candidate proteins, we found acute and lasting molecular, cellular, and behavioral changes following a single intoxication in alcohol-naïve mice. Immunofluorescence analysis revealed a shortening of axon initial segments. Longitudinal two-photon in vivo imaging showed increased synaptic dynamics and mitochondrial trafficking in axons. Knockdown of mitochondrial trafficking in dopaminergic neurons abolished conditioned alcohol preference in flies. This study introduces mitochondrial trafficking as a process implicated in reward learning and highlights the potential of high-resolution proteomics to identify cellular mechanisms relevant for addictive behavior.
早期酗酒是导致成瘾行为的一个风险因素。为了揭示急性乙醇中毒的神经元分子相关性，我们使用稳定同位素标记的小鼠结合定量质谱法筛选了超过 2000 种海马体蛋白，其中 72 种在乙醇暴露后突触丰度增加了两倍。这些蛋白质包括线粒体蛋白和对神经元形态很重要的蛋白，如 MAP6 和锚蛋白-G。基于这些候选蛋白，我们在酒精-naive 小鼠中发现单次中毒后会产生急性和持续的分子、细胞和行为变化。免疫荧光分析显示轴突起始段缩短。纵向双光子活体成像显示突触动态和线粒体在轴突中的运输增加。在多巴胺能神经元中敲低线粒体运输，可消除果蝇的条件性酒精偏好。本研究将线粒体运输作为一个与奖励学习相关的过程进行了介绍，并强调了高分辨率蛋白质组学在鉴定与成瘾行为相关的细胞机制方面的潜力。
