Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Nat Commun. 2020 Sep 14;11(1):4634. doi: 10.1038/s41467-020-18114-3.
The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.
目前阿片类药物泛滥，我们需要更好地了解人类成瘾的神经生物学，从而开发出有效的治疗方法。在这里，我们对海洛因使用者和匹配对照者的人类纹状体的染色质可及性进行了全基因组评估。我们的研究揭示了独特的神经元和非神经元表观遗传特征，并确定了一个基因座，该基因座靠近编码酪氨酸激酶 FYN 的基因，是神经元中受影响最严重的区域。海洛因使用会增加死后人类纹状体以及接受海洛因自我给药训练的大鼠和体外接受慢性吗啡处理的原代纹状体神经元中的 FYN 表达、激酶活性及其靶标 Tau 的磷酸化。FYN 活性的药理学或遗传操作可显著减弱海洛因的自我给药和对药物配对线索的反应。我们的研究结果表明，纹状体中的 FYN 是与海洛因相关的神经退行性样病理和药物摄取行为的重要驱动因素，这使得 FYN 成为治疗海洛因使用障碍的有前途的治疗靶点。
