Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder
Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder
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DOI：
10.1038/s41467-020-18114-3
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发表时间：
2020-09-14
影响因子：
16.6
通讯作者：
Hurd, Yasmin L.
中科院分区：
文献类型：
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作者：
Egervari, Gabor;Akpoyibo, Diana;Hurd, Yasmin L.
目前阿片类药物的流行需要更好地了解人类成瘾神经生物学，以开发有效的治疗方法。在这里，我们进行全基因组评估的人类纹状体的染色质可及性海洛因用户和匹配的控制。我们的研究揭示了不同的神经元和非神经元的表观遗传特征，并确定了一个位点的基因编码酪氨酸激酶FYN附近的神经元中受影响最严重的地区。FYN的表达，激酶活性和其目标Tau的磷酸化增加海洛因使用在死后的人纹状体，以及在大鼠训练的自我管理海洛因和初级纹状体神经元与慢性吗啡在体外治疗。药理学或遗传操纵FYN活动显着减弱海洛因自我管理和响应药物配对线索在啮齿动物。我们的研究结果表明，纹状体FYN是海洛因相关的神经退行性病变和吸毒行为的重要驱动因素，使FYN成为海洛因使用障碍的一个有前途的治疗靶点。
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.