Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes
Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes
复制标题
DOI：
10.1038/s41467-020-14331-y
复制
发表时间：
2020-01-24
影响因子：
16.6
通讯作者：
Heller, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Carpenter, Marco D.;Hu, Qiwen;Heller, Elizabeth A.
内源性稳态机制可在可卡因诱导的神经适应性改变后恢复正常的神经元功能。此类机制可被利用来开发针对可卡因成瘾的新疗法，但尚未确定一个分子靶点。在此，我们分析了小鼠在可卡因戒断早期和晚期的基因表达，以确定神经稳态的假定调节因子。可卡因激活了转录因子Nr4a1及其靶基因Cartpt，Cartpt是参与多巴胺代谢的关键分子。在戒断后期Cartpt的持续激活伴随着抑制性组蛋白修饰H3K27me3的减少以及活化标记H3K27ac和H3K4me3的富集。通过使用CRISPR介导的和小分子的Nr4a1激活，我们证明了Nr4a1在Cartpt的持续激活以及减轻可卡因诱发行为中的直接因果作用。我们的研究结果提供了证据，表明针对戒断诱导的稳态基因表达是可卡因成瘾的一个潜在治疗靶点。
Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations. Such mechanisms may be exploited to develop novel therapies for cocaine addiction, but a molecular target has not yet been identified. Here we profiled mouse gene expression during early and late cocaine abstinence to identify putative regulators of neural homeostasis. Cocaine activated the transcription factor, Nr4a1, and its target gene, Cartpt, a key molecule involved in dopamine metabolism. Sustained activation of Cartpt at late abstinence was coupled with depletion of the repressive histone modification, H3K27me3, and enrichment of activating marks, H3K27ac and H3K4me3. Using both CRISPR-mediated and small molecule Nr4a1 activation, we demonstrated the direct causal role of Nr4a1 in sustained activation of Cartpt and in attenuation of cocaine-evoked behavior. Our findings provide evidence that targeting abstinence-induced homeostatic gene expression is a potential therapeutic target in cocaine addiction.