The role of circTmeff-1 in incubation of context-induced morphine craving
The role of circTmeff-1 in incubation of context-induced morphine craving
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circTmeff-1 在情境诱导的吗啡渴望中的作用
DOI：
10.1016/j.phrs.2021.105722
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发表时间：
2021-08-01
影响因子：
9.3
通讯作者：
Ma，Chunling
中科院分区：
文献类型：
--
作者：
Yu，Hailei;Xie，Bing;Ma，Chunling
药物暴露后对药物的渴望逐渐增加是复发的重要触发因素。CircularRNA（CircRNA）是基因表达的关键调控因子，在神经系统疾病中起着重要作用。然而，circRNA在药物渴求中的作用尚不清楚。本研究采用吗啡条件性位置偏爱（CPP）训练小鼠，分别于戒断第1天（AD 1）和第14天（AD 14）取其丘脑核（NAc）切片进行RNA测序。CircTmeff-1在NAc核心中高度表达，与情境诱导的吗啡渴求的孵育相关。功能的获得和丧失表明circTmeff-1是孵育的正调节剂。同时，在孵育期间，miR-541- 5 p和miR-6934- 3 p在NAc核心中的表达下调。双荧光素酶报告基因、RNA pulldown和荧光原位杂交分析证实miR-541- 5 p和miR-6934- 3 p选择性结合circTmeff-1。此外，生物信息学和蛋白质印迹分析表明，囊泡相关膜蛋白1（VAMP 1）和神经成束蛋白（NFASC），这两个miR-541- 5 p和miR-6934- 3 p的重叠靶点，在孵育过程中高度表达。最后，AAV诱导的circTmeff-1的下调降低了VAMP 1和NFASC的表达和吗啡渴求的潜伏期。这些发现表明，circTmeff-1，一种新的circRNA，促进孵化的上下文诱导的吗啡渴求海绵状的miR-541/miR-6934在NAc核心。因此，circTmeff-1代表了一个潜在的治疗目标的背景诱导阿片类药物的渴望，延长禁欲。
A progressive increase in drug craving following drug exposure is an important trigger of relapse. CircularRNAs (CircRNAs), key regulators of gene expression, play an important role in neurological diseases. However, the role of circRNAs in drug craving is unclear. In the present study, we trained mice to morphine conditioned place preference (CPP) and collected the nucleus accumbens (NAc) sections on abstinence day 1 (AD1) and day 14 (AD14) for RNA-sequencing. CircTmeff-1, which was highly expressed in the NAc core, was associated with incubation of context-induced morphine craving. The gain- and loss- of function showed that circTmeff-1 was a positive regulator of incubation. Simultaneously, the expression of miR-541–5p and miR-6934–3p were down-regulated in the NAc core during the incubation period. The dual luciferase reporter, RNA pulldown, and fluorescenceinsituhybridization assays confirmed that miR-541–5p and miR-6934–3p bind to circTmeff-1 selectively. Furthermore, bioinformatics and western blot analysis suggested that vesicle-associated membrane protein 1 (VAMP1) and neurofascin (NFASC), both overlapping targets of miR-541–5p and miR-6934–3p, were highly expressed during incubation. Lastly, AAV-induced down-regulation of circTmeff-1 decreased VAMP1 and NFASC expression and incubation of morphine craving. These findings suggested that circTmeff-1, a novel circRNA, promotes incubation of context-induced morphine craving by sponging miR-541/miR-6934 in the NAc core. Thus, circTmeff-1 represents a potential therapeutic target for context-induced opioid craving, following prolonged abstinence.