Quinn R K, Brown A L, Goldie B J, Levi E M, Dickson P W, Smith D W, Cairns M J, Dayas C V
1] Neurobiology of Addiction Laboratory, School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia [2] The Centre for Translational Neuroscience and Mental Health Research, University of Newcastle, Newcastle, NSW, Australia [3] Hunter Medical Research Institute, Newcastle, NSW, Australia.
Transl Psychiatry. 2015 Feb 3;5(2):e503. doi: 10.1038/tp.2014.144.
Recently, we published data using an animal model that allowed us to characterize animals into two groups, addiction vulnerable and addiction resilient, where we identified that addiction/relapse vulnerability was associated with deficits in synaptic plasticity-associated gene expression in the dorsal striatum (DS). Notable was the strong reduction in expression for activity-regulated cytoskeleton-associated protein (Arc) considered a master regulator of synaptic plasticity. In the present study, we confirmed that Arc messenger RNA was significantly decreased in the DS, but importantly, we identified that this reduction was restricted to the dorsomedial (DMS) and not dorsolateral striatum (DLS). There is recent evidence of microRNA (miRNA)-associated posttranscriptional suppression of Arc and animal models of addiction have identified a key role for miRNA in the regulation of addiction-relevant genes. In further support of this link, we identified several differentially expressed miRNA with the potential to influence addiction-relevant plasticity genes, including Arc. A key study recently reported that miR-212 expression is protective against compulsive cocaine-seeking. Supporting this hypothesis, we found that miR-212 expression was significantly reduced in the DMS but not DLS of addiction-vulnerable animals. Together, our data provide strong evidence that miRNA promote ongoing plasticity deficits in the DS of addiction-vulnerable animals.
最近，我们发表了使用动物模型获得的数据，该模型使我们能够将动物分为两组，即成瘾易感性组和成瘾抗性组，我们发现成瘾/复发性易感性与背侧纹状体（DS）中与突触可塑性相关的基因表达缺陷有关。值得注意的是，被认为是突触可塑性主要调节因子的活性调节细胞骨架相关蛋白（Arc）的表达大幅降低。在本研究中，我们证实Arc信使核糖核酸在DS中显著减少，但重要的是，我们发现这种减少仅限于背内侧（DMS）而非背外侧纹状体（DLS）。最近有证据表明，微小核糖核酸（miRNA）与Arc的转录后抑制有关，而成瘾动物模型已确定miRNA在成瘾相关基因的调控中起关键作用。为进一步支持这种联系，我们鉴定了几种差异表达的miRNA，它们有可能影响成瘾相关的可塑性基因，包括Arc。最近一项关键研究报告称，miR-212的表达对强迫性觅可卡因行为具有保护作用。支持这一假设的是，我们发现成瘾易感性动物的DMS中miR-212表达显著降低，而DLS中则没有。总之，我们的数据提供了有力证据，表明miRNA会加剧成瘾易感性动物DS中持续存在的可塑性缺陷。
