Faculty of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Iran.
Department of Histology, School of Medicine, Urmia University of Medical Sciences, Iran.
Addict Biol. 2020 Jan;25(1):e12707. doi: 10.1111/adb.12707. Epub 2019 Feb 4.
Methamphetamine (METH) is a highly addictive psychostimulant that profoundly aimed at monoaminergic systems in the brain. Despite the leading role of cerebellum in sensorimotor control as well as augmented locomotor activity under the influence of METH, there are few studies examining the effect of METH administration on gene expression profiling and structural consequences in the cerebellar region. Thus, we sought to explore the effects of METH on the cerebellum, from gene expression changes to structural alterations. In this respect, we investigated genome-wide mRNA expression using high throughput RNA-seq technology and confirmatory quantitative real-time PCR, accompanied by stereological analysis of cerebellar layers along with identification of reactive astrogliosis by glial fibrillary acidic protein and behavioral assessment following METH exposure. According to our RNA-seq data, 473 unique differentially expressed genes (DEG) were detected upon METH injections in which a large number of these genes engage basically in biological regulations and metabolic processes, chiefly located in nucleus and membrane. In addition, pathway analysis of METH-induced DEG revealed several enriched signaling cascades related largely to immune response, neurotransmission, cell growth, and death. Further, METH induced a significant reduction in volumes of cerebellar layers (molecular, granular, and Purkinje) and a decrease in the white matter volume along with a rise in astrogliosis as well as increased locomotor activity. In conclusion, considering gene expression changes combined with structural alterations of the cerebellum in response to METH, these data suggest METH-induced neurotoxicity in the cerebellar region.
甲基苯丙胺（METH）是一种高度成瘾的精神兴奋剂，它主要作用于大脑中的单胺能系统。尽管小脑在感觉运动控制中起着主导作用，并且在 METH 的影响下增强了运动活性，但很少有研究检查 METH 给药对小脑区域的基因表达谱和结构后果的影响。因此，我们试图探索 METH 对小脑的影响，从基因表达变化到结构改变。在这方面，我们使用高通量 RNA-seq 技术和定量实时 PCR 进行了全基因组 mRNA 表达研究，并对小脑层进行了立体学分析，同时通过胶质纤维酸性蛋白鉴定反应性星形胶质细胞，并在 METH 暴露后进行行为评估。根据我们的 RNA-seq 数据，在 METH 注射后检测到 473 个独特的差异表达基因（DEG），其中许多基因主要参与生物调节和代谢过程，主要位于核和膜中。此外，METH 诱导的 DEG 途径分析揭示了几个与免疫反应、神经传递、细胞生长和死亡相关的丰富信号级联，这些信号级联主要涉及免疫反应、神经传递、细胞生长和死亡。此外，METH 导致小脑层（分子层、颗粒层和浦肯野层）体积显著减少，白质体积减少，星形胶质细胞增多，运动活性增加。总之，考虑到基因表达变化以及 METH 引起的小脑结构改变，这些数据表明 METH 引起的小脑区域神经毒性。
