Differential gene expression and stereological analyses of the cerebellum following methamphetamine exposure

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.