Brain Transcriptome Analysis Reveals Exercise Improves Methamphetamine‐Induced Impairments in Mouse Learning and Memory Abilities

Methamphetamine (METH) abuse can inflict profound and enduring neurotoxic effects on the brain, culminating in cognitive dysfunction and impairment of learning and memory. Physical exercise can stimulate both structural and functional adaptations in the central nervous system. The primary objective of this study was to elucidate the safeguarding effect and underlying mechanisms of treadmill exercise intervention in the brains of METH-addicted mice. Two-month-old adult mice were randomly assigned into three distinct groups: the control group (Group C), receiving intraperitoneal injections of saline; the METH treatment group (Group Ma), exposed to intraperitoneal METH administration; and the exercise group (Group Ea), which underwent a two-week regimen of treadmill exercise intervention following intraperitoneal METH exposure. The conditioned place preference experiment was executed to evaluate METH addiction. The results showed that both Groups Ma and Ea mice became addicted to METH after METH administration (p < 0.05, n = 6). In the Y-maze experiment, the exploration time of mice in Group Ea in the novel arm was significantly higher than that in Group Ma (p < 0.05, n = 6), indicating that exercise intervention improved the learning and memory capabilities of mice. Subsequently, the mouse brain specimens were harvested for transcriptome sequencing and real-time fluorescence quantitative PCR analysis (n = 3). Transcriptome sequencing analysis identified 316 differentially expressed genes (DEGs) in Group Ma compared to Group C, while 156 DEGs were detected in Group Ea compared to Group Ma. Kyoto Encyclopedia of Genes and Genomes analysis outcomes underscored the substantial association of DEGs, discerned in exercise-intervention mice compared to METH-treated mice, with key signalling pathways, notably the PI3K-Akt, mTOR and Wnt signalling pathways, among others. Cross-analysis revealed 43 DEGs in exercise-treated mice, such as NFKBIA, CXCL12 and Vav3. Our results revealed changes in the expression profile of the brain transcriptome of METH-addicted mice and indicated that treadmill exercise intervention affects the expression changes of the brain transcriptome of METH-addicted mice. The above research results provide unique insights into the further study of the mechanism of treadmill exercise intervention in improving the learning and memory abilities of METH-induced mice.