Running ameliorates methamphetamine-associated cognitive impairment by regulating hippocampal neurogenesis through the GSK3β/β-catenin pathway

Physical exercise is a non-pharmacological therapy that has been widely used in drug rehabilitation centers for the treatment of methamphetamine (METH). METH caused cognitive impairment and suppresses adult hippocampal neurogenesis (AHN) in experimental animals. Exercise can improve cognitive impairment caused by multiple factors through AHN. However, little is known about the role of AHN and exercise in METH-neurotoxic injury. We aim to investigate whether running could ameliorate METH-related cognitive impairment by promoting AHN and the underlying mechanisms. Behavioral experiments were performed to detect behavioral changes in running exercise-treated mice exposed to METH. Immunofluorescence was used to analyze the hippocampal neurogenic lineage, and western blotting and qRT-PCR were used to analyze the expression levels of GSK3β/β-catenin and downstream transcription factors. AAV-Nestin-Ctnnb1 was used to overexpress β-catenin in neural stem cells (NSCs). We found that low-dose METH induced cognitive impairment and decreased AHN instead of inducing cell death in the hippocampus. Moreover, it diminished the proliferation and differentiation of NSCs in the dentate gyrus. Running ameliorated METH-related cognitive impairment by modulating AHN through the GSK3β/β-catenin pathway. Notably, overexpressing β-catenin in NSCs promoted the expression of its downstream transcription factors, rescued AHN, and exerted effects of ameliorating cognitive impairment. Our findings show that METH could cause cognitive impairment through weaken the AHN, and running could effectively ameliorate METH-related cognitive impairment by enhancing AHN through the GSK3β/β-catenin pathway. In addition, our findings provide insights into how exercise ameliorates METH-related cognitive impairment and theoretical basis for exercise therapy.