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

Physical exercise is a non-pharmacological therapy widely used in drug rehabilitation centers for treating methamphetamine (METH) addiction. METH causes cognitive impairment and suppresses adult hippocampal neurogenesis (AHN) in experimental animals. Exercise can improve cognitive dysfunction caused by various factors through the enhancement of AHN. However, little is known about the role of AHN and exercise in METH-induced neurotoxic injury. In this study, we aimed to investigate whether running could ameliorate METH-related cognitive impairment by promoting AHN in a low-dose METH addiction model and to uncover the underlying mechanisms. Behavioral experiments were conducted to assess changes in the behavior of mice. Immunofluorescence was used to analyze hippocampal neurogenic lineage, while Western blotting and qRT-PCR were employed to measure the expression levels of GSK3β/β-catenin and their 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 without causing hippocampal cell death. Moreover, it reduced 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, overexpression of β-catenin in NSCs enhanced the expression of its downstream transcription factors, rescued AHN, and alleviated cognitive impairment. Our findings indicate that METH-induced cognitive impairment is linked to weakened AHN, and that running can effectively ameliorate METH-related cognitive dysfunction by enhancing AHN through the GSK3β/β-catenin pathway. Furthermore, these findings provide valuable insights into how exercise mitigates METH-related cognitive impairment and offer a theoretical basis for exercise-based therapies.