Exercise-induced hippocampal miR-212/132 expression is preserved despite psychostimulant exposure and viral infection.

Regular physical exercise promotes brain plasticity and cognitive functions; however, many individuals with neurological or neuropsychiatric impairments face barriers that limit adherence to exercise-based interventions. Exercise-induced microRNAs (miRNAs) have emerged as potential regulators of activity-dependent signaling pathways associated with brain health. Using a voluntary wheel-running mouse model, we identified hippocampal miRNAs responsive to five weeks of exercise in both male and female mice. Small RNA sequencing detected 698 hippocampal miRNAs. Although overall hippocampal miRNA expression profiles were not significantly separated by exercise status, differential expression analysis identified miR-212-3p, miR-212-5p, and miR-466d-3p as significantly upregulated following exercise after adjustment for sex. KEGG pathway analysis of 285 predicted target genes revealed enrichment in pathways related to synaptic function, neurogenesis, inflammation regulation, and tissue remodeling. To determine whether exercise-responsive miRNAs remain inducible under neuropathological conditions, we evaluated their expression in a chronic methamphetamine (METH) and EcoHIV co-exposure mouse model. Voluntary exercise significantly increased hippocampal expression of miR-212-3p, miR-212-5p, and the co-transcribed miR-132-3p in both female and male mice, whereas miR-466d-3p was no longer responsive. Exercise was also associated with reduced astrocyte activation in the caudate putamen and partial recovery of neuronal integrity, as reflected by increased NeuN immunoreactivity in the hippocampal CA1 region, although recognition memory was not significantly restored during the intervention period. Together, these findings identify the miR-212/132 cluster as a robust exercise-responsive miRNA signature that remains inducible in a chronic METH/EcoHIV mouse model and may represent a promising candidate for future studies of exercise-mimetic strategies aimed at promoting brain resilience.