Voluntary running exercise is associated with metabolic shifts linked to adult hippocampal neurogenesis

Adult hippocampal neurogenesis is a metabolically demanding process requiring tight coordination between energy production and biosynthetic flux. Although voluntary running is a potent stimulus for this plasticity, the metabolic landscape sustaining the neurogenic niche remains incompletely defined. Using untargeted gas chromatography/mass spectrometry-based metabolomics to characterize the hippocampal metabolome of mice following eight weeks of voluntary running, we identified metabolic changes consistent with coordinated metabolic reprogramming that suggest an adaptive metabolic stress response. A significant catabolic shift, marked by depletion of glutamic and aspartic acids, is associated with increased bioenergetic utilization and possible integration of neurotransmitter-derived substrates into central carbon metabolism. The exercise-induced elevation of CoA-related metabolites and tricarboxylic acid cycle intermediates is indicative of increased mitochondrial bioenergetic demand. Simultaneously, elevated nitrogenous metabolites, such as asparagine and glycine, coincide with increased availability of biosynthetic precursors for nucleotide synthesis, redox balance, and structural remodeling linked to neurogenesis. Enrichment of one-carbon metabolism is compatible with integration of metabolic pathways involved in biosynthetic and regulatory processes related to neurogenic remodeling. Together, these findings align with the interpretation that voluntary running may act as a metabolic hormetic stimulus, linked to reconfiguration of hippocampal metabolic networks to support a permissive environment for neurogenic plasticity and cognitive resilience.