Comparative effectiveness of moderate treadmill training and venlafaxine treatment on long-lasting brain changes induced by prenatal dexamethasone exposure

Abstract

Prenatal exposure to dexamethasone (DEX) is known to induce long-term behavioral and molecular impairments. This research investigated whether moderate physical exercise (treadmill running) and venlafaxine administration, or their combination, applied in early adulthood, could modulate the behavioral and brain molecular alterations induced by prenatal DEX exposure in Sprague-Dawley male rats. It was demonstrated that both exercise and venlafaxine treatment ameliorated deficits in memory, depressive-like behavior, and anxiety-like behavior. Subsequent proteomic analysis of the frontal cortex revealed significant modulation in the proteome following each intervention. Analysis disclosed convergent effects of all three interventions, notably the upregulation of LYAR and downregulation of KLHL36. Increased LYAR expression may counteract DEX-induced ribosomal inhibition, while reduced KLHL36 aligns with potential stress resilience modulation. Shared protein changes between exercise and venlafaxine implicated pathways governing learning, regulation of neurotransmitter levels and their metabolism, and cell-cell organization. Combined treatment uniquely impacted 164 proteins involved in 44 distinct biological pathways, which suggests that joint use of training and venlafaxine has a pleiotropic effect. Among the altered pathways besides behavior, cognition, and memory were glycerophospholipid and arachidonic acid metabolism, which potentially influence neuronal membrane integrity and synaptic function, as well as exocytosis and MAPK signaling pathways. Notably, among the investigated mitochondrial proteins, HIGD1a exhibited a consistent pattern of upregulated expression across all three experimental treatment groups, suggesting altered mitochondrial function and antioxidant defense by the treatments used.