Chronic low-grade hippocampal inflammation blunts exercise-induced neurogenesis and alters the exercise-induced microglia transcriptome in the rat hippocampus

Chronic low-grade neuroinflammation contributes to inflammageing by compromising hippocampal plasticity, with interleukin-1β (IL-1β) as a key mediator. The extent to which sustained hippocampal inflammation can interfere with the potential beneficial effects of exercise on plasticity and hippocampus-related behaviour remains unclear. Here we combined bilateral hippocampal IL-1β overexpression (IL-1β-OE), to mimic chronic low-grade neuroinflammation with voluntary wheel running, to mimic human exercise training, in adult male Sprague-Dawley rats and assessed effects on multiple dorsal hippocampal-related behaviours, adult hippocampal neurogenesis, microglial phenotype, and immune cell infiltration. Hippocampal IL-1β-OE impaired pattern separation, independent of exercise training, and attenuated exercise-induced increases in neurogenesis in the dorsal hippocampus. Hippocampal IL-1β-OE promoted microglial lipid-droplet accumulation, which exercise paradoxically exacerbated. Transcriptomic profiling revealed that exercise in combination with hippocampal IL-1β-OE, enriched immune and leukocyte trafficking pathways in microglia, while hippocampal IL-1β-OE alone increased hippocampal CD8 + T cell infiltration. These findings indicate that chronic hippocampal inflammation alters microglial and neurogenic responses to exercise, suggesting that inflammatory status critically influences exercise efficacy in supporting hippocampal plasticity.