From Treadmill to Textbook: Neurovascular and Immune Mechanisms of Exercise-Induced Cognitive Enhancement

It has been well established that physical exercise is associated with augmented cognitive function, but the exact mechanisms by which peripheral activity affects the plasticity of the brain remain mechanistically elusive. This narrative review synthesises evidence from mouse models and human studies to clarify how physical exercise may enhance hippocampus-dependent cognition through systemic, neurovascular, immune, and metabolic mechanisms instead of direct "brain training" alone. This distinction is supported by the limited far transfer shown in many cognitive training models, wherein improvements tend to remain task- or circuit-specific rather than reflecting general skill transfer. In rodent models, voluntary physical exercise improves learning, memory, and pattern separation, and these effects correlate with changes in hippocampal neurogenesis, synaptic plasticity, vascular remodelling, and neuroimmune state. A smaller pool of plasma-transfer studies suggests that these effects carry over between individual mice via circulating exercise-induced factors, reproducing select molecular and behavioural effects in completely sedentary recipient mice, but in humans, the causal relevance of such pathways remains unresolved. In rodent transfer experiments, exercise-conditioned blood plasma has been reported to reduce neuroinflammation and to modulate brain endothelial cells, positioning the neurovascular unit as a critical interface for peripheral-to-central nervous system communication. Beyond clusterin and Gpld1, a conceptual muscle-brain endocrine axis is emerging, where specific myokines (e.g., irisin, cathepsin B) and downstream metabolites released during physical exercise may act on vascular and immune interfaces to modulate structural plasticity. Emerging human data reinforce some of these investigated mechanisms, although causal relationships have yet to be established and remain limited. Overall, the available evidence supports a model whereby physical exercise improves cognitive function through changes in the immunometabolic environment, supporting hippocampal plasticity. These pathways may inform future studies aiming to preserve cognitive health during ageing, and the development of exercise-mimetic therapeutic strategies.