Exercising the brain: Molecular pathways linking exercise, neuronal mitochondria, and synaptic plasticity

Regular exercise is the most effective lifestyle intervention to improve cognitive function and reduce the risk of age-related neurodegenerative diseases. However, the underlying mechanisms are not yet well understood. Accumulating evidence suggests that exercise improves mitochondrial structure and function in neurons and enhances synaptic plasticity. We propose that exercise-elicited neuronal activity and associated cellular cues (e.g., AMP/ATP ratios and calcium influx) activate signaling transcription regulators, such as AMPK, PGC-1α, and SIRT1, to promote mitochondrial remodeling and redox balance, and hence improve synaptic function. In parallel, exerkines, a plethora of humoral factors induced by exercise in peripheral organs and tissues, may mediate some of the positive benefits of exercise through endocrine mechanisms. This review focuses on current evidence and highlights the need for additional mechanistic studies to improve exercise-based interventions to promote brain health.