The Mechanistic Pathways Linking Exercise to Neuroprotection and Mental Health: Construction and Elaboration of an Integrative Theoretical Model

Objective: This study proposes the Exercise–Neuroprotection–Mental Health (ENM) model, an integrative framework explaining how exercise enhances mental health through multilevel neurobiological mechanisms. Methods: Drawing on evidence related to exercise-induced neurotrophic factors, myokines, neuroplasticity, and emotion-related neural circuits, we synthesized current findings and developed mechanistic inferences following the pathway from physiological activation to molecular signaling, neuroplastic changes, neural-circuit modulation, and mental-health outcomes. Results: The ENM model suggests that exercise triggers peripheral activation leading to increased BDNF, irisin, and anti-inflammatory and antioxidant responses. These molecular changes enhance synaptic plasticity, neurogenesis, and network efficiency in the hippocampus and prefrontal cortex. At the circuit level, improved functioning of the PFC–amygdala emotion-regulation pathway, the hippocampus–HPA axis, and the VTA–NAc reward system contributes to better emotional stability, stress resilience, and motivation. The model yields testable hypotheses regarding the mediating role of BDNF, the involvement of the PFC–amygdala circuit in anxiolytic effects, the role of the VTA–NAc pathway in antidepressant effects, and myokines and inflammation as intervention targets. Conclusion: The ENM model offers a coherent framework linking exercise to neuroprotection and mental-health improvement and provides theoretical guidance for targeted exercise prescriptions and future neuroimaging, biomarker, and clinical validation studies.