Exercise-related brain remodeling through bidirectional brain-body crosstalk: an integrative narrative review

Abstract

Exercise is associated with favorable brain and cognitive outcomes, yet the supporting evidence spans molecular, cellular, organ, neural-circuit, imaging, and behavioral levels that differ substantially in causal strength. This narrative review develops an integrative framework across biological levels in which exercise-related brain remodeling emerges from bidirectional brain-body crosstalk rather than from a single peripheral factor or a one-way endocrine pathway. The framework links central motor commands, sensory feedback, autonomic regulation, and cerebral hemodynamics with signal generation by skeletal muscle, liver, adipose tissue, bone, the gut microbiome, and the circulating immune-vascular milieu. Metabolites, secreted factors, extracellular vesicles, and neural afferents may influence the central nervous system through blood-brain and blood-cerebrospinal fluid interfaces, circumventricular organs, cerebral endothelium, and brainstem-hypothalamic networks. Candidate central responses include neurotrophic and synaptic signaling, glial-state regulation, adult hippocampal neurogenesis, and neurovascular adaptation, which may correspond to group-level changes in brain structure, functional connectivity, and cognition. However, direct causal mediation across the complete human pathway remains largely untested: many cellular mechanisms derive from animal or in vitro studies, whereas human biomarker and neuroimaging findings are often indirect and process-nonspecific. Age, sex and hormonal state, genotype, disease stage, baseline function, exercise dose, recovery, and adherence further shape response heterogeneity. A stronger translational evidence base will require preregistered longitudinal interventions, source-resolved and time-resolved biomarker sampling, cross-species validation, multimodal target-engagement measures, and externally validated prediction models.