ABSTRACT Although environmental enrichment (EE) promotes post‐stroke motor recovery, the mechanisms underlying its regulation of cerebellar dentate nucleus (DN) plasticity remain unclear; this study therefore investigated how EE coordinates autophagy, mitochondrial homeostasis, and synaptic remodeling in the contralateral DN to facilitate functional restoration. Using a permanent middle cerebral artery occlusion (pMCAO) mouse model, we combined behavioral tests (rotarod and ladder rung) with electron microscopy, Western blotting (LC3B, p62, mTOR/p‐mTOR), and ELISA (TNF‐α, IL‐1β, IL‐6) to assess motor function, ultrastructural changes, autophagy, and neuroinflammation. Results demonstrated that EE significantly improved cerebellar‐mediated motor coordination, reduced neuronal degeneration, and preserved mitochondrial integrity, while enhancing autophagic activity via increased LC3B expression and decreased p62 accumulation. Ultrastructural analysis revealed elevated synaptic density and a shift toward mitochondrial rejuvenation, paralleled by attenuated neuroinflammatory responses and suppressed pro‐inflammatory cytokine levels, consistent with mTOR pathway inhibition. These findings indicate that EE promotes motor recovery by activating a self‐reinforcing repair loop in the DN, wherein autophagy‐mediated mitochondrial clearance and neuroinflammation suppression create a permissive microenvironment for synaptic remodeling, thereby establishing the DN as a pivotal hub for EE's therapeutic effects and supporting combinatory strategies targeting autophagy–mitochondrial pathways to optimize rehabilitation.
Wang et al. (Mon,) studied this question.