Environmental enrichment promotes functional recovery from stroke via enhancing neuroplasticity through the action of β-HB.

Stroke is a leading cause of adult disability worldwide, unfortunately, no drugs are clinically available to promote functional recovery after stroke. Although animal environmental enrichment is a recognized paradigm for promoting stroke repair, elusive mechanisms hinder its clinical translation. Here, we show that β-hydroxybutyrate (β-HB) level in the peri-infarct cortex is upregulated after environmental enrichment (EE) exposure. Importantly, exogenous supplementation of β-HB promotes functional recovery to a similar extent as EE exposure. Moreover, the beneficial effects of EE on stroke recovery, including functional recovery, neuroplasticity-related proteins upregulation, and structural and functional plasticity enhancement, are abolished by β-HB transporter inhibitor, AR-C155858. Intriguingly, supplementation with (R)-3-hydroxybutyl (R)-β-HB, a ketone ester (KE), substantially increases β-HB level and lessens motor functional impairments. Together, our findings indicate that β-HB is a critical substrate for EE-mediated stroke recovery and supplementation with β-HB monoester drinks may serve as a novel strategy to translate EE from bench to bedside.