Rapid antidepressant effect of single-bout exercise is mediated by adiponectin-induced APPL1 nucleus translocation in anterior cingulate cortex

Emerging evidence suggests that a single bout of physical exercise can induce rapid antidepressant effects, yet the underlying neural mechanisms remain largely unknown. We established a mouse model designed to mimic the mood-elevating effects of acute exercise observed in humans. We found that this rapid antidepressant response in exercised mice correlated with increased brain levels of adiponectin, an adipocyte-secreted hormone. Using whole-brain c-Fos mapping, immunofluorescence staining of glutamatergic neurons using the marker CaMKII, and in vivo calcium imaging, we identified ACC glutamatergic neurons that were rapidly activated by single-bout physical exercise. Chemogenetic manipulation of these neurons modulated the rapid antidepressant effects of exercise. Genetic manipulations demonstrated that the global knockout of adiponectin or the selective deletion of its receptor, AdipoR1, in ACC-glutamatergic neurons abolished both neural activation and the rapid antidepressant response. Mechanistically, acute exercise upregulated adiponectin, activating AdipoR1 and promoting nuclear translocation of APPL1 in ACC-glutamatergic neurons. This molecular cascade enhanced the epigenetic regulation of synaptic protein expression and spinogenesis, culminating in a rapid antidepressant response. These findings not only elucidate a novel role for APPL1 nuclear translocation in mediating the antidepressant effects of acute exercise but also identify AdipoR1 as a potential therapeutic target for developing rapid-acting antidepressant interventions.