Medium-intensity aerobic exercise can relieve mice anxiety by activating cannabinoid type 1 receptors on medial prefrontal cortex GABAergic neurons

Anxiety disorders are highly prevalent, yet current pharmacological treatments often have limited efficacy and adverse effects. As a safe and accessible non-pharmacological intervention, physical exercise has shown promise in alleviating anxiety; however, its precise neural mechanisms remain unclear. This study aimed to elucidate how moderate-intensity aerobic exercise reduces anxiety, with a specific focus on the role of distinct cell populations within the medial prefrontal cortex (mPFC). Using a chronic restraint stress (CRS) mouse model, we combined behavioral tests, protein analysis, pharmacological interventions, and optogenetics to systematically examine the effects of exercise on anxiety-like behaviors and the associated molecular and cellular mechanisms in the mPFC. Moderate-intensity aerobic exercise significantly alleviated stress-induced anxiety-like behaviors. Further investigation revealed that exercise enhanced endocannabinoid system (ECS) activity in the mPFC, specifically by activating cannabinoid type 1 receptors (CB1Rs) located on local inhibitory neurons. Cell type-specific manipulation demonstrated that CB1Rs on GABAergic neurons are essential for the anxiolytic effect of exercise, whereas CB1Rs on other neuronal subtypes were not involved. Our findings indicate that moderate-intensity aerobic exercise reduces anxiety by selectively enhancing CB1R function on GABAergic neurons in the mPFC, thereby restoring circuit balance. This study not only advances the understanding of exercise-induced neurobiological benefits but also offers a novel theoretical basis for developing targeted antianxiety strategies.