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

Authors

Hao Li, Mingqing Yang, Yang Yang, Hongxia Ren, Hongyang Wang, Jiajia Huang, Huijuan Zhou, Xuefei Hu, Zhu Yuan, Guangjian Qi, Ouyang Zhanmu, Man Li

Published in

Translational psychiatry. Jul 02, 2026. Epub Jul 02, 2026.

Abstract

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.

PMID:
42393030
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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