Medial Prefrontal Cortical CB1Rs and Astrocytes Are Involved in Depression and the Antidepressant Effects of Running Exercise

Depression represents a growing global health challenge, with current pharmacological treatments often exhibiting limited efficacy and significant side effects. Although physical exercise, particularly running exercise, has shown promising antidepressant properties, its underlying neurobiological mechanisms remain poorly understood. In this study, we hypothesized that cannabinoid receptor type 1 (CB1R) in the medial prefrontal cortex (mPFC) mediates the therapeutic benefits of running exercise through astrocyte modulation. Using a chronic restraint stress (CRS) rat model of depression, we integrated behavioral assessments (saccharin preference and forced swim tests) with multimodal molecular and cellular analyses, including immunohistochemical staining, an unbiased stereological method, an immunofluorescence technique, RT‒PCR and Western blotting. Our findings demonstrate that running exercise alleviated depressive-like behaviors, restored mPFC CB1R expression, and prevented astrocyte loss. Conversely, mPFC-specific CB1R knockdown induced depressive behaviors and astrocyte deficits, whereas CB1R overexpression replicated the antidepressant effects of running exercise. Critically, running exercise failed to alleviate depression and astrocyte pathology in CB1R-knockdown rats, indicating CB1R dependence. These results establish mPFC CB1R as a pivotal mediator of running exercise-induced antidepressant effects and implicate astrocyte preservation as a key cellular mechanism. Our work reveals the mPFC CB1R-astrocyte axis as a promising target for novel antidepressant strategies and emphasizes the importance of glial plasticity in exercise neuroscience.