Compound Ciwujia Granules Attenuate Stress‐Induced Anxiety‐ and Depression‐Like Behaviors via Inhibition of TNF ‐α‐Associated Neuroinflammation in the dmPFC

ABSTRACT Aims Compound Ciwujia Granules (CWJ) have shown antidepressant‐like effects, but the neural and molecular mechanisms underlying these effects remain unclear. This study aimed to investigate the mechanisms by which CWJ ameliorates anxiety‐ and depression‐like behaviors. Methods A 6‐week chronic unpredictable mild stress (CUMS) model was established in rats, and behavioral tests were performed to assess the antidepressant‐like effects of CWJ. Resting‐state functional magnetic resonance imaging (rs‐fMRI), in vivo fiber photometry, and chemogenetic manipulation were used to identify the brain region and neuronal population involved in the effects of CWJ. Transcriptomic analysis combined with network pharmacology was used to predict candidate molecular pathways, which were further validated by quantitative real‐time polymerase chain reaction, immunofluorescence, western blotting, and pharmacological interventions. Results CWJ increased the open‐arm ratio in the EPM, reduced FST immobility, and lowered serum corticosterone (CORT) levels in CUMS rats. Convergent rs‐fMRI, c‐Fos immunostaining, and fiber photometry identified that the dorsomedial prefrontal cortex (dmPFC) was a key brain region involved in the antidepressant‐like effects of CWJ. CWJ increased glutamatergic neuronal activity and reduced neuroinflammatory responses associated with TNF‐related inflammatory signaling in the dmPFC. Moreover, pharmacological activation of TNF‐related inflammatory signaling partially attenuated the behavioral benefits of CWJ, supporting the involvement of  TNF‐related inflammatory signaling in mediating its antidepressant effects. Conclusions These findings suggest that CWJ attenuated CUMS‐induced anxiety‐ and depression‐like behaviors by restoring dmPFC glutamatergic neuronal activity and suppressing TNF‐related neuroinflammation in the dmPFC.