Fei Tian

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.

Emerging evidence indicates that gut microbiota influences host physiology and behavior through the microbiota‐gut‐brain axis, potentially contributing to the pathogenesis of obsessive‐compulsive disorder (OCD). Our preliminary research demonstrated that mice colonized with fecal microbiota from OCD patients developed compulsive‐like behaviors, associated with a significant increase in the microbial metabolite succinate. However, the mechanisms linking succinate to compulsive‐like behavior remain to be fully elucidated. Here, we demonstrate that succinate is associated with significant compulsive‐like behaviors. Succinate is associated with disruptions of glutamatergic neurons within the dorsal medial prefrontal cortex (dmPFC), and we characterize dual pathways linked to the behavioral abnormality: both by dmPFC microglial engagement via the succinate cognate receptor SUCNR1, and by gut‐to brain signaling conveyed through vagal afferents and the 5‐HT ₄ receptor. Pharmacological modulation of the succinate metabolism pathway through succinate dehydrogenase inhibition ameliorates compulsive‐like behavior in Hoxb8 ^−/− OCD‐model mice. Circulating succinate levels significantly distinguish OCD patients from healthy controls with an AUC of 0.73, and correlate with prefrontal cortex activity on functional imaging. Collectively, our study delineates a gut‐brain axis implicating succinate in central nervous system dysregulation associated compulsive‐like behavior, elucidates novel immunometabolism and neural circuit mechanisms underlying OCD pathogenesis, and identifies druggable targets for potential precise interventions.