Ying-Dan Zhang

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.

Obsessive-compulsive disorder (OCD) is a chronic, severe psychiatric disorder that has been ranked by the World Health Organization as one of the leading causes of illness-related disability, and first-line interventions are limited in efficacy and have side-effect issues. However, the exact pathophysiology underlying this complex, heterogeneous disorder remains unknown. This scenario is now rapidly changing due to the advancement of powerful technologies that can be used to verify the function of the specific gene and dissect the neural circuits underlying the neurobiology of OCD in rodents. Genetic and circuit-specific manipulation in rodents has provided important insights into the neurobiology of OCD by identifying the molecular, cellular, and circuit events that induce OCD-like behaviors. This review will highlight recent progress specifically toward classic genetic animal models and advanced neural circuit findings, which provide theoretical evidence for targeted intervention on specific molecular, cellular, and neural circuit events.

Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive-compulsive disorder (OCD). Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice and showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16 S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota–brain–immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice. We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.

Early-life stress is normally thought of as a major risk for psychiatric disorders, but many researchers have revealed that adversity early in life may enhance stress resilience later in life. Few studies have been performed in rodents to address the possibility that exposure to early-life stress may enhance stress resilience, and the underlying neural mechanisms are far from being understood. Here, we established a “two-hit” stress model in rats by applying two different early-life stress paradigms: predictable and unpredictable maternal separation (MS). Predictable MS during the postnatal period promotes resilience to adult restraint stress, while unpredictable MS increases stress susceptibility. We demonstrate that structural and functional impairments occur in glutamatergic synapses in pyramidal neurons of the medial prefrontal cortex (mPFC) in rats with unpredictable MS but not in rats with predictable MS. Then, we used differentially expressed gene (DEG) analysis of RNA sequencing data from the adult male PFC to identify a hub gene that is responsible for stress resilience. Oxytocin, a peptide hormone, was the highest ranked differentially expressed gene of these altered genes. Predictable MS increases the expression of oxytocin in the mPFC compared to normal raised and unpredictable MS rats. Conditional knockout of the oxytocin receptor in the mPFC was sufficient to generate excitatory synaptic dysfunction and anxiety behavior in rats with predictable MS, whereas restoration of oxytocin receptor expression in the mPFC modified excitatory synaptic function and anxiety behavior in rats subjected to unpredictable MS. These findings were further supported by the demonstration that blocking oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the mPFC was sufficient to exacerbate anxiety behavior in rats exposed to predictable MS. Our findings provide direct evidence for the notion that predictable MS promotes stress resilience, while unpredictable MS increases stress susceptibility via mPFC oxytocin signaling in rats.