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Social hierarchy and resilience affect stress-induced PTSD via Uba7 gene expression and subsequent inflammation in microglia of the mPFC

Molecular Psychiatry (2025)Cite this article

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Abstract

Post-traumatic stress disorder (PTSD) occurs in individuals who have experienced a traumatic event; however, not everyone who has experienced a traumatic event will develop this condition, highlighting the significance of susceptibility factors. Social hierarchy is a critical behavioral regulator of stress susceptibility and a risk factor for mental disorders. Individual resilience, the ability to recover from acute stress and preclinical injury, also plays a role in PTSD susceptibility. Some studies found that individuals with higher social rank were more resilient. Furthermore, individuals of a lower social rank exhibit increased microglial activity and the release of pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α); however, their exact role in PTSD remains unclear. Research has indicated that the nuclear factor kappa B (NF-κB) signaling pathway in the medial prefrontal cortex (mPFC) was activated abnormally in PTSD and correlated with changes in ubiquitin-like modifier activating enzyme 7 (Uba7) gene expression. However, the specific roles of Uba7 and the NF-κB pathway in PTSD susceptibility necessitate further investigation. Understanding these factors is crucial for comprehending the psychopathological changes in PTSD and developing preventive strategies. Our study validated three PTSD phenotypes using the mouse single prolonged stress (SPS) model, finding that resilience influenced PTSD recovery over time. Subsequently, we employed the chronic social defeat stress (CSDS) model to evaluate differential stress responses and recovery patterns over 14 days in mice of various social hierarchies and examined the related molecular changes in their mPFC. The results indicated that social hierarchy predicted PTSD susceptibility, with dominant individuals exhibiting greater vulnerability and more severe initial symptoms. Over time, resilient individuals in the lower-ranked groups recovered faster from anxiety and depression than those in the higher-ranked groups. Overactivation of microglia in the mPFC of susceptible individuals was associated with increased expression of NF-κB p65 and signals transducer and activator of transcription (STAT1) proteins, Uba7 gene expression, and TNF-α. Our findings highlight the complex interplay between social status and PTSD risk factors.

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Fig. 1: Experimental Flow Chart and Social Interaction Experiments for Categorizing Stress Response Phenotypes and Predicting Development Trends.
Fig. 2: The Effect of SPS Procedure on Behavior Tests.
Fig. 3: Establishment of social hierarchies.
Fig. 4: Group-Based Statistical Analysis for OFT, EPM, and FST Across Time Points.
Fig. 5: Comparison of behavioral indicators between dominant and subordinate CSDS resilience or susceptibility groups.
Fig. 6: Effects of CSDS Procedure on physiological indicators in the mPFC (n = 5 per group).

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All data needed to evaluate the conclusions of the present study are present in the main paper and/or the Supplementary Materials. Additional data are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (NSFC) 82101588, the Education and Teaching Reform Project of the Psychology and Education Reference Committee of the Ministry of Education 20221013, the Surface project of the Natural Science Foundation of Shandong Province ZR2020MC218, the Institute of Psychology, Chinese Academy of Sciences GJ202002, and the Graduate Student Research Grant from Weifang Medical University.

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Author notes

  1. These authors contributed equally: Luping Gou, Hao Zheng.

Authors and Affiliations

  1. School of Psychology, Shandong Second Medical University, 7166# Baotong West Street, Weifang Shandong, 261053, P. R. China

    Luping Gou, Hao Zheng, Xianqiang Zhang, Guohua Lu, Hongwei Sun & Lin Sun

  2. School of Clinical Medicine, Shandong Second Medical University, 7166# Baotong West Street, Weifang Shandong, 261053, P. R. China

    Jiaming Chen, Dantong Chen & Ziyi Li

  3. Department of Bioscience and Technology, Shandong Second Medical University, 7166# Baotong West Street, Weifang, Shandong, 261053, China

    Yingjie Gao, Jiangyu Ma & Bo Lian

  4. Department of Neurology, Affiliated Hospital of Shandong Second Medical University, Weifang, PR China

    Chunyan Wu

  5. National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital/Institute of Mental Health and the Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China

    Xianqiang Zhang

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Contributions

L.P.G. and L.S. conceived the project and designed the experiments. L.P.G and H.Z. were responsible for the collection, analysis of overall experimental data, the interpretation of the results and revised the manuscript. J.M.C., Y.J.G., J.Y.M., D.T.C. and Z.Y.L. contributed to data collection of behavioral tests. C.Y.W., B.L., X.Q.Z., G.H.L. and H.W.S. contributed to data interpretation and manuscript editing; L.S. contributed to editing as well as final approval of the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Lin Sun.

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This work was carried out based on the Regulations of Experimental Animal Administration issued by the State Committee of Science and Technology of the People’s Republic of China, with the approval of the Ethics Committee of Shandong Second Medical University (Approval No. 2021SDL203). All methods were performed in accordance with the relevant guidelines and regulations.

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Gou, L., Zheng, H., Chen, J. et al. Social hierarchy and resilience affect stress-induced PTSD via Uba7 gene expression and subsequent inflammation in microglia of the mPFC. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03171-1

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