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Prefrontal corticotropin-releasing factor promotes resilience to social stress

Neuropsychopharmacology (2025)Cite this article

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Abstract

Variations in individual coping styles have been linked to either resilience or vulnerability towards stress, thereby influencing the probability of developing stress-related disorders. The involvement of corticotropin-releasing factor (CRF) neurons within the medial prefrontal cortex (mPFC) plays a crucial role in modulating behavioral responses to stressful situations. In this study utilizing a mouse model of social defeat stress (SDS), we demonstrate how coordinated activation and localized release of CRF within the mPFC contribute to promoting adaptive responses under stressful conditions leading to enhanced resilience against subsequent challenges. Specifically, during SDS exposure, heightened activity levels were observed among mPFC CRF neurons coincide with increased local release triggered by active exploration and defensive behaviors, while decreased responses were detected upon exposure to aggression. Interestingly, the CRF neural activity and local release responding to coping behaviors throughout chronic social defeat stress (CSDS) differed between susceptible and resilient mice. Furthermore, activation of CRF receptor 1 (CRFR1) signaling in the mPFC enhanced active coping behaviors and conferred resilience to CSDS, while inhibition of CRF system promoted passive coping behaviors and induced susceptibility to sub-threshold SDS. Additionally, inhibition of CRFR1 in the mPFC nullified the pro-resilience effect elicited by activation of CRF neurons during CSDS. The collective findings provide evidence supporting the crucial role of local endogenous CRF derived from mPFC CRF neurons in maintaining resilience through active coping styles when confronted with social stress. Moreover, these results suggest that targeting the mPFC CRF system could hold promise as a therapeutic approach for managing stress-related disorders.

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Fig. 1: Behaviour-dependent CRF neuronal Ca2+ activity and CRF real-time release in the mPFC during acute social defeat.
Fig. 2: CRF neural activity and local release in the mPFC drove different outcomes to social stress.
Fig. 3: CSDS decreased excitability of mPFC CRF neurons in stress-susceptible mice.
Fig. 4: CRF/CRFR1 signaling in the mPFC contributes to the persistent resilience against CSDS induced by the increase of mPFC CRF neuronal activity.
Fig. 5: Activation of CRF/CRFR1 signaling in the mPFC exerts persistent resilience against CSDS.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank Prof. Yu Long Li and Dr. Huan Wang (Peking University) for providing CRF sensor; Prof. Ji Liu (University of Science and Technology of China) for providing Crhr1-Cre and Crhr1flox/flox mice; Rui-Hua Li, Sen-Miao Fang and Jin-Kun Guo (Institute of Brain Science, the First Affiliated Hospital of Anhui Medical University) for help with the experiment.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82471540; 32030046; 32200798; 82201671), Anhui Provincial Natural Science Foundation (2408085Y043).

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  1. These authors contributed equally: Ya-Tao Wang, Yong Li.

Authors and Affiliations

  1. Institute of Brain Science, The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Ya-Tao Wang, Yong Li, Meng-Yun Li, Yue-Ming Zhang, Yue Wang, Qi-Qi Xu, Xin-Ya Qin, Qing-Hong Shan, Yu Wang, Jiang-Ning Zhou & Peng Chen

  2. Anhui Geriatrics Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Rong-Yu Liu

  3. Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Anhui Medical University, Hefei, China

    Jiang-Ning Zhou & Peng Chen

  4. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Jiang-Ning Zhou

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Contributions

J-NZ and PC designed the research; Y-TW and YL performed most of the experiment and statistical analysis and wrote the draft manuscript; M-YL and YW preformed behavioral experiments and statistical analysis; Y-MZ and Q-QX contributed to electrophysiology in vitro; R-YL provided the reagents and helpful suggestions to the manuscript; Q-HS, X-YQ and YW modified the manuscript; J-NZ and PC supervised all aspects of the project and conducted a critical revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jiang-Ning Zhou or Peng Chen.

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Wang, YT., Li, Y., Li, MY. et al. Prefrontal corticotropin-releasing factor promotes resilience to social stress. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02148-6

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