Abstract
Rationale
The growing evidence has demonstrated the importance of endoplasmic reticulum stress (ERS) in the pathophysiology of depression. ERS genes were considered to be potential novel therapeutic targets for depression.
Objectives
To clarify the mechanisms of the chronic unpredictable mild stress (CUMS)–induced ERS response and the potential contributing pathways in depression, and further investigate the potential link between N-3 polyunsaturated fatty acids (PUFAs) and stress-induced ERS disturbances.
Methods
This study analyzed the expression of ERS-related genes including GRP78, ATF-4, ATF-6, XBP-1, and CHOP, and sigma-1R with real-time PCR in peripheral blood mononuclear cell (PBMC) RNA samples from participants. All of the rats except for those in the control groups were subjected to 5 consecutive weeks of CUMS to establish the depression model, and the antidepressant effects of N-3 PUFAs were observed by behavior tests. Moreover, the effect of diet and stress on the ERS pathways was also investigated using the western blot.
Results
Blood CHOP, ATF-4, and XBP-1 levels were notably elevated in depressed patients relative to healthy individuals. Moreover, increased sigma-1R and decreased ATF-6 implied the protective role of sigma-1R through modulating ERS in patients with depression. Animal studies disclosed the novel findings that supplementary N-3 PUFAs in rats alleviated CUMS-induced disturbance of ERS through the ATF-4/XBP-1/CHOP pathway, implying its potential strategy for depression.
Conclusion
CUMS-induced depressive-like behaviors are related to the disturbance of ERS. Furthermore, supplementary N-3 PUFAs might be an effective way to alleviate ERS.
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Data availability
Data described in the manuscript, code book, and analytic code will be made available upon request pending after corresponding author’s approval through E-mailing.
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Funding
The study was supported by the National Natural Science Foundation of China (No. 81803233), the fellowship of China Postdoctoral Science Foundation (2021M693561), the Key Research Project of Ningxia Hui Autonomous Region in 2021 (Major Project) (2021BEG01001), the Natural Science Foundation of Hunan Province (No. 2018JJ3834), and the Science Foundation of Xiangya Hospital for Young Scholar (No. 2017Q13).
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The authors’ contributions are as follows: Z.C.G. and T.Y. designed the experiments. M.M.T. wrote the protocol and the manuscript. M.M.T., T.L., and L.W. performed the experiments and collected the data. T.L. and Y.X. analyzed and interpreted the data. T.Y.Z., K.Q.X., and Y.M.S. managed the literature searches. M.M.T., Z.C.G., and T.Y. amended the manuscript. All authors read and approved the final manuscript.
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Ethical approval for the involvement of human subjects in this study was granted by Ethics Committee of the Second Xiangya Hospital of Central South University, reference number MDD201610. The study was conducted in accordance with the Declaration of Helsinki, and informed consent was obtained from all subjects involved in the study. Ethical approval for the involvement of animals in this study was granted by Ethics Committee of Xiangya Hospital of Central South University, reference number 201803464, 2018/3/9. The animal experiment was conducted in accordance with the ARRIVE guidelines.
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Tang, M., Liu, T., Shen, Y. et al. Potential antidepressant-like effects of N-3 polyunsaturated fatty acids through inhibition of endoplasmic reticulum stress. Psychopharmacology 240, 1877–1889 (2023). https://doi.org/10.1007/s00213-023-06377-9
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DOI: https://doi.org/10.1007/s00213-023-06377-9