Abstract
Although clinical reports have highlighted association of the deacetylase sirtuin 1 (SIRT1) gene with anxiety, its exact role in the pathogenesis of anxiety disorders remains unclear. The present study was designed to explore whether and how SIRT1 in the mouse bed nucleus of the stria terminalis (BNST), a key limbic hub region, regulates anxiety. In a chronic stress model to induce anxiety in male mice, we used site- and cell-type-specific in vivo and in vitro manipulations, protein analysis, electrophysiological and behavioral analysis, in vivo MiniScope calcium imaging and mass spectroscopy, to characterize possible mechanism underlying a novel anxiolytic role for SIRT1 in the BNST. Specifically, decreased SIRT1 in parallel with increased corticotropin-releasing factor (CRF) expression was found in the BNST of anxiety model mice, whereas pharmacological activation or local overexpression of SIRT1 in the BNST reversed chronic stress-induced anxiety-like behaviors, downregulated CRF upregulation, and normalized CRF neuronal hyperactivity. Mechanistically, SIRT1 enhanced glucocorticoid receptor (GR)-mediated CRF transcriptional repression through directly interacting with and deacetylating the GR co-chaperone FKBP5 to induce its dissociation from the GR, ultimately downregulating CRF. Together, this study unravels an important cellular and molecular mechanism highlighting an anxiolytic role for SIRT1 in the mouse BNST, which may open up new therapeutic avenues for treating stress-related anxiety disorders.
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Acknowledgements
The authors would like to thank Prof.Dr. Paul J. Lucassen (University of Amsterdam, The Netherlands) for editing the manuscript and providing helpful suggestions; Dr. Troy A. Roepke (Rutgers University, NJ, USA), Dr. Tao Zhang (Johns Hopkins University School of Medicine, MD, USA), Dr. Li-Feng Zhang (PKU-Nanjing Institute of Translational Medicine, Nanjing, China), and Prof. Guang-Hui Wang (Soochow University, Suzhou, China), for technical consultation; and thank Mr. Zhen-Bang Liu; Dr. Hui Fang; Dr. Chuan Huang; Dr. Xin-Ya Qin; Dr. Chen-Wei Wang; Dr. Gao Wu; (all from USTC); Mr. Meng-Cheng Huang (Shanghai Applied Protein Technology Co. Ltd, Shanghai, China); and Dr. Hui Gong (Huazhong University of Science and Technology, Wuhan, China) for technical support. We thank Dr. Wu Zhang and Mr. Hong-Jun Liu from Brain VTA ltd (Wuhan, China) for consultation of virus information. We thank Dr. Minmin Luo (NIBS Institute, Beijing, China) for providing the Ai14-reporter mice line. We also thank Dr. Yan-Yan Su from Anhui Medical University for graphical assistance.
Funding
This work was supported by National Science Foundation of China (Grant No. 32030046; 32000716; 82271554; 82201671), the Strategic Priority Research Program of the Chinese Academy of Science (Grant No. XDB32020200), the National Key R&D Program of China (Grant No. 2022ZD0205202), the Key Direction Cultivation Funding from the University of Science and Technology of China (Grant No. WK3460000007).
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PH and JNZ conceptualized the study. PH and YW designed experiments. PH and YW conducted experiments and analyzed data. XHQ helped with cell culture and molecular experiments and analyzed data. QHS helped with electrophysiological recording and calcium imaging data analysis. ZHH and PC contributed reagents and provided transgenic mice line. XM helped with calcium imaging data analysis. YPY and ZZ contributed reagents and provided helpful suggestions to the manuscript. PH wrote the paper together with JNZ with inputs from all co-authors. DFS, BAS and ZZ edited and revised the manuscript and provided helpful suggestions. All authors have read and approved the final version of the manuscript.
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Hu, P., Wang, Y., Qi, XH. et al. SIRT1 in the BNST modulates chronic stress-induced anxiety of male mice via FKBP5 and corticotropin-releasing factor signaling. Mol Psychiatry 28, 5101–5117 (2023). https://doi.org/10.1038/s41380-023-02144-6
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DOI: https://doi.org/10.1038/s41380-023-02144-6