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Salt-inducible kinase 1-CREB-regulated transcription coactivator 1 signalling in the paraventricular nucleus of the hypothalamus plays a role in depression by regulating the hypothalamic–pituitary–adrenal axis

Molecular Psychiatry (2022)Cite this article

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Abstract

Elucidating the molecular mechanism underlying the hyperactivity of the hypothalamic–pituitary–adrenal axis during chronic stress is critical for understanding depression and treating depression. The secretion of corticotropin-releasing hormone (CRH) from neurons in the paraventricular nucleus (PVN) of the hypothalamus is controlled by salt-inducible kinases (SIKs) and CREB-regulated transcription co-activators (CRTCs). We hypothesised that the SIK-CRTC system in the PVN might contribute to the pathogenesis of depression. Thus, the present study employed chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioural tests, virus-mediated gene transfer, enzyme-linked immunosorbent assay, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunofluorescence to investigate this connection. Our results revealed that both CSDS and CUMS induced significant changes in SIK1-CRTC1 signalling in PVN neurons. Both genetic knockdown of SIK1 and genetic overexpression of CRTC1 in the PVN simulated chronic stress, producing a depression-like phenotype in naive mice, and the CRTC1-CREB-CRH pathway mediates the pro-depressant actions induced by SIK1 knockdown in the PVN. In contrast, both genetic overexpression of SIK1 and genetic knockdown of CRTC1 in the PVN protected against CSDS and CUMS, leading to antidepressant-like effects in mice. Moreover, stereotactic infusion of TAT-SIK1 into the PVN also produced beneficial effects against chronic stress. Furthermore, the SIK1-CRTC1 system in the PVN played a role in the antidepressant actions of fluoxetine, paroxetine, venlafaxine, and duloxetine. Collectively, SIK1 and CRTC1 in PVN neurons are closely involved in depression neurobiology, and they could be viable targets for novel antidepressants.

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Fig. 1: Exposure to chronic stress notably modulated SIK1-CRTC1 signalling in the PVN of mice.
Fig. 2: AAV-mediated genetic knockdown of SIK1 in the PVN of naive mice produced various depression-like symptoms.
Fig. 3: AAV-mediated genetic overexpression of SIK1 in the PVN exerted significant antidepressant-like effects in mice.
Fig. 4: AAV-mediated genetic overexpression of SIK1 in the PVN exerted significant protective effects against chronic stress on the SIK1-CRTC1-CRH pathway in the PVN and the BDNF signalling cascade in the hippocampus and mPFC.
Fig. 5: Repeated administration of fluoxetine and venlafaxine notably reversed the effects of chronic stress on the SIK1-CRTC1-CRH pathway in the PVN.
Fig. 6: Schematic representation of a suggested model describing the role of SIK1-CRTC1 signalling in PVN neurons in chronic stress-induced depression is provided.

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The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary information files.

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Acknowledgements

This work was supported by four grants from the National Natural Science Foundation of China (Nos. 82071519, 81873795, 81900551, and 82001606).

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  1. These authors contributed equally: Yuan Wang, Ling Liu, Jiang-Hong Gu.

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001, Jiangsu, China

    Yuan Wang, Ling Liu, Jiang-Hong Gu, Wei Guan, Yue Liu, Wen-Qian Tang, Chun-Hui Ji, Yan-Mei Chen, Jie Huang, Wei-Yu Li, Tian-Shun Shi, Wei-Jia Chen, Bao-Lun Zhu & Bo Jiang

  2. Provincial Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China

    Yuan Wang, Ling Liu, Jiang-Hong Gu, Wei Guan, Yue Liu, Wen-Qian Tang, Chun-Hui Ji, Yan-Mei Chen, Jie Huang, Wei-Yu Li, Tian-Shun Shi & Bo Jiang

  3. Basic Medical Research Centre, Medical College, Nantong University, Nantong, 226001, Jiangsu, China

    Cheng-Niu Wang

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Contributions

Conceptualisation: BJ. Methodology: YW, LL, J-HG, C-NW, WG, YL, W-QT, C-HJ, Y-MC, and JH. Investigation: YW, LL, J-HG, YL, W-QT, C-HJ, Y-MC, JH, W-YL, T-SS, W-JC, and B-LZ. Formal analysis: BJ. Resources: BJ, C-NW, and WG. Writing—original draft: BJ. Writing—review and editing: BJ. Visualisation: BJ. Supervision: BJ. Project administration: BJ. Funding acquisition: BJ, C-NW, and WG.

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Wang, Y., Liu, L., Gu, JH. et al. Salt-inducible kinase 1-CREB-regulated transcription coactivator 1 signalling in the paraventricular nucleus of the hypothalamus plays a role in depression by regulating the hypothalamic–pituitary–adrenal axis. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01881-4

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