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Glucocorticoid Receptor Down-Regulation Affects Neural Stem Cell Proliferation and Hippocampal Neurogenesis

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Abstract

Dysregulation of the hypothalamic–pituitary–adrenal axis and abnormalities in the glucocorticoid receptor (GR) have been linked to major depressive disorder. Given the critical role of GR in stress response regulation, we investigated the impact of GR changes on neural stem cells (NSCs) proliferation and hippocampal neurogenesis. Stress response was induced using dexamethasone (DEX), a GR agonist, which led to reduced proliferation of neural stem cells and neural progenitor cells, as well as decreased expression of GR. Additionally, a reduction of serum concentration within the culture media resulted in suppressed cell proliferation, accompanied by decreased GR expression. The association between GR expression and cell proliferation was further confirmed through GR siRNA knockdown and overexpression experiments. Furthermore, in vivo studies utilizing young male C57BL/6 mice demonstrated that corticosterone (CORT) (35 μg/ml) administered through drinking water for four weeks induced depression-like behavior, as indicated by increased immobility times in forced swimming and tail suspension tests. CORT exposure led to reduced GR and nestin expression levels, along with diminished numbers of BrdU-positive cells in the hippocampi, indicating impaired hippocampal neurogenesis. Taken together, our findings provide the first evidence that stress-induced downregulation of GR negatively affects neurogenesis by inhibiting NSCs proliferation.

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Data Availability

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

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Funding

This work was supported by the National Research Foundation of Korea (Grant No. Grant no. NRF-2021R1A2C1010091). This work was also supported under the framework of international cooperation program managed by the National Research Foundation of Korea (NRF-2022K2A9A2A08000187).

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  1. Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea

    Seoyeong Kim, Seonguk Yang, Jaehoon Kim, Ki Wung Chung, Young-Suk Jung, Hae Young Chung & Jaewon Lee

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Contributions

Seoyeong Kim: Investigation, Validation, Visualization, Methodology, Writing-original draft, Formal analysis. Seonguk Yang: Investigation, Validation, Visualization, Methodology. Jaehoon Kim: Investigation, Methodology. Ki Wung Chung: Formal analysis. Young-Suk Jung: Validation, Formal analysis. Hae Young Chung: Conceptualization. Jaewon Lee: Conceptualization, Funding acquisition, Resources, Supervision, Project administration, Writing—review & editing.

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Correspondence to Jaewon Lee.

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No human subjects were involved in this study. The animal protocol used was reviewed and approved by the Pusan National University-Institutional Animal Care Committee (PNU-IACUC; Approval Number PNU-2021–0083).

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Seoyeong Kim and Seonguk Yang contributed equally to the study and should be considered first authors.

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Kim, S., Yang, S., Kim, J. et al. Glucocorticoid Receptor Down-Regulation Affects Neural Stem Cell Proliferation and Hippocampal Neurogenesis. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03785-y

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