TERT mediates the U‐shape of glucocorticoids effects in modulation of hippocampal neural stem cells and associated brain function

• Published in: CNS neuroscience & therapeutics 2024-02, Vol.30 (2), p.e14577-n/a
• Main Authors: Liu, Meng‐Ying, Fan, Yixin, Ni, Ningjie, Yu, Tao, Mao, Zhiyuan, Huang, Hanyu, Zhang, Jing, Tang, Yulin, He, Hongliang, Meng, Fan, You, Yongping, Zhou, Qi‐Gang
• Format: Article
• Language: English
• Subjects: Adenoviruses; Adrenal cortex; Adrenalectomy; Alzheimer's disease; Animals; Apoptosis; bidirectional regulation; Brain research; Cell growth; Cognitive ability; Corticosterone; Corticosterone - pharmacology; Dentate gyrus; depression; Doublecortin protein; Flow cytometry; Glucocorticoid receptors; Glucocorticoids; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; Growth factors; Hippocampus; Hippocampus - metabolism; learning and memory; Memory; Memory Disorders - metabolism; Mice; Microinjection; Mineralocorticoid receptors; Mood; Neural stem cells; Neural Stem Cells - metabolism; Neurogenesis; NSCs; Original; RNA-directed DNA polymerase; Stem cells; Surgery; Telomerase; Telomerase reverse transcriptase; TERT
• ISSN: 1755-5930; 1755-5949; 1755-5949
• DOI: 10.1111/cns.14577

Background Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological‐level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U‐shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood‐related disorders. Methods Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 μL of Ad‐mTERT‐GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. Results Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U‐shaped manner. The physiological level of GCs (0.01 μM) promoted NSC proliferation in vitro, while the stress level of GCs (10 μM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)‐positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD‐mTERT‐GFP reversed both chronic stresses‐ and ADX‐induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses‐associated depressive symptoms, and ADX‐associated learning and memory impairment. Conclusion The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U‐shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction‐associated diseases. Schematic indicating that the U‐shaped effects of glucocorticoids (GCs) are mainly dependent on telomerase reverse transcriptase (TERT). Physiological levels of GCs can activate mineralocorticoid receptor, induce the upregulation of TERT, and ameliorate depressive‐like behavior in mice; in contrast, stressful levels o