Glucocorticoid receptor activation induces decrease of hippocampal astrocyte number in rats
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The decrease of astrocyte number and hypothalamic-pituitary-adrenal (HPA) axis overactivity are observed in individuals with major depressive disorder. Elevated levels of glucocorticoids induced by hyperactivation of the HPA axis may result in glucocorticoid receptor (GR) activation. However, it is unclear whether there is a direct link between GR activation and the decrease of astrocyte number.
Animals were exposed to chronic unpredictable stress (CUS) for 28 days and treated with continuous subcutaneous injections of vehicle or corticosterone (CORT; 40 mg/kg/day) for 21 days. We then administered mifepristone on day 21 after CUS and on day 18 after the CORT treatment. We observed behavioral deficits in the sucrose preference test, open field test, and forced swim test. Protein expression was analyzed using immunofluorescence (IF) and western blot (WB).
Animals exposed to CUS exhibited behavioral deficits in tests measuring anhedonia, anxiety, and despair state. They also had decreases in glial fibrillary acidic protein (GFAP) expression and numbers of GFAP-positive cells in the hippocampus. The behavioral and cellular alterations induced by CUS were reversed by subchronic treatment with the GR antagonist mifepristone. We also found that the subcutaneous injection of glucocorticoids may induce depression-like behavior and reduce GFAP protein expression in rats, which was similarly reversed by mifepristone.
These findings provide experimental evidence that GR activation due to elevated CORT levels induces the decrease of hippocampal astrocyte number in rats.
KeywordsGFAP Glucocorticoid receptor Corticosterone Depression Astrocyte
This work was supported by the National Natural Science Foundation of China (81573636, 81773924, U1402221, 81560663), Beijing Natural Science Foundation (7182114), PUMC Youth Fund (3332016058), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-004), the Scientific Research Foundation of the Higher Education Institutions of Hunan Province (15K091), Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150), PUMC Graduate Education and Teaching Reform Project (10023201600801), The State Key Laboratory Fund Open Project (GTZK201610), and China Postdoctoral Science Foundation (2013M540066).
- Czeh B, Simon M, Schmelting B, Hiemke C, Fuchs E (2006) Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology: official publication of the American College of. Neuropsychopharmacology 31:1616–1626CrossRefGoogle Scholar
- Dong L, Wang S, Li Y, Zhao Z, Shen Y, Liu L, Xu G, Ma C, Li S, Zhang X, Cong B (2017) RU486 Reverses Emotional Disorders by Influencing Astrocytes and Endoplasmic Reticulum Stress in Chronic Restraint Stress Challenged Rats. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and. Pharmacology 42:1098–1108Google Scholar
- Garcia-Caceres C, Lagunas N, Calmarza-Font I, Azcoitia I, Diz-Chaves Y, Garcia-Segura LM, Baquedano E, Frago LM, Argente J, Chowen JA (2010) Gender differences in the long-term effects of chronic prenatal stress on the HPA axis and hypothalamic structure in rats. Psychoneuroendocrinology 35:1525–1535CrossRefGoogle Scholar
- Gong MJ, Han B, Wang SM, Liang SW, Zou ZJ (2016) Icariin reverses corticosterone-induced depression-like behavior, decrease in hippocampal brain-derived neurotrophic factor (BDNF) and metabolic network disturbances revealed by NMR-based metabonomics in rats. J Pharm Biomed Anal 123:63–73CrossRefGoogle Scholar
- Iwata M, Shirayama Y, Ishida H, Hazama GI, Nakagome K (2011) Hippocampal astrocytes are necessary for antidepressant treatment of learned helplessness rats. Hippocampus 21:877–884Google Scholar
- Karisetty BC, Maitra S, Wahul AB, Musalamadugu A, Khandelwal N, Guntupalli S, Garikapati R, Jhansyrani T, Kumar A, Chakravarty S (2017) Differential effect of chronic stress on mouse hippocampal memory and affective behavior: Role of major ovarian hormones. Behav Brain Res 318:36–44CrossRefGoogle Scholar
- Lante F, Chafai M, Raymond EF, Pereira AR, Mouska X, Kootar S, Barik J, Bethus I, Marie H (2015) Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 40:1772–1781CrossRefGoogle Scholar
- Lenk K, Raisanen E, Hyttinen JA, Lenk K, Raisanen E, Hyttinen JA, Lenk K, Hyttinen JA, Raisanen E (2016) Understanding the role of astrocytic GABA in simulated neural networks. Conference proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society IEEE Engineering in Medicine and Biology Society Annual Conference 2016: 6121-6124.Google Scholar
- Wu LM, Han H, Wang QN, Hou HL, Tong H, Yan XB, Zhou JN (2007) Mifepristone repairs region-dependent alteration of synapsin I in hippocampus in rat model of depression. Neuropsychopharmacology: official publication of the American College of. Neuropsychopharmacology 32:2500–2510CrossRefGoogle Scholar