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Plasma corticosterone activates SGK1 and induces morphological changes in oligodendrocytes in corpus callosum.

Miyata S, Koyama Y, Takemoto K, Yoshikawa K, Ishikawa T, Taniguchi M, Inoue K, Aoki M, Hori O, Katayama T, Tohyama M - PLoS ONE (2011)

Bottom Line: Further, stress activates the hypothalamic-pituitary-adrenocortical (HPA) system by elevating plasma cortisol levels.However, little is known about the related downstream molecular pathway.Our data strongly suggest that these abnornalities of oligodendrocytes are possibly related to depression-like symptoms.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. smiyata@anat2.med.osaka-u.ac.jp

ABSTRACT
Repeated stressful events are known to be associated with onset of depression. Further, stress activates the hypothalamic-pituitary-adrenocortical (HPA) system by elevating plasma cortisol levels. However, little is known about the related downstream molecular pathway. In this study, by using repeated water-immersion and restraint stress (WIRS) as a stressor for mice, we attempted to elucidate the molecular pathway induced by elevated plasma corticosterone levels. We observed the following effects both, in vivo and in vitro: (1) repeated exposure to WIRS activates the 3-phosphoinositide-dependent protein kinase (PDK1)-serum glucocorticoid regulated kinase (SGK1)-N-myc downstream-regulated gene 1 (NDRG1)-adhesion molecule (i.e., N-cadherin, α-catenin, and β-catenin) stabilization pathway via an increase in plasma corticosterone levels; (2) the activation of this signaling pathway induces morphological changes in oligodendrocytes; and (3) after recovery from chronic stress, the abnormal arborization of oligodendrocytes and depression-like symptoms return to the control levels. Our data strongly suggest that these abnornalities of oligodendrocytes are possibly related to depression-like symptoms.

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Repeated exposure to WIRS (chronic stress) upregulates SGK1 and SGK1 is activated by PDK1.(A, B) In situ hybridization images of Sgk1 mRNA. Dark-field photomicrographs show the upregulation of Sgk1 mRNA expression in the fiber tracts after repeated exposure to WIRS (A, controls; B, stress). cc, corpus callosum; ac, anterior commissure. Scale bar = 5 mm. (C, D) In situ hybridization images of Sgk1 mRNA. Upregulation of Sgk1 mRNA (C) after repeated exposure to WIRS was abolished in the brain of adrenalectomized mice (D). cc, corpus callosum; ac, anterior commissure. Scale bar = 2 mm. (E) Real-time PCR analysis shows a significant increase in Sgk1 mRNA levels in the corpus callosum of mice exposed to repeated WIRS. *p<0.05, t-test. (F) Western blot analysis of SGK1 protein in the control and test (repeated exposure to WIRS) mice. (G, H) Western blot analysis shows SGK1 protein, its phosphorylation at positions T-256 (SGK1-256T-P) and S-422 (SGK1-422S-P), and the phosphorylation of PDK1 at position S-241 (PDK-241S-P) in the oligodendrocytes of the corpus callosum after repeated exposure to WIRS. (I, J) Western blot analysis shows that elevated corticosterone levels upregulate the phosphorylation of PDK1 (I) and SGK1 (J) in HEK293 cells with (+) or without (−) DEX treatment (100 µM). Wortmannin (WORT) was used as an inhibitor of the PI3K signaling pathway.
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pone-0019859-g003: Repeated exposure to WIRS (chronic stress) upregulates SGK1 and SGK1 is activated by PDK1.(A, B) In situ hybridization images of Sgk1 mRNA. Dark-field photomicrographs show the upregulation of Sgk1 mRNA expression in the fiber tracts after repeated exposure to WIRS (A, controls; B, stress). cc, corpus callosum; ac, anterior commissure. Scale bar = 5 mm. (C, D) In situ hybridization images of Sgk1 mRNA. Upregulation of Sgk1 mRNA (C) after repeated exposure to WIRS was abolished in the brain of adrenalectomized mice (D). cc, corpus callosum; ac, anterior commissure. Scale bar = 2 mm. (E) Real-time PCR analysis shows a significant increase in Sgk1 mRNA levels in the corpus callosum of mice exposed to repeated WIRS. *p<0.05, t-test. (F) Western blot analysis of SGK1 protein in the control and test (repeated exposure to WIRS) mice. (G, H) Western blot analysis shows SGK1 protein, its phosphorylation at positions T-256 (SGK1-256T-P) and S-422 (SGK1-422S-P), and the phosphorylation of PDK1 at position S-241 (PDK-241S-P) in the oligodendrocytes of the corpus callosum after repeated exposure to WIRS. (I, J) Western blot analysis shows that elevated corticosterone levels upregulate the phosphorylation of PDK1 (I) and SGK1 (J) in HEK293 cells with (+) or without (−) DEX treatment (100 µM). Wortmannin (WORT) was used as an inhibitor of the PI3K signaling pathway.

Mentions: The Sgk1 mRNA expression was markedly increased in the fiber tracts such as the corpus callosum and the anterior commissure after repeated exposure to WIRS (Figure 3A, B). Sgk1 mRNA was almost exclusively localized in oligodendrocytes (Figure 4A–F). In addition, Sgk1 mRNA upregulation in the fiber tracts after the mice were exposed to repeated WIRS was abolished after adrenolectomy (Figure 3C, D), indicating that elevated levels of corticosterone after exposure to repeated stress increase Sgk1 expression in the oligodendrocytes. Sgk1 mRNA and SGK1 protein upregulation in the fiber tracts such as the corpus callosum was also confirmed by quantitative real-time PCR (Figure 3E) and western blotting analysis (Figure 3F), respectively.


Plasma corticosterone activates SGK1 and induces morphological changes in oligodendrocytes in corpus callosum.

Miyata S, Koyama Y, Takemoto K, Yoshikawa K, Ishikawa T, Taniguchi M, Inoue K, Aoki M, Hori O, Katayama T, Tohyama M - PLoS ONE (2011)

Repeated exposure to WIRS (chronic stress) upregulates SGK1 and SGK1 is activated by PDK1.(A, B) In situ hybridization images of Sgk1 mRNA. Dark-field photomicrographs show the upregulation of Sgk1 mRNA expression in the fiber tracts after repeated exposure to WIRS (A, controls; B, stress). cc, corpus callosum; ac, anterior commissure. Scale bar = 5 mm. (C, D) In situ hybridization images of Sgk1 mRNA. Upregulation of Sgk1 mRNA (C) after repeated exposure to WIRS was abolished in the brain of adrenalectomized mice (D). cc, corpus callosum; ac, anterior commissure. Scale bar = 2 mm. (E) Real-time PCR analysis shows a significant increase in Sgk1 mRNA levels in the corpus callosum of mice exposed to repeated WIRS. *p<0.05, t-test. (F) Western blot analysis of SGK1 protein in the control and test (repeated exposure to WIRS) mice. (G, H) Western blot analysis shows SGK1 protein, its phosphorylation at positions T-256 (SGK1-256T-P) and S-422 (SGK1-422S-P), and the phosphorylation of PDK1 at position S-241 (PDK-241S-P) in the oligodendrocytes of the corpus callosum after repeated exposure to WIRS. (I, J) Western blot analysis shows that elevated corticosterone levels upregulate the phosphorylation of PDK1 (I) and SGK1 (J) in HEK293 cells with (+) or without (−) DEX treatment (100 µM). Wortmannin (WORT) was used as an inhibitor of the PI3K signaling pathway.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3104997&req=5

pone-0019859-g003: Repeated exposure to WIRS (chronic stress) upregulates SGK1 and SGK1 is activated by PDK1.(A, B) In situ hybridization images of Sgk1 mRNA. Dark-field photomicrographs show the upregulation of Sgk1 mRNA expression in the fiber tracts after repeated exposure to WIRS (A, controls; B, stress). cc, corpus callosum; ac, anterior commissure. Scale bar = 5 mm. (C, D) In situ hybridization images of Sgk1 mRNA. Upregulation of Sgk1 mRNA (C) after repeated exposure to WIRS was abolished in the brain of adrenalectomized mice (D). cc, corpus callosum; ac, anterior commissure. Scale bar = 2 mm. (E) Real-time PCR analysis shows a significant increase in Sgk1 mRNA levels in the corpus callosum of mice exposed to repeated WIRS. *p<0.05, t-test. (F) Western blot analysis of SGK1 protein in the control and test (repeated exposure to WIRS) mice. (G, H) Western blot analysis shows SGK1 protein, its phosphorylation at positions T-256 (SGK1-256T-P) and S-422 (SGK1-422S-P), and the phosphorylation of PDK1 at position S-241 (PDK-241S-P) in the oligodendrocytes of the corpus callosum after repeated exposure to WIRS. (I, J) Western blot analysis shows that elevated corticosterone levels upregulate the phosphorylation of PDK1 (I) and SGK1 (J) in HEK293 cells with (+) or without (−) DEX treatment (100 µM). Wortmannin (WORT) was used as an inhibitor of the PI3K signaling pathway.
Mentions: The Sgk1 mRNA expression was markedly increased in the fiber tracts such as the corpus callosum and the anterior commissure after repeated exposure to WIRS (Figure 3A, B). Sgk1 mRNA was almost exclusively localized in oligodendrocytes (Figure 4A–F). In addition, Sgk1 mRNA upregulation in the fiber tracts after the mice were exposed to repeated WIRS was abolished after adrenolectomy (Figure 3C, D), indicating that elevated levels of corticosterone after exposure to repeated stress increase Sgk1 expression in the oligodendrocytes. Sgk1 mRNA and SGK1 protein upregulation in the fiber tracts such as the corpus callosum was also confirmed by quantitative real-time PCR (Figure 3E) and western blotting analysis (Figure 3F), respectively.

Bottom Line: Further, stress activates the hypothalamic-pituitary-adrenocortical (HPA) system by elevating plasma cortisol levels.However, little is known about the related downstream molecular pathway.Our data strongly suggest that these abnornalities of oligodendrocytes are possibly related to depression-like symptoms.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. smiyata@anat2.med.osaka-u.ac.jp

ABSTRACT
Repeated stressful events are known to be associated with onset of depression. Further, stress activates the hypothalamic-pituitary-adrenocortical (HPA) system by elevating plasma cortisol levels. However, little is known about the related downstream molecular pathway. In this study, by using repeated water-immersion and restraint stress (WIRS) as a stressor for mice, we attempted to elucidate the molecular pathway induced by elevated plasma corticosterone levels. We observed the following effects both, in vivo and in vitro: (1) repeated exposure to WIRS activates the 3-phosphoinositide-dependent protein kinase (PDK1)-serum glucocorticoid regulated kinase (SGK1)-N-myc downstream-regulated gene 1 (NDRG1)-adhesion molecule (i.e., N-cadherin, α-catenin, and β-catenin) stabilization pathway via an increase in plasma corticosterone levels; (2) the activation of this signaling pathway induces morphological changes in oligodendrocytes; and (3) after recovery from chronic stress, the abnormal arborization of oligodendrocytes and depression-like symptoms return to the control levels. Our data strongly suggest that these abnornalities of oligodendrocytes are possibly related to depression-like symptoms.

Show MeSH
Related in: MedlinePlus