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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 causes morphological alterations in oligodendrocytes in the corpus callosum.(A, B): Representative histological coronal sections through the forebrain of control (Cont) and repeated WIRS-exposed mice (stress) with Kluver–Barrera stain. No distinct changes were detected in the corpus callosum (cc) between the 2 groups of mice at either lower (A) or higher (B) magnification. Scale bar = 2 mm in (A) and 1 mm in (B). (C) Results of the quantification of the width of the corpus callosum. Results are expressed as the mean ± SEM of 3 independent experiments. (D, E) Representative transverse electron micrographs of the corpus callosum from control (upper panels of D and E) and repeated WIRS-exposed mice (lower panels of D and E). Scale bars = 5 µm. (E) The higher magnification of the square region of (D). Scale bar = 2 µm. (F) Results of the quantification of the sum of oligodendrocytes in the cross-sectional area. The results are expressed as the mean ± SEM of 3 independent experiments. *p<0.05, t-test. (G, H) The distributions of the axon diameters (G) and myelin thicknesses (H) of the corpus callosum in the control and repeated WIRS-exposed mice were assessed. The results are expressed as the mean ± SEM of 3 independent experiments. *p<0.05, t-test.
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pone-0019859-g007: Repeated exposure to WIRS causes morphological alterations in oligodendrocytes in the corpus callosum.(A, B): Representative histological coronal sections through the forebrain of control (Cont) and repeated WIRS-exposed mice (stress) with Kluver–Barrera stain. No distinct changes were detected in the corpus callosum (cc) between the 2 groups of mice at either lower (A) or higher (B) magnification. Scale bar = 2 mm in (A) and 1 mm in (B). (C) Results of the quantification of the width of the corpus callosum. Results are expressed as the mean ± SEM of 3 independent experiments. (D, E) Representative transverse electron micrographs of the corpus callosum from control (upper panels of D and E) and repeated WIRS-exposed mice (lower panels of D and E). Scale bars = 5 µm. (E) The higher magnification of the square region of (D). Scale bar = 2 µm. (F) Results of the quantification of the sum of oligodendrocytes in the cross-sectional area. The results are expressed as the mean ± SEM of 3 independent experiments. *p<0.05, t-test. (G, H) The distributions of the axon diameters (G) and myelin thicknesses (H) of the corpus callosum in the control and repeated WIRS-exposed mice were assessed. The results are expressed as the mean ± SEM of 3 independent experiments. *p<0.05, t-test.

Mentions: Light microscopic observations using Kluver–Barrera staining revealed no clear alterations in the corpus callosum with respect to thickness; a travelling pattern was clearly identifiable after repeated exposure to WIRS (Figure 7A–C). However, the electron microscopy analysis clearly showed morphological changes in the oligodendrocytes in the corpus callosum after repeated exposure to WIRS (Figure 7D–F). In the control mice, a number of myelinated fibers were compactly gathered in the corpus callosum (Figure 7D, E, Cont). However, the interfibral space, which is occupied almost entirely by the oligodendrocytes, increased markedly in the corpus callosum following repeated exposure to WIRS (Figure 7D, E, Stress). Statistical analysis shows that the interfibral space in WIRS-exposed mice was twice as large as that in the control mice (Figure 7F). In addition, the average diameter of the nerve fibers was smaller in the corpus callosum of WIRS-exposed mice than those of the controls (Figure 7G). However, there was no significant change in the thickness of the myelin in the corpus callosum of the WIRS-exposed mice compared to the controls (Figure 7H). Thus, these findings demonstrate that repeated exposure to WIRS causes excess arborization of oligodendrocyte processes. However, it is not clear whether the PDKI-SGK1-NDRG1-adhesion molecules pathway or another unknown system activated by repeated exposure to WIRS induces the excess arborization of their processes. Therefore, we addressed this question in the following experiments.


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 causes morphological alterations in oligodendrocytes in the corpus callosum.(A, B): Representative histological coronal sections through the forebrain of control (Cont) and repeated WIRS-exposed mice (stress) with Kluver–Barrera stain. No distinct changes were detected in the corpus callosum (cc) between the 2 groups of mice at either lower (A) or higher (B) magnification. Scale bar = 2 mm in (A) and 1 mm in (B). (C) Results of the quantification of the width of the corpus callosum. Results are expressed as the mean ± SEM of 3 independent experiments. (D, E) Representative transverse electron micrographs of the corpus callosum from control (upper panels of D and E) and repeated WIRS-exposed mice (lower panels of D and E). Scale bars = 5 µm. (E) The higher magnification of the square region of (D). Scale bar = 2 µm. (F) Results of the quantification of the sum of oligodendrocytes in the cross-sectional area. The results are expressed as the mean ± SEM of 3 independent experiments. *p<0.05, t-test. (G, H) The distributions of the axon diameters (G) and myelin thicknesses (H) of the corpus callosum in the control and repeated WIRS-exposed mice were assessed. The results are expressed as the mean ± SEM of 3 independent experiments. *p<0.05, t-test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3104997&req=5

pone-0019859-g007: Repeated exposure to WIRS causes morphological alterations in oligodendrocytes in the corpus callosum.(A, B): Representative histological coronal sections through the forebrain of control (Cont) and repeated WIRS-exposed mice (stress) with Kluver–Barrera stain. No distinct changes were detected in the corpus callosum (cc) between the 2 groups of mice at either lower (A) or higher (B) magnification. Scale bar = 2 mm in (A) and 1 mm in (B). (C) Results of the quantification of the width of the corpus callosum. Results are expressed as the mean ± SEM of 3 independent experiments. (D, E) Representative transverse electron micrographs of the corpus callosum from control (upper panels of D and E) and repeated WIRS-exposed mice (lower panels of D and E). Scale bars = 5 µm. (E) The higher magnification of the square region of (D). Scale bar = 2 µm. (F) Results of the quantification of the sum of oligodendrocytes in the cross-sectional area. The results are expressed as the mean ± SEM of 3 independent experiments. *p<0.05, t-test. (G, H) The distributions of the axon diameters (G) and myelin thicknesses (H) of the corpus callosum in the control and repeated WIRS-exposed mice were assessed. The results are expressed as the mean ± SEM of 3 independent experiments. *p<0.05, t-test.
Mentions: Light microscopic observations using Kluver–Barrera staining revealed no clear alterations in the corpus callosum with respect to thickness; a travelling pattern was clearly identifiable after repeated exposure to WIRS (Figure 7A–C). However, the electron microscopy analysis clearly showed morphological changes in the oligodendrocytes in the corpus callosum after repeated exposure to WIRS (Figure 7D–F). In the control mice, a number of myelinated fibers were compactly gathered in the corpus callosum (Figure 7D, E, Cont). However, the interfibral space, which is occupied almost entirely by the oligodendrocytes, increased markedly in the corpus callosum following repeated exposure to WIRS (Figure 7D, E, Stress). Statistical analysis shows that the interfibral space in WIRS-exposed mice was twice as large as that in the control mice (Figure 7F). In addition, the average diameter of the nerve fibers was smaller in the corpus callosum of WIRS-exposed mice than those of the controls (Figure 7G). However, there was no significant change in the thickness of the myelin in the corpus callosum of the WIRS-exposed mice compared to the controls (Figure 7H). Thus, these findings demonstrate that repeated exposure to WIRS causes excess arborization of oligodendrocyte processes. However, it is not clear whether the PDKI-SGK1-NDRG1-adhesion molecules pathway or another unknown system activated by repeated exposure to WIRS induces the excess arborization of their processes. Therefore, we addressed this question in the following experiments.

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