Plasma Corticosterone Activates SGK1 and Induces Morphological Changes in Oligodendrocytes in Corpus Callosum

Shingo Miyata,Taiichi Katayama,Masaya Tohyama,Miwa Aoki,Manabu Taniguchi,Osamu Hori,Kiyoshi Inoue,Yoshihisa Koyama,Keiko Yoshikawa,Kana Takemoto,Toshiko Ishikawa,Takeo Yoshikawa

doi:10.1371/journal.pone.0019859

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.

Highlights

Major depression is thought to be a multifactorial disease related to both environmental and genetic factors
In situ hybridization histochemistry for Sgk1 mRNA in the brains of normal adult mice shows that two types of cells express Sgk1 mRNA: those preferentially localized in the fiber tracts such as the corpus callosum and anterior commissure and the neurons that are localized in the CA3 region of the hippocampal formation (Figure 1A)
Since it is well known that stress activates the hypothalamic–pituitary– adrenocortical (HPA) axis, we compared the alteration in the plasma corticosterone levels with the time-course expression of Sgk1 mRNA after exposure to acute stress

Summary

Introduction

Major depression is thought to be a multifactorial disease related to both environmental and genetic factors. Among many environmental factors, repeated stressful events are associated with the onset of depression, and stress activates the hypothalamic–pituitary– adrenocortical (HPA) system [1,2,3,4,5]. The HPA system is initiated by the activation of the paraventricular nucleus of the hypothalamus, leading to the secretion of corticotropin-releasing hormone from the neuron terminals of the paraventricular nucleus. Corticotropin-releasing hormone triggers the release of adrenocorticotropic hormone from the anterior pituitary. It is reported that the negative feedback of corticosteroids on the HPA system occurs at the level of the hypothalamus and the anterior pituitary via the glucocorticoid receptors [6]

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Conclusion