Chronic Psychosocial Stress and Negative Feedback Inhibition: Enhanced Hippocampal Glucocorticoid Signaling despite Lower Cytoplasmic GR Expression.

Andrea M Füchsl,Stefan O Reber,Judith Homberg

doi:10.1371/journal.pone.0153164

Andrea M Füchsl, Stefan O Reber + Show 1 more

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https://doi.org/10.1371/journal.pone.0153164

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Journal: PloS one	Publication Date: Apr 8, 2016
Citations: 12	License type: CC BY 4.0

Affiliation: University of Regensburg

Abstract

Chronic subordinate colony housing (CSC), a pre-clinically validated mouse model for chronic psychosocial stress, results in increased basal and acute stress-induced plasma adrenocorticotropic hormone (ACTH) levels. We assessed CSC effects on hippocampal glucocorticoid (GC) receptor (GR), mineralocorticoid receptor (MR), and FK506 binding protein (FKBP51) expression, acute heterotypic stressor-induced GR translocation, as well as GC effects on gene expression and cell viability in isolated hippocampal cells. CSC mice showed decreased GR mRNA and cytoplasmic protein levels compared with single-housed control (SHC) mice. Basal and acute stress-induced nuclear GR protein expression were comparable between CSC and SHC mice, as were MR and FKBP51 mRNA and/or cytoplasmic protein levels. In vitro the effect of corticosterone (CORT) on hippocampal cell viability and gene transcription was more pronounced in CSC versus SHC mice. In summary, CSC mice show an, if at all, increased hippocampal GC signaling capacity despite lower cytoplasmic GR protein expression, making negative feedback deficits in the hippocampus unlikely to contribute to the increased ACTH drive following CSC.

Highlights

The homeostasis of an individual is constantly challenged by acute internal or external disturbances, called stressors
Statistical analysis revealed an increase in absolute adrenal weight (P < 0.001; Fig 1A) in Chronic subordinate colony housing (CSC) compared with single-housed control (SHC) mice
Statistical analysis revealed an increase in plasma adrenocorticotropic hormone (ACTH) concentrations (P = 0.028; Fig 1C) but not in plasma CORT concentrations (Fig 1B) in CSC compared with SHC mice

Summary

Introduction

The homeostasis of an individual is constantly challenged by acute internal or external disturbances, called stressors. Chronic or repeated stressor exposure, at least in part via altering the negative feedback system, often leads to a dysregulation of normal HPA axis functionality and a prolonged activation of the stress axis in response to acute and non-harmful challenges Alterations in the negative feedback response, due for instance to changes in glucocorticoid (GC) signaling, are discussed to promote the development of stress-related psychiatric disorders, like major depression, posttraumatic stress disorder and anxiety disorders (for review see [1, 4, 5]). The GR, in contrast, has a ten-fold lower affinity and, is only occupied under conditions of high GC levels, i.e. at the circadian peak and during stressor exposure (for review see [6]), [7]. While the GR is widely distributed throughout the brain, the MR is mainly localized in limbic brain structures, like the hippocampus, lateral septum, amygdala, hypothalamus, and medial prefrontal cortex (PFC) [6, 8]

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