Effects of Long-Term Endogenous Corticosteroid Exposure on Brain Volume and Glial Cells in the AdKO Mouse.

Jorge Miguel Amaya,Typhanie Dumontet,Louise Van Der Weerd,Guilhem Pagès,Antoine Martinez,Isabelle Sahut-Barnola,Nathanaëlle Montanier,Onno C Meijer,Ernst Suidgeest,Cécile Keller,Alberto M Pereira

doi:10.3389/fnins.2021.604103

Abstract

Chronic exposure to high circulating levels of glucocorticoids has detrimental effects on health, including metabolic abnormalities, as exemplified in Cushing’s syndrome (CS). Magnetic resonance imaging (MRI) studies have found volumetric changes in gray and white matter of the brain in CS patients during the course of active disease, but also in remission. In order to explore this further, we performed MRI-based brain volumetric analyses in the AdKO mouse model for CS, which presents its key traits. AdKO mice had reduced relative volumes in several brain regions, including the corpus callosum and cortical areas. The medial amygdala, bed nucleus of the stria terminalis, and hypothalamus were increased in relative volume. Furthermore, we found a lower immunoreactivity of myelin basic protein (MBP, an oligodendrocyte marker) in several brain regions but a paradoxically increased MBP signal in the male cingulate cortex. We also observed a decrease in the expression of glial fibrillary acidic protein (GFAP, a marker for reactive astrocytes) and ionized calcium-binding adapter molecule 1 (IBA1, a marker for activated microglia) in the cingulate regions of the anterior corpus callosum and the hippocampus. We conclude that long-term hypercorticosteronemia induced brain region-specific changes that might include aberrant myelination and a degree of white matter damage, as both repair (GFAP) and immune (IBA1) responses are decreased. These findings suggest a cause for the changes observed in the brains of human patients and serve as a background for further exploration of their subcellular and molecular mechanisms.

Highlights

Glucocorticoid hormones (GCs) are mediators of the response to stress, a state following real or perceived threat to homeostasis (Smith and Vale, 2006)
We observed volumetric differences that were widespread over the brain, including both gray and white matter areas (Figure 1A), with prominent differences, in the corpus callosum and large parts of the cortex
We found a significantly reduced brain size in males, with a trend toward significance in females (Figure 1B)

Summary

Introduction

Glucocorticoid hormones (GCs) are mediators of the response to stress, a state following real or perceived threat to homeostasis (Smith and Vale, 2006). GCs act throughout the body via the widely expressed glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) (Pujols et al, 2002). A major aspect of GR-mediated effects concerns its metabolic effects on carbohydrate, lipid, and protein metabolism (from their action on liver, adipose tissue, and muscle), which in the long term predispose for obesity and metabolic syndrome. Chronic exposure to high levels of GCs increases visceral adipose tissue (Debono et al, 2013) and upregulates the expression of lipogenic pathway genes (Hochberg et al, 2015). Central obesity and dyslipidemia are very common signs in Cushing’s syndrome (CS) patients, a disorder caused by prolonged exposure to excess GCs (Angeli et al, 1997; Garrapa et al, 2001; Sharma et al, 2015). By screening populations of patients with simple obesity, prevalence rates of CS might be as high as 9% (Tiryakioglu et al, 2010)

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Conclusion