Acute and chronic glucocorticoid treatments regulate astrocyte-enriched mRNAs in multiple brain regions in vivo

Bradley S. Carter,David E. Hamilton,Robert C. Thompson

doi:10.3389/fnins.2013.00139

Bradley S. Carter, David E. Hamilton + Show 1 more

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https://doi.org/10.3389/fnins.2013.00139

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Abstract

Previous studies have primarily interpreted gene expression regulation by glucocorticoids in the brain in terms of impact on neurons; however, less is known about the corresponding impact of glucocorticoids on glia and specifically astrocytes in vivo. Recent microarray experiments have identified glucocorticoid-sensitive mRNAs in primary astrocyte cell culture, including a number of mRNAs that have reported astrocyte-enriched expression patterns relative to other brain cell types. Here, we have tested whether elevations of glucocorticoids regulate a subset of these mRNAs in vivo following acute and chronic corticosterone exposure in adult mice. Acute corticosterone exposure was achieved by a single injection of 10 mg/kg corticosterone, and tissue samples were harvested 2 h post-injection. Chronic corticosterone exposure was achieved by administering 10 mg/mL corticosterone via drinking water for 2 weeks. Gene expression was then assessed in two brain regions associated with glucocorticoid action (prefrontal cortex and hippocampus) by qPCR and by in situ hybridization. The majority of measured mRNAs regulated by glucocorticoids in astrocytes in vitro were similarly regulated by acute and/or chronic glucocorticoid exposure in vivo. In addition, the expression levels for mRNAs regulated in at least one corticosterone exposure condition (acute/chronic) demonstrated moderate positive correlation between the two conditions by brain region. In situ hybridization analyses suggest that select mRNAs are regulated by chronic corticosterone exposure specifically in astroctyes based on (1) similar general expression patterns between corticosterone-treated and vehicle-treated animals and (2) similar expression patterns to the pan-astrocyte marker Aldh1l1. Our findings demonstrate that glucocorticoids regulate astrocyte-enriched mRNAs in vivo and suggest that glucocorticoids regulate gene expression in the brain in a cell type-dependent fashion.

Highlights

At the level of the organism, stress occurs via environmental or psychological stimuli that disrupt homeostasis
Previous reports have characterized extensive glucocorticoid-mediated mRNA regulation in CNS tissue using in vitro systems and hippocampal slice models, demonstrating that stress hormones have a broad impact on mRNA expression in the brain
Many cell types in the brain express receptors for glucocorticoids [e.g., neurons (McEwen et al, 1968), astrocytes and oligodendrocytes (Vielkind et al, 1990), microglia (Sierra et al, 2008)] and are presumably responsive to glucocorticoids, most studies of glucocorticoid signaling in the brain have interpreted resulting data in terms of glucocorticoid regulation in neurons

Summary

Introduction

At the level of the organism, stress occurs via environmental or psychological stimuli (stressors) that disrupt homeostasis. Glucocorticoids act in negative feedback mechanisms at multiple levels of the HPA axis (e.g., limbic system, hypothalamus) to regulate stress response activation and return the system to baseline following stress. Chronic disruption of appropriate stress signaling (e.g., altered HPA axis signaling, chronic stress) can have drastic impact on well-being and has been linked to numerous disease states, including Cushing’s disease [HPA hyperactivity (Newell-Price et al, 2006)], Addison’s disease [HPA hypoactivity (Ten et al, 2001)], and multiple psychiatric disorders, including depression and bipolar disorder (McEwen, 2005). Given the importance of the stress response to health and disease, there is great interest in understanding the impact of glucocorticoids on the brain, both in terms of acute exposure (e.g., stress mechanisms) and chronic exposure (e.g., disease states)

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