Previous History of Chronic Stress Changes the Transcriptional Response to Glucocorticoid Challenge in the Dentate Gyrus Region of the Male Rat Hippocampus

Abstract

Chronic stress is a risk factor for several neuropsychiatric diseases, such as depression and psychosis. In response to stress glucocorticoids (GCs) are secreted that bind to mineralocorticoid and glucocorticoid receptors, ligand-activated transcription factors that regulate the transcription of gene networks in the brain necessary for coping with stress, recovery, and adaptation. Chronic stress particularly affects the dentate gyrus (DG) subregion of the hippocampus, causing several functional and morphological changes with consequences for learning and memory, which are likely adaptive but at the same time make DG neurons more vulnerable to subsequent challenges. The aim of this study was to investigate the transcriptional response of DG neurons to a GC challenge in male rats previously exposed to chronic restraint stress (CRS). An intriguing finding of the current study was that having a history of CRS had profound consequences for the subsequent response to acute GC challenge, differentially affecting the expression of several hundreds of genes in the DG compared with challenged nonstressed control animals. This enduring effect of previous stress exposure suggests that epigenetic processes may be involved. In line with this, CRS indeed affected the expression of several genes involved in chromatin structure and epigenetic processes, including Asf1, Ash1l, Hist1h3f, and Tp63. The data presented here indicate that CRS alters the transcriptional response to a subsequent GC injection. We propose that this altered transcriptional potential forms part of the molecular mechanism underlying the enhanced vulnerability for stress-related disorders like depression caused by chronic stress.

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

“…Chronic Stress Effects. In the nuclear genome, acute stress and GC treatment regulate a larger number of genes than chronic stress (24)(25)(26), and this pattern holds true for our observations of mitochondrial gene expression as well. Acute stress caused a significant main effect on mitochondrial gene expression and a significant down-regulation of 4 of 13 mitochondrial genes examined, although all but one gene showed reduced expression.…”

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

“…Finally, characterization of expression profiles after an extended recovery from chronic stress (21 days) revealed that, despite a normalization of anxiety-related behaviors, recovery did not represent a return to the stress-naïve baseline, but rather represented a new state in which reactivity to a novel stressor produced a unique expression profile . Studies in rats have also confirmed that gene expression profiles can vary significantly from the immediate end of stress (1 h) to 24 h after the end of stress (Wang et al, 2010), and that chronic stress can alter the transcriptional response to an acute corticosterone injection in dentate gyrus (Datson et al, 2013). These studies demonstrate that a history of stress exposure can have a lasting impact on future stress reactivity and hippocampal function.…”

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

“…2A and Dataset S2). The set of GC-responsive genes we considered originates from experiments where male rats were exposed to GC treatment in a chronic restraint stress (CRS) condition as well as in a control situation (17). These experiments resulted in three sets of genes differentially expressed in DG neurons: (i) GC-responsive genes in CRS rats, (ii) GC-responsive genes in control rats, and (iii) genes that show differential expression in GC treatment for both conditions (common GC-responsive genes).…”

“…We initially considered these negative control regions, given that the target genes were identified in microdissected DG granule neurons (17) and the presumed high degree of cell specificity. However, the coexpression of Gr with GC-responsive genes in CA3 prompted us to test whether this coexpression also occurs in other brain areas.…”