Transcriptional profiles underlying vulnerability and resilience in rats exposed to an acute unavoidable stress

Abstract

A complex interplay between gene and environment influences the vulnerability or the resilience to stressful events. In the acute escape deficit (AED) paradigm, rats exposed to an acute unavoidable stress (AUS) develop impaired reactivity to noxious stimuli. Here we assessed the behavioral and molecular changes in rats exposed to AUS. A genome-wide microarray experiment generated a comprehensive picture of changes in gene expression in the hippocampus and the frontal cortex of animals exposed or not to AUS. Exposure to AUS resulted in two distinct groups of rats with opposite behavioral profiles: one developing an AED, called "stress vulnerable," and one that did not develop an AED, called "stress resilient." Genome-wide profiling revealed a low percentage of overlapping mechanisms in the two areas, suggesting that, in the presence of stress, resilience or vulnerability to AUS is sustained by specific changes in gene expression that can either buffer or promote the behavioral and molecular adverse consequences of stress. Specifically, we observed in the frontal cortex a downregulation of the transcript coding for interferon-β and leukemia inhibitory factor in resilient rats and an upregulation of neuroendocrine related genes, growth hormone and prolactin, in vulnerable rats. In the hippocampus, the muscarinic M2 receptor was downregulated in vulnerable but upregulated in resilient rats. Our findings demonstrate that opposite behavioral responses did not correspond to opposite regulatory changes of the same genes, but resilience rather than vulnerability to stress was associated with specific changes, with little overlap, in the expression of patterns of genes.

Behavioural and transcriptional effects of escitalopram in the chronic escape deficit model of depression

“…By exposing rats to an unavoidable stress, a group of animals develop an escape deficit when presented with an avoidable noxious stimulus, this deficit can be maintained over time by exposing animals to repeated administration of mild stressors [8,27,37]. The core symptoms of depression mimicked in this model, the hyporeactivity to aversive stimuli and the anhedonic state [8,26], are coupled with homeostatic modifications, like alteration in central monoamine levels or increased activity of the HPA axis [11].…”

“…For the analysis of differentially expressed transcripts the following filtering criteria were adopted: probe sets with p ≤ 0.01, fold change > 1.3 (30% increase or decrease) and DABG p ≤ 0.05 in at least 3 on 5 replicate for each comparison. This moderate stringency approach was previously applied by us and others when characterizing brain function in microarray studies [24,27,[33][34][35].…”

“…These Arrays developed by Affymetrix are the first available experimental tools to survey expression of gene transcripts on the whole-genome scale within a single array, using specific probes targeting each individual exon belonging to rat genome [27]. Combining the genome-wide Exon Array technology with a custom "transcript-based" approach for genomic annotations, we measured the expression of 31,601 transcripts.…”

“…1); hippocampi were dissected as previously described [27], immediately frozen on dry ice and stored at −80 • C until microarray analyses.…”

“…1). Quantity of total RNA was determined as previously described [27]. A cut-off of 8 of RNA band intensities (RIN) value was applied in order to ensure the high quality of the samples.…”