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Determination of steady-state transcriptome modifications associated with repeated homotypic stress in the rat rostral posterior hypothalamic region

ABSTRACT: Chronic stress is epidemiologically correlated with physical and psychiatric disorders. Whereas many animal models of chronic stress induce symptoms of psychopathology, repeated homotypic stress typically fails to induce these symptoms and may even protect against the effects of subsequent stress exposures. Recent results indicate that the rostral posterior hypothalamic (rPH) region is a significant component of the brain circuitry underlying response reductions (habituation) associated with repeated homotypic stress. To test whether posterior hypothalamic transcriptional regulation associates with the behavioral modifications induced by repeated homotypic stress, RNA-seq was performed in the rPH dissected from adult male rats that experienced either no stress, 1, 3, or 7 stressful loud noise exposures. Plasma samples displayed reliable increases of corticosterone in all stressed groups, with the smallest increase in the group exposed to 7 loud noises, indicating significant habituation compared to the other stressed groups. While no differentially expressed genes were detected 24-hrs after a single loud noise exposure, 36 and 405 transcripts were differentially expressed between the control vs 3-stress and control vs 7-stress groups, respectively, which correlated with the corticosterone habituation observed. Gene ontology analyses indicated multiple significant functional terms related to neuron differentiation, neural membrane potential, pre- and post-synaptic elements, chemical synaptic transmission, vesicles, axon guidance and projection, glutamatergic and GABAergic neurotransmission. Some of the differentially expressed genes (Zmat4, Dlx6) encoded transcription factors that were independently predicted by transcription factor enrichment analysis to target other differentially regulated genes in the set. A similar experiment employing in situ hybridization histochemical analysis in additional animals validated the direction of change of the 5 transcripts investigated (Camk4, Gabrb2, Gad1, Grin2a and Slc32a) with a high level of temporal and regional specificity for the rPH. In aggregate, the results suggest that distinct patterns of gene regulation are obtained in response to repeated homotypic vs. heterotypic stress regimens; they also point to a significant reorganization of the rPH region that may critically contribute to the phenotypic modifications associated with repeated homotypic stress habituation.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE229159 | GEO | 2023/06/20

REPOSITORIES: GEO

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Project description:Chronic stress is a key risk factor for a variety of diseases, but the determinants of individual stress susceptibility are still unclear. Using a recently developed paradigm for chronic social stress in mice we identified animals that were resistant or susceptible to the persistent effects of chronic stress exposure. Gene expression analysis in laser-microdissected hippocampal subfields of both groups revealed differentially regulated AMPA receptor subunits, which might affect the susceptibility of an individual to chronic social stress. To test this hypothesis, animals were treated with the AMPA receptor potentiator LY451646 or vehicle during the last 4 weeks of chronic stress exposure. Enhanced AMPA receptor function in chronically stressed animals ameliorated the lasting effects of the chronic stress exposure on physiological, neuroendocrine and behavioural parameters. Our data suggest that differences in AMPA receptor function may underlie individual stress susceptibility and support AMPA receptor potentiators as potential medication in stress-related diseases. Keywords: phenotype, chronic stress, AMPA We have subjected 120 individuals to the chronic social stress procedure, which was recently shown to result in robust effects on neuroendocrine and behavioural parameters (Sterlemann V, 2008). Following the stress procedure all animals were single housed for 7 days. Corticosterone secretion was significantly increased in the chronic stress group compared to controls after one week of single housing. Within the chronic stress group we observed a large variation, where some individuals had recovered from the stress procedure, while others still showed a largely increased corticosterone secretion. After 4 more weeks of single housing, the difference in basal corticosterone secretion between the animals susceptible to chronic stress and unsusceptible or control subjects was still evident. From the group extremes in the chronically stressed animals we selected the 6 most-affected and the 6 most resistant individuals. To investigate the mechanisms underlying the observed differences in individual stress susceptibility between these mice we laser dissected the CA1 and the dentate gyrus region of the hippocampus in the selected mice and performed a gene expression profiling analysis. Pooled amplified RNA samples were then hybridised on Illumina mouse BeadChips (N=4 per group) and detected in the Illumina BeadArray Reader (Illumina, Inc., San Diego, CA).

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Determination of steady-state transcriptome modifications associated with repeated homotypic stress in the rat rostral posterior hypothalamic region

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