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Transcriptional profiling reveals high sensitivity to social vs. metabolic stress in frontal cortex of male mice

ABSTRACT: Chronic psychosocial and metabolic stressors disrupt affective state and drive frequently co-morbid mood and cardio-metabolic disorders. However, central mechanisms underlying dysregulation of mood and metabolic homeostasis await definition. Behavioural and transcriptome-wide influences of chronic social and metabolic stresses were explored (testing for shared and unique mechanistic themes in male C57Bl/6 mice subjected to: chronic social stress (CSS) - social isolation for 7 wks + twice daily social confrontation in final 20 days; type 2 diabetes (T2D) - 75 mg.kg-1 streptozotocin/21 wk high-fat diet (43.2% kcal as fat); or control conditions. Frontal cortex (FC) was profiled via RNAseq (Illumina NovaSeq 6000 Sequencing System, 2x107 paired-end reads/sample). CSS induced anxiety-like behaviour together with anhedonia (reduced sucrose preference), in association with relative weight loss. T2D mice exhibited anxiety-like behaviour (reduced locomotion and thigmotaxis in open field) in association with modest (+20-30%) weight gain and hyperglycaemia, and 65-80% elevations in fasting insulin and insulin-resistance (HOMA-IR). The FC transcriptome was particularly sensitive to CSS, with 640 (316 down/324 up) differentially expressed genes (DEGs) from 15,097 detected (FDR<0.05, P<0.001). Gene-set enrichment analysis (GSEA) identified 222 Biological Processes and 25 Reactome Pathways sensitive to CSS. Most significant themes centred upon up-regulation of: growth/remodelling (axonogenesis, epithelial growth/morphogenesis, angiogenesis, cell junction, synapse and ECM organisation, brain/limb/heart/gland/eye development), Ras signalling and growth factor response genes; and down-regulation of: ATP metabolism, mitochondrial and RNA processing pathways. In contrast, the FC transcriptome was relatively insensitive to metabolic stress, however 107 DEGs (71 down/36 up) and 187 Biological Processes/5 Reactome Pathways were identified using less conservative criteria (FDR<0.10, un-corrected P<0.01). Despite little to no overlap in individual genes, GSEA indicates ~25% of pathway responses are shared, including organ development/morphogenesis (though not ATP metabolism/mitochondrial) processes. In summary, FC appears particularly responsive to social rather than metabolic stress, characterised by repression of mitochondrial metabolism together with adaptive induction of nerve growth/development. Shared anxiogenesis may involve disturbed neurogenesis/neuroplasticity, with depressive outcomes reflecting additional mitochondrial dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE233225 | GEO | 2023/05/31

REPOSITORIES: GEO

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Project description:Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the “internalizing” bred Low Responder (bLR) line versus the “externalizing” bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions and psychosocial stress, and how these determinants of stress response interact. Animals were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interaction and anxiety-like behavior. Adolescent enrichment caused bLR rats to display less social avoidance, more social interaction, less submission during defeat, and resilience to the prolonged effects of social stress on corticosterone, while enrichment caused bHR animals to show greater aggression during defeat and during a neutral social encounter, and decreased anxiety-like behavior. To gain insight into the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. These findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.

Project description:A group of postnatal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased MeCP2 dosage causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however, the gene expression changes observed in the hypothalamus and cerebellum of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression. In this study, we compared gene expression changes in the amygdalae of mice lacking MeCP2 (Mecp2-null) and mice overexpressing MeCP2 (MECP2-TG). We chose the amygdala because it is a neuroanatomical region implicated in the control of anxiety and social behavior, two prominent phenotypes in MECP2-TG mice, and hypothesized that transcriptional profiling of this particular brain region may reveal expression changes relevant to heightened anxiety-like behavior and abnormal social behavior. A total of 1,060 genes were altered in opposite directions in both MeCP2 mouse models compared with wild-type littermates, with ~60% up-regulated and ~40% down-regulated. Interestingly, we found a significant enrichment of anxiety- and/or social behavior-related genes among the differentially expressed genes. To determine whether these genes contribute to the anxiety and social behavior phenotypes in MECP2-TG mice, we performed genetic and pharmacologic studies and found that a reduction in Crh suppresses anxiety-like behavior, and a reduction in Oprm1 improves social approach behavior. These studies suggest that MeCP2 impacts molecular pathways involved in anxiety and social behavior, and provide insight into potential therapies for MeCP2 disorders. This study is published in Nature Genetics http://dx.doi.org/10.1038/ng.1066. Total amygdala RNA samples were collected from Mecp2-null male mice (n=4), MECP2-transgenic male mice (n=5), and their wild type male littermates at 6 weeks of age (n=4, n=5 for each group respectively).

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Transcriptional profiling reveals high sensitivity to social vs. metabolic stress in frontal cortex of male mice

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