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

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. Overall design: RNA-seq of male mouse frontal cortex subjected to chronic social stress or type 2 diabetes.