GSE204675
The metabolic regulator USF1 is involved in the control of affective behaviour in mice
Epidemiological studies indicate a bidirectional association between metabolic disturbances, including obesity and related pathological states, and mood disorders, most prominently major depression. However, the biological mechanisms mediating the comorbid relationship between the deranged metabolic and mood states remain incompletely understood.   Here we tested the hypothesis that the enhanced activation of brown fat tissue (BAT), known to beneficially regulate obesity and accompanying dysfunctional metabolic states is also paralleled by an alteration of affective behaviour. We used upstream stimulatory factor 1 (USF1) knock-out mice as a genetic model of constitutively activated BAT with a positive cardiometabolic profile and find a reduction of depression- and anxiety-like behaviour associated with USF1 deficiency. Surgical removal of interscapular BAT did not impact the behavioural phenotype of USF1 KO mice which was not accompanied by alterations of neural progenitor cell proliferation, differentiation or survival in the hippocampal dentate gyrus. RNAseq analysis characterized the molecular signature of USF1 deficiency in the hippocampus and revealed a significant increase in the expression of several members of the X-linked lymphocyte-regulated (xlr) genes, including xlr3b and xlr4b, implicated in the regulation of dendritic branching, dendritic spine number and morphology. These molecular changes were accompanied by morphological alterations in hippocampal neurons, manifested reduced dendritic length and complexity.  Collectively these data suggest that the metabolic regulator USF1 is involved in the control of affective behaviour in mice and that this modulation of mood states is unrelated to USF1-dependent BAT activation, but instead associates with structural changes in the brain. Overall design: Comparative gene expression profiling analysis of RNA-seq data in hippocampal tissue of Wild-Type and USF-1 KO mice