The metabolic regulator USF1 is involved in the control of affective behaviour in mice. 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

流行病学研究表明，包括肥胖及相关病理状态在内的代谢紊乱与情绪障碍（尤以重度抑郁症最为突出）之间存在双向关联。然而，介导紊乱代谢状态与情绪状态共病关系的生物学机制仍未完全阐明。本研究检验了如下假说：已知可有益调控肥胖及伴随代谢功能紊乱的棕色脂肪组织（brown adipose tissue, BAT）的活化增强，同时也会伴随情感行为的改变。我们采用上游刺激因子1（upstream stimulatory factor 1, USF1）敲除小鼠作为组成性活化BAT且具备良性心脏代谢表型的遗传模型，结果发现USF1缺失可降低小鼠的抑郁样与焦虑样行为。手术摘除肩胛间BAT并不会影响USF1敲除小鼠的行为表型，且该操作未伴随海马齿状回内神经祖细胞的增殖、分化或存活出现改变。RNA测序（RNAseq）分析刻画了海马组织中USF1缺失的分子特征，发现X连锁淋巴细胞调控基因（X-linked lymphocyte-regulated, Xlr）家族的多个成员（包括xlr3b与xlr4b）的表达显著上调，这些基因已被证实参与树突分支、树突棘数量与形态的调控。这些分子变化伴随海马神经元的形态学改变，具体表现为树突长度缩短与复杂度降低。综上，本研究数据表明代谢调节因子USF1参与调控小鼠的情感行为，且这种情绪状态的调节与USF1依赖的BAT活化无关，而是与大脑的结构变化相关。整体实验设计：对野生型与USF1敲除小鼠的海马组织RNA测序数据开展比较基因表达谱分析。