Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites.
Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites.
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雄性小鼠的炎症后行为绝望与皮质谷氨酸-谷氨酰胺比率以及循环脂质和能量代谢物的降低有关。
DOI：
10.1038/s41598-020-74008-w
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发表时间：
2020-10-08
影响因子：
4.6
通讯作者：
Burnet PWJ
中科院分区：
文献类型：
--
作者：
Chan SY;Probert F;Radford-Smith DE;Hebert JC;Claridge TDW;Anthony DC;Burnet PWJ
啮齿类动物的炎症后行为被广泛用于模拟人类抑郁症并测试新型抗抑郁药的功效。注射脂多糖（LPS）的小鼠在施用内毒素二十四小时后表现出抑郁样表型。尽管该模型得到广泛使用，但短暂性外周炎症反应后持续行为变化的机制仍然难以捉摸。代谢组的研究（样本中所有小分子代谢物的集合）与多元统计技术相结合，提供了一种研究受 LPS 挑战影响的生化途径的方法。成年雄性 CD-1 小鼠接受腹腔注射 LPS (0.83 mg/kg) 或盐水，并在 24 小时后评估抑郁样行为。在一个单独的小鼠队列中，对脑组织和血液中的促炎细胞因子基因表达和 1H 核磁共振 (NMR) 代谢组学测量进行了测量。统计分析包括基因表达数据的独立样本 t 检验，以及使用正交偏最小二乘判别分析进行代谢组学的监督多变量分析。雄性小鼠的血浆和脑代谢在一次外周脂多糖刺激后发生改变，导致强迫游泳测试中出现抑郁样行为。 LPS改变的血浆代谢物参与能量代谢，包括脂蛋白、葡萄糖、肌酸和异亮氨酸。在大脑中，LPS 后谷氨酸、丝氨酸和 N-乙酰天冬氨酸 (NAA) 减少，而谷氨酰胺增加。丝氨酸调节的谷氨酸信号和生物能量学的变化可能介导 LPS 诱导的行为表型。鉴于其他数据支持抑郁症中谷氨酸-谷氨酰胺循环的中枢失衡，我们的结果表明，异常的中枢谷氨酰胺能信号传导可能是炎症和非免疫病理生理学导致的抑郁样行为的基础。使谷氨酰胺能信号转导正常化，而不是寻求增加血清素能信号转导，可能被证明是开发情绪障碍新疗法的更连贯的方法。
Post-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Despite the widespread use of this model, the mechanisms that underlie the persistent behavioural changes after the transient peripheral inflammatory response remain elusive. The study of the metabolome, the collection of all the small molecule metabolites in a sample, combined with multivariate statistical techniques provides a way of studying biochemical pathways influenced by an LPS challenge. Adult male CD-1 mice received an intraperitoneal injection of either LPS (0.83 mg/kg) or saline, and were assessed for depressive-like behaviour 24 h later. In a separate mouse cohort, pro-inflammatory cytokine gene expression and 1H nuclear magnetic resonance (NMR) metabolomics measurements were made in brain tissue and blood. Statistical analyses included Independent Sample t-tests for gene expression data, and supervised multi-variate analysis using orthogonal partial least squares discriminant analysis for metabolomics. Both plasma and brain metabolites in male mice were altered following a single peripheral LPS challenge that led to depressive-like behaviour in the forced swim test. The plasma metabolites altered by LPS are involved in energy metabolism, including lipoproteins, glucose, creatine, and isoleucine. In the brain, glutamate, serine, and N-acetylaspartate (NAA) were reduced after LPS, whereas glutamine was increased. Serine-modulated glutamatergic signalling and changes in bioenergetics may mediate the behavioural phenotype induced by LPS. In light of other data supporting a central imbalance of glutamate-glutamine cycling in depression, our results suggest that aberrant central glutaminergic signalling may underpin the depressive-like behaviours that result from both inflammation and non-immune pathophysiology. Normalising glutaminergic signalling, rather than seeking to increase serotonergic signalling, might prove to be a more coherent approach to the development of new treatments for mood disorder.
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DOI：
10.1523/jneurosci.5818-10.2011
发表时间：
2011-03-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cortese GP;Barrientos RM;Maier SF;Patterson SL
通讯作者：
Patterson SL
影响因子：
4.8
作者：
Chan SY;Matthews E;Burnet PW
通讯作者：
Burnet PW
影响因子：
3.3
作者：
Felger JC;Lotrich FE
通讯作者：
Lotrich FE
影响因子：
2.7
作者：
Francija, Ester;Petrovic, Zorica;Adzic, Miroslav
通讯作者：
Adzic, Miroslav
影响因子：
8.2
作者：
Choleris, E;Thomas, AW;Prato, FS
通讯作者：
Prato, FS