Porter Grace A, O'Connor Jason C
Department of Pharmacology, UT Health San Antonio, San Antonio, Texas, USA.
Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, Texas, USA.
Neurol Neurobiol (Tallinn). 2021;4(3). doi: 10.31487/j.nnb.2021.03.03. Epub 2021 Sep 25.
Chronic stress is a well-known risk factor in major depressive disorder and disrupts the kynurenine and serotonin pathways of tryptophan metabolism. Here, we characterize the temporal central and peripheral changes in tryptophan metabolism and concomitant depressive-like behavioural phenotype induced during the progression of chronic unpredictable stress (CUS). Mice were exposed to 0, 10, 20, or 30 days of CUS followed by a panel of behavioural assays to determine depressive-like phenotypes. Immediately after behavioural testing, plasma and brain tissue were collected for metabolic analysis. While anhedonia-like and anxiety-like behaviours were unaffected by stress, nesting behaviour and cognitive deficits became apparent in response to CUS exposure. While CUS caused a transient reduction in circulating quinolinic acid, no other tryptophan metabolites significantly changed in response to CUS. In the brain, tryptophan, kynurenine, picolinic acid, and 5-hydroxyindoleacetic acid concentrations were significantly elevated in CUS-exposed mice compared with non-stress control animals, while kynurenic acid, xanthurenic acid, and serotonin decreased in CUS-exposed mice. Metabolic turnover of serotonin to the major metabolite 5- hydroxyindoleacetic acid was markedly increased in response to CUS. These results suggest that CUS impairs hippocampal-dependent working memory and enhances nascent nesting behaviour in C57BL/6J male mice, and these behaviours are associated with increased brain kynurenine pathway metabolism leading to accumulation of picolinic acid and a significant reduction in serotonin levels.
慢性应激是重度抑郁症中一个众所周知的风险因素，它会扰乱色氨酸代谢的犬尿氨酸和血清素途径。在此，我们描述了慢性不可预测应激（CUS）进展过程中色氨酸代谢的中枢和外周随时间的变化以及伴随的抑郁样行为表型。将小鼠暴露于0、10、20或30天的CUS中，随后进行一系列行为测定以确定抑郁样表型。行为测试后立即收集血浆和脑组织进行代谢分析。虽然快感缺失样和焦虑样行为不受应激影响，但筑巢行为和认知缺陷在暴露于CUS后变得明显。虽然CUS导致循环喹啉酸短暂降低，但没有其他色氨酸代谢物因CUS而发生显著变化。在大脑中，与非应激对照动物相比，暴露于CUS的小鼠中色氨酸、犬尿氨酸、吡啶甲酸和5-羟基吲哚乙酸浓度显著升高，而暴露于CUS的小鼠中犬尿酸、黄尿酸和血清素减少。血清素向主要代谢物5-羟基吲哚乙酸的代谢周转率因CUS而显著增加。这些结果表明，CUS损害了C57BL/6J雄性小鼠海马依赖性工作记忆并增强了新生筑巢行为，并且这些行为与大脑犬尿氨酸途径代谢增加有关，导致吡啶甲酸积累和血清素水平显著降低。
