Supplementary Material for: MATERNAL STRESS DURING PREGNANCY IN MICE INDUCES SEX-DEPENDENT BEHAVIORAL ALTERATIONS IN OFFSPRING ALONG WITH IMPAIRED SEROTONIN AND KYNURENINE PATHWAYS OF TRYPTOPHAN METABOLISM

Maternal stress during pregnancy results in increased risk of developing psychiatric disorders in the offspring including anxiety, depression, schizophrenia and autism. However, the mechanisms underlying this disease susceptibility remain largely to be determined. In this study, the involvement of the serotonin (5-HT) and kynurenine (KYN) pathways of tryptophan metabolism on the behavioral deficits induced by maternal stress during the late phase of gestation in mice was investigated. Adult offspring born to control or restraint-stressed dams were exposed to the elevated plus-maze and tail suspension tests. Metabolites of the KYN and 5-HT pathways were measured in the hippocampus and brainstem by ultra‐performance liquid chromatography‐tandem mass spectrometry. Female, but not male, prenatal stressed (PNS) offspring displayed a depressive-like phenotype, mainly when in proestrus/diestrus, along with reduced hippocampal 5-HT levels and high serotonin turnover rate in hippocampus and brainstem. In contrast, male PNS mice showed enhanced anxiety-like behaviors and higher hippocampal and brainstem quinolinic acid levels compared to male offspring born to non-stressed dams. These results indicate that maternal stress affects the behavior and brain metabolism of tryptophan in the offspring in a sex-dependent manner, and suggest that alterations in both the 5-HT and KYN pathways may underlie the emotional dysfunctions observed in individuals exposed to stress during in utero development.

妊娠期母体应激可增加后代罹患焦虑症、抑郁症、精神分裂症及孤独症等精神疾病的风险。然而，该类疾病易感性的潜在机制仍未完全阐明。本研究针对小鼠妊娠晚期母体应激诱导的行为缺陷，探究了色氨酸代谢的血清素（Serotonin，5-HT）通路与犬尿氨酸（Kynurenine，KYN）通路的参与作用。研究人员对对照组及束缚应激母鼠所产的成年后代小鼠实施了高架十字迷宫（Elevated Plus-Maze）与悬尾实验（Tail Suspension Test），并采用超高效液相色谱-串联质谱法（Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry）检测了海马体与脑干中KYN通路及5-HT通路的代谢物水平。结果显示，仅雌性产前应激（Prenatal Stressed，PNS）后代小鼠呈现抑郁样表型，该现象主要出现于动情前期/动情间期阶段，同时伴随海马体5-HT水平降低，以及海马体与脑干内5-HT更新速率升高。与之相反，雄性PNS小鼠相较于非应激母鼠所产的雄性后代，表现出更显著的焦虑样行为，且海马体与脑干内喹啉酸（Quinolinic Acid）水平更高。上述结果表明，母体应激会以性别依赖的方式影响后代的行为与脑内色氨酸代谢，提示5-HT与KYN通路的异常可能是宫内应激暴露个体出现情感功能障碍的潜在机制。