Coplan Jeremy D, George Roza, Syed Shariful A, Rozenboym Annalam V, Tang Jean E, Fulton Sasha L, Perera Tarique D
Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY, United States.
Firstox Laboratories, Irving, TX, United States.
Front Hum Neurosci. 2021 Apr 29;15:636144. doi: 10.3389/fnhum.2021.636144. eCollection 2021.
Early life stress (ELS) precedes alterations to neuro-immune activation, which may mediate an increased risk for stress-related psychiatric disorders, potentially through alterations of central kynurenine pathway (KP) metabolites, the latter being relatively unexplored. We hypothesized that ELS in a non-human primate model would lead to a reduction of neuroprotective and increases of neurotoxic KP metabolites. Twelve adult female bonnet macaques reared under conditions of maternal variable foraging demand (VFD) were compared to 27 age- and weight-matched non-VFD-exposed female controls. Baseline behavioral observations of social affiliation were taken over a 12-week period followed by the first cerebrospinal fluid (CSF) sample. Subjects were then either exposed to a 12-week repeated separation paradigm (RSP) or assigned to a "no-RSP" condition followed by a second CSF. We used high-performance liquid chromatography for kynurenine (KYN), tryptophan, 5-hydroxyindoleacetic acid, kynurenic acid (KYNA), and anthranilic acid (ANTH) as a proxy for quinolinic acid determination. At baseline, social affiliation scores were reduced in VFD-reared versus control subjects. CSF log KYNA and log KYNA/KYN ratio were lower in VFD-reared versus control subjects. CSF log KYNA/KYN was positively correlated with CSF log ANTH in VFD only ( = 0.82). Controlling for log KYNA/KYN, log ANTH was elevated in VFD-reared subjects versus controls. CSF log KYNA/KYN obtained post-RSP was positively correlated with mean social affiliation scores during RSP, specifically in VFD. ELS is associated with a reduced neuroprotective and increased neurotoxic pathway products. That the two contrasting processes are paradoxically correlated following ELS suggests a cross-talk between two opposing KP enzymatic systems.
早期生活应激（ELS）先于神经免疫激活的改变，这可能介导应激相关精神障碍风险的增加，可能是通过中枢犬尿氨酸途径（KP）代谢产物的改变，而后者相对未被充分研究。我们假设在非人类灵长类动物模型中，ELS会导致神经保护性犬尿氨酸代谢产物减少以及神经毒性犬尿氨酸代谢产物增加。将12只在母体可变觅食需求（VFD）条件下饲养的成年雌性帽猴与27只年龄和体重匹配的未暴露于VFD的雌性对照猴进行比较。在12周的时间内进行社会依恋的基线行为观察，随后采集第一份脑脊液（CSF）样本。然后，将受试者暴露于为期12周的重复分离范式（RSP），或分配到“无RSP”组，随后采集第二份CSF样本。我们使用高效液相色谱法测定犬尿氨酸（KYN）、色氨酸、5-羟吲哚乙酸、犬尿喹啉酸（KYNA）和邻氨基苯甲酸（ANTH），以替代喹啉酸的测定。在基线时，与对照受试者相比，VFD饲养的受试者的社会依恋得分降低。与对照受试者相比，VFD饲养的受试者的脑脊液log KYNA和log KYNA/KYN比值较低。仅在VFD组中，脑脊液log KYNA/KYN与脑脊液log ANTH呈正相关（r = 0.82）。在控制log KYNA/KYN后，与对照相比，VFD饲养的受试者的log ANTH升高。RSP后获得的脑脊液log KYNA/KYN与RSP期间的平均社会依恋得分呈正相关，特别是在VFD组中。ELS与神经保护性产物减少和神经毒性途径产物增加有关。ELS后这两个相反的过程呈矛盾相关，这表明两个相反的KP酶系统之间存在相互作用。
