Abstract：
Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.
摘要：
汇总数据显示，子宫内暴露于母体免疫激活（MIA）会改变动物的大脑发育，并增加人类神经发育障碍的风险。最近开发的非人灵长类MIA模型提供了与人类神经发育具有独特强烈翻译相关性的研究机会。当前的纵向研究使用1H-MRS来研究暴露于改良形式的炎性病毒模拟物的雄性恒河猴后代（n=14）的前额叶皮质代谢物的发育轨迹，聚肌苷酸：聚胞苷酸（聚IC），在头三个月晚期。将这些动物的脑代谢产物与接受盐水（n=10）或未注射（n=4）的大坝的后代进行比较。N-乙酰天冬氨酸(NAA),谷氨酸,肌酸,胆碱，肌醇,牛磺酸,和谷胱甘肽是根据PRESS和MEGA-PRESS在6、12、24、36和45个月大时获得的。该队列的先前研究报告了MIA后代的额叶皮质灰质和白质减少以及细微的认知障碍。我们假设MIA诱导的神经发育变化将扩展到异常的脑代谢物水平，这将与观察到的认知障碍有关。在所有年龄的MIA后代中，前额叶NAA均显着较高（p<0.001），并且在MIA动物中对损害最敏感的两种认知指标上表现更好（p<0.05）。在MIA后代中，所有年龄段的肌醇均显着降低，但与认知能力无关。MIA后代在36和45个月时牛磺酸升高。谷胱甘肽在组间没有差异。男性非人类灵长类动物中的MIA暴露与童年和青春期前额叶皮质代谢物的改变有关。NAA升高与认知表现之间的正相关关系表明，在这些发育阶段NAA升高反映了MIA暴露后代的保护性或韧性相关过程。讨论了这些发现与人类神经发育障碍的潜在相关性。
