Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA.
Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
Brain Behav Immun. 2024 Oct;121:280-290. doi: 10.1016/j.bbi.2024.07.011. Epub 2024 Jul 18.
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.
汇聚的数据表明，子宫内母体免疫激活 (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。最近开发的非人类灵长类动物 MIA 模型为具有与人类神经发育高度转化相关性的研究提供了机会。本纵向研究使用 1H-MRS 研究了母体接受改良形式的炎症病毒类似物聚肌胞苷酸 (Poly IC) 后雄性恒河猴后代前额叶皮层代谢物的发育轨迹，该动物处于第一孕期晚期。这些动物的脑代谢物与接受生理盐水 (n=10) 或未注射 (n=4) 的母鼠的后代进行了比较。在 6、12、24、36 和 45 个月时，从 PRESS 和 MEGA-PRESS 采集物中估计了 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。该队列的先前研究报告称，MIA 后代的额皮质灰质和白质减少，以及认知功能轻微受损。我们假设 MIA 引起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。在所有年龄段，MIA 后代的前额叶 NAA 均显著升高 (p<0.001)，并且与 MIA 动物中最敏感的两种认知测量的更好表现相关 (均 p<0.05)。在所有年龄段，MIA 后代的肌醇均显著降低，但与认知表现无关。牛磺酸在 MIA 后代的 36 和 45 个月时升高。谷胱甘肽在各组之间没有差异。雄性非人类灵长类动物的 MIA 暴露与儿童和青少年时期的前额叶皮层代谢物改变有关。NAA 升高与认知表现呈正相关，这表明 NAA 在整个发育阶段升高反映了 MIA 暴露后代中的一种保护或恢复相关过程的假说。讨论了这些发现对人类神经发育障碍的潜在相关性。
