Table_1_Consolidated Biochemical Profile of Subacute Stage Traumatic Brain Injury in Early Development.DOCX

Traumatic brain injury (TBI) in general has varied neuropathological consequences depending upon the intensity and biomechanics of the injury. Furthermore, in pediatric TBI, intrinsic developmental changes add further complexity, necessitating a biochemical dimension for improved TBI characterization. In our earlier study investigating the subacute stage TBI metabolome (72 h post-injury) in a developmental rat model, significant ipsilateral brain biochemical changes occurred across 25 metabolite sets as determined by metabolite set enrichment analysis (MSEA). The broad metabolic perturbation was accompanied by behavioral deficits and neuronal loss across the ipsilateral hemisphere containing the injury epicenter. In order to obtain a consolidated biochemical profile of the TBI assessment, a subgrouping of the 190 identified brain metabolites was performed. Metabolites were divided into seven major subgroups: oxidative energy/mitochondrial, glycolysis/pentose phosphate pathway, fatty acid, amino acid, neurotransmitters/neuromodulators, one-carbon/folate and other metabolites. Subgroups were based on the chemical nature and association with critically altered biochemical pathways after TBI as obtained from our earlier untargeted analysis. Each metabolite subgroup extracted from the ipsilateral sham and TBI brains were modeled using multivariate partial least square discriminant analysis (PLS-DA) with the model accuracy used as a measurable index of TBI neurochemical impact. Volcano plots of each subgroup, corrected for multiple comparisons, determined the TBI neurochemical specificity. The results provide a ranked biochemical profile along with specificity of changes after developmental TBI, enabling a consolidated biochemical template for future classification of different TBI intensities and injury types in animal models.

创伤性脑损伤（Traumatic brain injury, TBI）的整体神经病理后果因损伤强度和生物力学特性而异。此外，儿童创伤性脑损伤还会因固有的发育性改变进一步增加复杂性，亟需引入生化维度以优化TBI的特征解析。在我们此前针对发育性大鼠模型的亚急性期TBI代谢组（损伤后72小时）开展的研究中，通过代谢物集富集分析（MSEA）证实，损伤同侧脑区的25组代谢物均发生了显著的生化改变。这种广泛的代谢紊乱同时伴随了损伤同侧（含损伤中心）脑区的行为缺陷与神经元丢失。为了获取统一的TBI评估生化特征谱，我们对已鉴定出的190种脑代谢物进行了亚组划分。依据此前非靶向分析得到的TBI后关键生化通路的改变情况及化学性质，将代谢物划分为7大类：氧化能量代谢/线粒体代谢、糖酵解/磷酸戊糖途径、脂肪酸代谢、氨基酸代谢、神经递质/神经调质、一碳代谢/叶酸代谢及其他代谢物。针对从同侧假手术组与TBI组脑样本中提取的每一类代谢物亚组，我们采用多元偏最小二乘判别分析（PLS-DA）进行建模，并以模型准确率作为衡量TBI神经化学影响的量化指标。通过对每一类亚组的火山图进行多重比较校正，明确了TBI相关神经化学变化的特异性。本研究结果提供了发育性TBI后具有特异性的分级生化特征谱，可为未来动物模型中不同TBI强度与损伤类型的分类提供统一的生化参考模板。