Research Service, Washington DC VA Medical Center, Washington, DC, United States.
Department of Neuroscience, Georgetown University School of Medicine, Washington, DC, United States.
Front Endocrinol (Lausanne). 2020 Sep 18;11:556380. doi: 10.3389/fendo.2020.556380. eCollection 2020.
Glucose is an essential cellular fuel for maintaining normal brain functions. Traumatic brain injury (TBI) decreases brain glucose utilization in both human and experimental animals during the acute or subacute phase of TBI. It remains unclear as to how the damages affect brain glucose utilization and its association with persistent neurobehavioral impairments in the chronic phase of mild TBI (mTBI). Accordingly, we compared expression of selected genes important to brain glucose utilization in different brain regions of mice during the chronic phase in mTBI vs. sham operated mice. These genes included hexokinase-1 (HK1), phosphofructokinase (PFK), pyruvate kinase (PK), pyruvate dehydrogenase (PDH), capillary glucose transporter (Glut-1), neuron glucose transporter (Glut-3), astrocyte lactate transpor1 (MCT-1), neuron lactate transporter (MCT-2), lactate receptor (GPR81), and Hexokinase isoform-2 (HK2). Young adult male C57BL/6J mice were brain injured with repetitive closed-head concussions. Morris water maze (MWM), elevated plus maze (EPM), and neurological severity score test (NSS) were performed for evaluation of mice neurobehavioral impairments at 2, 4, and 6 months post mTBI. Two days after completion of the last behavioral test, the frontal cortex, hippocampus, brainstem, hypothalamus, and cerebellum were collected for gene expression measurements. The expression of the mRNAs encoding PK, and PDH, two critical enzymes in glucose metabolism, was decreased at all-time points only in the hippocampus, but was unchanged in the brainstem, hypothalamus, and cortex in mTBI mice. mTBI mice also exhibited the following behavioral alterations: (1) decreased spatial learning and memory 2, 4, and 6 months after the injury, (2) increased proportion of time spent on open vs. closed arms determined by EPM, and (3) accelerated reduction in motor activity observed at 4 months, two months earlier than observed in the sham group, during the EPM testing. There were no significant differences in NSS between injury and sham groups at any of the three time points. Thus, mTBI in male mice led to persistent decreased hippocampal expression of mRNAs that encode critical glucose utilization related enzymes in association with long-term impairments in selected neurobehavioral outcomes.
葡萄糖是维持正常大脑功能的重要细胞燃料。在创伤性脑损伤 (TBI) 的急性期或亚急性期，人类和实验动物的大脑葡萄糖利用率都会降低。目前尚不清楚这些损伤如何影响大脑葡萄糖利用及其与轻度创伤性脑损伤 (mTBI) 慢性期持续神经行为障碍的关系。因此，我们比较了 mTBI 与假手术小鼠在慢性期不同脑区与大脑葡萄糖利用相关的选定基因的表达。这些基因包括己糖激酶-1 (HK1)、磷酸果糖激酶 (PFK)、丙酮酸激酶 (PK)、丙酮酸脱氢酶 (PDH)、毛细血管葡萄糖转运蛋白 (Glut-1)、神经元葡萄糖转运蛋白 (Glut-3)、星形胶质细胞乳酸转运蛋白 1 (MCT-1)、神经元乳酸转运蛋白 2 (MCT-2)、乳酸受体 (GPR81) 和己糖激酶同工酶-2 (HK2)。年轻成年雄性 C57BL/6J 小鼠接受重复闭合性颅脑损伤。在 mTBI 后 2、4 和 6 个月进行 Morris 水迷宫 (MWM)、高架十字迷宫 (EPM) 和神经严重程度评分测试 (NSS)，以评估小鼠的神经行为障碍。在最后一次行为测试完成后的两天，采集额皮质、海马、脑干、下丘脑和小脑进行基因表达测量。在 mTBI 小鼠中，仅在海马中，葡萄糖代谢的两个关键酶 PK 和 PDH 的编码 mRNA 的表达在所有时间点均降低，但在脑干、下丘脑和皮质中不变。mTBI 小鼠还表现出以下行为改变：(1) 损伤后 2、4 和 6 个月空间学习和记忆能力下降，(2) EPM 确定的开放臂与封闭臂时间比例增加，(3) EPM 测试中，运动活动的减少加速，比假手术组早两个月，发生在 4 个月时。在三个时间点，损伤组和假手术组的 NSS 之间没有显著差异。因此，雄性小鼠的 mTBI 导致与选定神经行为结果的长期损害相关的关键葡萄糖利用相关酶的海马表达持续降低。
