Impaired glucose utilization and behavior in a mouse model of chronic, mild TBI

描述(由申请人提供)： 轻、中度创伤性脑损伤(MTBI)是伊拉克和阿富汗冲突中的“标志性损伤”，并导致严重残疾。在mTBI的慢性期，一致的资金来源是人类和动物的大脑葡萄糖利用率降低。葡萄糖及其中间代谢产物是维持神经细胞功能的重要燃料。大脑中葡萄糖及其中间代谢物供应的减少也会导致记忆丧失，这在mTBI患者中是常见的发现。到目前为止，旨在改善大脑葡萄糖利用的策略还没有被用于mTBI康复的范例中。目的：利用小鼠mTBI模型，研究mTBI对脑葡萄糖利用、神经行为恢复的远期影响及其相互关系。具体目标：(1)纵向描述和修改已建立的显示持续性神经行为损伤的小鼠mTBI模型，(2)确定这种损伤是否与离散大脑区域与葡萄糖利用相关的蛋白质和基因的表达改变有关，以及(3)评估通过特定饮食干预增加内源性生长素激素GLP-1是否改善这些慢性神经行为和生物标记物异常，作为一种“概念证明”。假设：(1)慢性mTBI可降低特定脑区葡萄糖利用相关转运蛋白和酶的表达，并与神经行为功能受损有关。(2)脑创伤后急性期内源性GLP-1的增强可改善脑葡萄糖利用相关转运蛋白/酶的表达及相关的神经行为结果。方法：采用24或96h内的重复性轻度闭合性颅脑损伤建立小鼠mTBI模型。这个小鼠mTBI模型将用于三个实验：(1)在这个小鼠mTBI模型中确定慢性(7周)神经行为损伤的时间进程：学习和记忆测试的Morris水迷宫；运动协调的旋转机器人；以及快感缺失的2瓶蔗糖/水偏好测试；(2)测量神经行为损伤与大脑不同区域(如皮质(前叶、顶叶、颞叶和枕叶)、膝盖体、海马体、丘脑和下丘脑)中葡萄糖利用相关转运蛋白和酶的表达之间的时间关系；(3)研究通过特定的饮食干预增加内源性GLP-1是否能促进mTBI小鼠葡萄糖利用相关生物标志物的表达和神经行为的恢复。拟议研究的结果将为进一步的合作研究提供必要的数据，这些研究将为有关mTBI慢性期的更多基础科学和翻译研究提供信息，并为更详细的细胞和分子机制研究mTBI后长期脑葡萄糖利用减少提供信息。我们的长期目标是在逆转退伍军人和非退伍军人受损的脑葡萄糖代谢的基础上，改善对退伍军人和非退伍军人的mTBI的管理。

DESCRIPTION (provided by applicant): Mild-moderate traumatic brain injury (mTBI) is the "signature injury" of both Iraq and Afghanistan conflicts and leads to significant disability. During the chronic phase of mTBI, a consistent funding is a decreased cerebral glucose utilization in both humans and animals. Glucose and its intermediate metabolites are essential fuels to maintain neuronal cell function. The decreased supply of glucose and its intermediary metabolite in the brain also lead to memory loss, a common findings in patients with mTBI. To date, strategies that target improvements in brain glucose utilization have not been employed in paradigms for mTBI rehabilitation. Objective: using mouse model of mTBI to study long-term effects of mTBI on brain glucose utilization, neurobehavioral recovery, and their inter-relationships. Specific aims: (1) to longitudinally characterize and modify an established mouse mTBI model that demonstrates persistent neurobehavioral impairments, (2) to determine whether such impairments are associated with altered expression of proteins and genes related to glucose utilization in discrete brain areas, and (3) to assess as a "proof of concept" whether augmenting endogenous incretin hormone, GLP-1, via a specific dietary intervention ameliorates these chronic neurobehavioral and biomarker abnormalities. Hypothesis: (1) Chronic mTBI decreases expression of glucose utilization related transporters and enzymes in specific brain regions, in association with impaired neurobehavioral functions. (2) Augmentation of endogenous GLP- 1during the post-acute phase of TBI improves expression of brain glucose utilization related transporters/enzymes and related neurobehavioral outcomes in the above mTBI model. Methods: The repetitive mild closed-skull traumatic brain injuries within 24 or 96 hours will be used to generate mouse model of mTBI. This mouse mTBI model will be used for three experiments proposed: (1) determining the time course of chronic (> 7 weeks) neurobehavioral impairments in this mouse mTBI model: Morris water maze for learning and memory test; the rotarotor for motor coordination; and 2-bottle sucrose/water preference test for anhedonia; (2) measuring the temporal relationships between neurobehavioral impairments and expression of glucose utilization related transporters and enzymes in discrete brain regions, such as cortex (frotal lobe, parietal lobe, temporal lobe and occipital lobe), corpus callosum, hippocampus, thalamus, and hypothalamus; (3) examining whether increasing endogenous GLP-1 by a specific dietary intervention enhances expression of glucose utilization related biomarkers and neurobehavioral recovery in mTBI mice. The results from proposed studies will provide necessary data for further collaborative researches that will inform additional basic science and translational investigations on chronic phase of mTBI; and for more detailed cellular and molecular mechanistic studies on prolonged decreased brain glucose utilization following mTBI. Our long term goal is to improve the management of mTBI in both Veterans and non-Veterans, based upon reversing their impaired brain glucose metabolism.