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的“标志性损伤”，并导致严重残疾。在mTBI的慢性阶段，一致的资金是人类和动物的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必需燃料。大脑中葡萄糖及其中间代谢物的供应减少也会导致记忆丧失，这是mTBI患者的常见发现。迄今为止，针对改善脑葡萄糖利用的策略尚未用于mTBI康复的范例。目的：利用小鼠mTBI模型研究mTBI对脑葡萄糖利用、神经行为恢复的长期影响及其相互关系。具体目标：（1）纵向表征和修饰已建立的小鼠mTBI模型，该模型显示出持续的神经行为损伤，（2）确定这种损伤是否与离散脑区域中与葡萄糖利用相关的蛋白质和基因的表达改变有关，和（3）评估作为“概念验证”是否增加内源性肠促胰岛素激素GLP-1，通过特定的饮食干预改善这些慢性神经行为和生物标志物异常。假设：（1）慢性mTBI降低特定脑区域中葡萄糖利用相关转运蛋白和酶的表达，与受损的神经行为功能相关。(2)在上述mTBI模型中，在TBI后急性期增加内源性GLP-1可改善脑葡萄糖利用相关转运蛋白/酶的表达和相关神经行为结果。方法：采用24 h或96 h内的闭合性颅脑损伤模型，建立小鼠mTBI模型。该小鼠mTBI模型将用于提出的三个实验：（1）确定慢性TBI的时间过程。（> 7周）在该小鼠mTBI模型中的神经行为损伤：用于学习和记忆测试的Morris水迷宫;用于运动协调的旋转器;和用于快感缺乏的2瓶蔗糖/水偏好测试;（2）测量神经行为损伤与离散脑区域（例如皮质）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）检查通过特定饮食干预增加内源性GLP-1是否增强mTBI小鼠中葡萄糖利用相关生物标志物的表达和神经行为恢复。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mTBI慢性期的其他基础科学和转化研究提供信息;并为mTBI后脑葡萄糖利用率长期下降的更详细的细胞和分子机制研究提供必要的数据。我们的长期目标是改善退伍军人和非退伍军人的mTBI管理，基于逆转他们受损的大脑葡萄糖代谢。

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.