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

慢性轻度 TBI 小鼠模型中葡萄糖利用和行为受损

• 批准号: 8820791
• 负责人: June Zhou
• 金额: --
• 依托单位: U.S. DEPT/VETS AFFAIRS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820791
• 关键词: Acute; Address; Afghanistan; Anhedonia; Animals; Area; Basic Science; Behavior; Biological Markers; Brain; Brain region; Cell physiology; Cerebrum; Chronic; Chronic Phase; Clinical Research; Clinical Trials; Conflict (Psychology); Corpus Callosum; Data; Dietary Intervention; Dose; Drug Targeting; Enzymes; Exhibits; FDA approved; Functional disorder; Funding; Future; Gene Proteins; Glucose; Goals; Hippocampus (Brain); Hour; Human; Hypothalamic structure; Impairment; Inflammation; Injury; Intervention; Investigation; Iraq; Knockout Mice; Lead; Lobe; Long-Term Effects; Maze Learning; Measures; Memory; Memory Loss; Methods; Modeling; Molecular; Motor; Mus; Neurons; Neurosecretory Systems; Occipital lobe; Outcome; Parietal Lobe; Pathogenesis; Patients; Phase; Physical activity; Proteins; Recovery; Recovery of Function; Rehabilitation therapy; Research; Rodent; Rodent Model; Sleep; Sucrose; TBI treatment; Temporal Lobe; Testing; Thalamic structure; Time; Traumatic Brain Injury; Veterans; Water; Work; analog; base; behavioral impairment; combat; cranium; disability; glucagon-like peptide; glucose metabolism; improved; incretin hormone; injured; mild traumatic brain injury; morris water maze; mouse model; neurobehavioral; nutrition; pre-clinical; preclinical study; preference; protein expression; public health relevance; receptor; research study; response; therapeutic development; translational study

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.

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”，可导致严重残疾。在 mTBI 的慢性阶段，持续的资金来源是人类和动物脑葡萄糖利用率的降低。葡萄糖及其中间代谢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，这是 mTBI 患者的常见症状。迄今为止，以改善脑葡萄糖利用为目标的策略尚未在 mTBI 康复范例中采用。目的：利用mTBI小鼠模型研究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) 纵向描述和修改已建立的小鼠 mTBI 模型，该模型显示持续的神经行为损伤，(2) 确定这种损伤是否与离散大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，以及 (3) 评估作为“概念证明”是否通过特定饮食增强内源性肠促胰岛素激素 GLP-1 干预可改善这些慢性神经行为和生物标志物异常。假设：(1) 慢性 mTBI 会降低特定脑区域葡萄糖利用相关转运蛋白和酶的表达，与神经行为功能受损相关。 (2) TBI急性期后内源性GLP-1的增强改善了上述mTBI模型中脑葡萄糖利用相关转运蛋白/酶的表达以及相关神经行为结果。方法：采用24小时或96小时内重复性轻度闭合性颅骨外伤性脑损伤建立小鼠mTBI模型。该小鼠 mTBI 模型将用于三个实验：（1）确定该小鼠 mTBI 模型中慢性（> 7 周）神经行为损伤的时间进程：用于学习和记忆测试的 Morris 水迷宫；用于运动协调的旋转器；以及针对快感缺失的两瓶蔗糖/水偏好测试； (2) 测量神经行为障碍与离散脑区（如皮质（额叶、顶叶、颞叶和枕叶）、胼胝体、海马、丘脑和下丘脑）葡萄糖利用相关转运蛋白和酶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 是否会增强 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，从而为 mTBI 慢性期的更多基础科学和转化研究提供信息；以及关于 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。我们的长期目标是在扭转退伍军人和非退伍军人受损的大脑葡萄糖代谢的基础上，改善他们的 mTBI 管理。