Behavioral and Neural Plasticity in TBI and PTSD

TBI 和 PTSD 的行为和神经可塑性

• 批准号: 9147494
• 负责人: Gary B. Kaplan
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147494
• 关键词: Abnormal Cell; Afghanistan; Age; Animal Model; Animals; Area; Attention; Basic Science; Behavioral; Behavioral Mechanisms; Biocompatible Materials; Biological Markers; Brain; Brain Injuries; Brain region; C57BL/6 Mouse; Chronic; Chronic Post Traumatic Stress Disorder; Clinical; Cognition; Cognitive; Cognitive deficits; Comorbidity; Cues; Dendritic Spines; Department of Defense; Development; Diagnostic; Diffuse Brain Injury; Disease model; Extinction (Psychology); Face; Fright; Functional disorder; Gelatin; Glial Fibrillary Acidic Protein; Goals; Golgi Apparatus; Harvest; Health; Histone Deacetylase Inhibitor; Human; Immunohistochemistry; Impairment; Injectable; Injury; Interleukin-6; Intervention; Iraq; Knowledge; Lead; Learning; Lesion; Literature; Measurable; Measures; Memory; Memory Loss; Memory impairment; Mental disorders; Military Personnel; Modeling; Morphology; Mus; Nerve Degeneration; Neurobiology; Neurocognitive; Neuroglia; Neurologic; Neuronal Plasticity; Neurons; Neuroprotective Agents; Outcome; Outcome Study; Percussion; Pharmacological Treatment; Pharmacology; Population; Post-Traumatic Stress Disorders; Procedures; Publications; Publishing; Quality of Care; Rehabilitation Research; Research; Research Methodology; Rodent Model; Safety; Serum; Services; Site; Staining method; Stains; Testing; Therapeutic; Therapeutic Agents; Time; Translating; Translations; Traumatic Brain Injury; Treatment outcome; Veterans; War; axon injury; base; behavior test; behavioral plasticity; classical conditioning; combat; conditioned fear; cost; disability; effective therapy; health administration; health care service utilization; improved; learning extinction; long term memory; male; morris water maze; mouse model; neurobiological mechanism; neuroinflammation; neuromechanism; novel; novel strategies; potential biomarker; preclinical study; public health relevance; relating to nervous system; response; restoration; service member; spatial memory; symptomatology; valproate

 DESCRIPTION (provided by applicant): (1) PURPOSE - The purpose of the project is to evaluate mechanisms and related treatment approaches in chronic traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) using a mouse model. The three goals of this project are: 1) To determine the effects of chronic TBI and PTSD on memory and fear extinction learning. 2) To examine the effects of chronic TBI and PTSD on neuroinflammation, DAI, glia reactivity and dendritic spine morphology in PFC, HIPP and BLA regions; to examine the relationship between brain and behavioral changes. 3) To examine the effects of valproate (VPA) on memory and fear extinction and neurobiological changes in chronic TBI/PTSD. (2) BACKGROUND- (a) Scientific Rationale- TBI and PTSD have become the signature injuries from OEF/OIF war zones. Focal and diffuse brain injury occurs in TBI and this damage contributes to the associated neurocognitive and behavioral deficits. This proposed study comprehensively examines the effects of combined TBI and PTSD on axonal injury, neuroinflammation, and dendritic plasticity. Based on the research literature, we hypothesize that pharmacological treatment with VPA will enhance fear extinction learning and spatial memory and promote neural restoration in models of TBI and PTSD. (b) How this Research will Advance Knowledge in Rehabilitation Research - By increasing our understanding of the mechanisms and sequelae of brain injury and co-existing fear conditioning in animal models, we can examine potential biomarkers and screen candidate treatment approaches for humans with TBI/PTSD. (c) Significance of the Research and How it Relates to RR&D Priority Areas - The research relates to the RR&D Priority Area of Chronic Traumatic Brain Injury. Using a model of chronic TBI and PTSD is of critical importance for understanding brain and behavioral mechanisms and for the development of effective treatments for veterans. (d) Direct Benefits and Quality of Services - This study examines the effects of TBI and PTSD that have been sustained by many OIF/OEF veterans and will examine biomarkers for these conditions that can be then tested in humans. After testing in this model, the clinically available agent VPA can be carefully developed in studies for its pro-cognitive and fear extinction enhancing effects for veterans with TBI and/or PTSD. (3) EXPECTED OUTCOMES OR PRODUCTS - The first outcome of this study is to demonstrate that FPI and coexisting fear conditioning (FC) in mice impair long-term memory and extinction learning; these effects are associated with reductions in dendritic morphology in PFC, HIPP, and BLA. The second outcome is to show that the cognitive and fear extinction impairments in the TBI/PTSD model are associated with axonal injury, glial reactivity, and neuroinflammation in PFC, HIPP and BLA. The third outcome is to demonstrate that VPA treatment reverses spatial memory and fear extinction deficits in this model and reduces these neurobiological changes at 6 and 12 months post-injury. Additionally, we will demonstrate that administration of VPA from injectable gelatin delivered to the FPI injury site enhances cognition and reverses neurobiological effects. (4) METHODS AND RESEARCH PLAN - Male C57BL/6 mice are used because of their demonstrated utility in our FPI and FC model. Our FPI model uses a moderate level of percussive force to produce long-term brain injury. FPI mice will undergo cued FC procedures to produce a comorbid TBI/PTSD model. Behavioral testing is performed in FPI/FC mice using Morris Water Maze memory testing and fear extinction procedures. Brains are harvested from mice to measure changes in PFC, HIPP, and BLA using quantitative immunohistochemistry for axonal injury (as measured by -APP), neuroinflammation (as measured by IL-6 and GFAP) and dendritic plasticity (Golgi-Cox staining). In our FPI/FC model, we will test the effects of parenteral treatment with VPA at two separate chronic time points at 6 and 12 months. We will also pilot an approach using a biomaterial matrix for direct and continuous VPA administration at the TBI injury site.

 描述（由申请人提供）： （1）目的 - 该项目的目的是使用小鼠模型评估慢性创伤性脑损伤（TBI）和创伤后应激障碍（PTSD）的机制和相关治疗方法。该项目的三个目标是：1）确定慢性TBI和PTSD对记忆和恐惧扩展学习的影响。 2）检查慢性TBI和PTSD对PFC，HIPP和BLA区域中神经炎症，DAI，神经胶质反应性和树突状脊柱形态的影响；检查大脑与行为变化之间的关系。 3）检查丙戊酸（VPA）对慢性TBI/PTSD的记忆和恐惧扩展和神经生物学变化的影响。 （2）背景 - （a）科学原理TBI和PTSD已成为签名伤害 OEF/OIF战区。局灶性和弥漫性脑损伤发生在TBI中，这种损害有助于相关的神经认知和行为定义。这项拟议的研究全面研究了TBI和PTSD对轴突损伤，神经炎症和树突可塑性的影响。基于研究文献，我们假设使用VPA的药物治疗将增强恐惧扩展学习和空间记忆，并促进TBI和PTSD模型中的神经恢复。 （b）这项研究将如何提高康复研究知识 - 通过增加对动物模型中脑损伤的机制和后遗症的理解，并在动物模型中共存恐惧条件，我们可以检查潜在的生物标志物，并使用TBI/PTSD对人类的筛查候选方法。 （c）研究的重要性及其与RR＆D优先区域的关系 - 该研究与慢性创伤性脑损伤的RR＆D优先级有关。使用慢性TBI和PTSD的模型对于理解大脑和行为机制以及为退伍军人开发有效治疗至关重要。 （d）直接利益和服务质量 - 本研究检查了许多OIF/OEF退伍军人所维持的TBI和PTSD的影响，并将检查这些疾病的生物标志物，然后在人类中进行测试。在此模型中进行了测试后，临床上可用的代理VPA可以在 研究其对具有TBI和/或PTSD的退伍军人的促进认知和恐惧增强效果的研究。 （3）预期的结果或产品 - 这项研究的第一个结果是证明小鼠中的FPI和共存的恐惧调节（FC）会损害长期记忆和扩展学习；这些影响与PFC，HIPP和BLA中树突状形态的降低有关。第二个结果是表明TBI/PTSD模型中的认知和恐惧扩展障碍与PFC，HIPP和BLA中的轴突损伤，神经胶质反应性和神经炎症有关。第三个结果是证明VPA治疗逆转空间记忆和恐惧扩展在此模型中定义，并在伤害后6和12个月减少这些神经生物学变化。此外，我们将证明，输送到FPI损伤部位的可注射明胶的VPA可以增强认知并逆转神经生物学作用。 （4）方法和研究计划 - 雄性C57BL/6小鼠由于在我们的FPI和FC模型中证明了效用，因此使用了雄性C57BL/6小鼠。我们的FPI模型使用现代水平的打击力来产生长期的脑损伤。 FPI小鼠将接受提示的FC程序，以产生合并TBI/PTSD模型。使用莫里斯水迷宫记忆测试和恐惧扩展程序在FPI/FC小鼠中进行行为测试。使用定量免疫组织化学（通过-APP测量），神经炎症（通过IL-6和GFAP测量）和树突可变性（GOLGI-COX染色），使用定量免疫组织化学（通过-APP），神经炎症（通过-app）来测量PFC，HIPP和BLA的变化，以测量大脑。在我们的FPI/FC模型中，我们将在6和12个月的两个单独的慢性时间点在两个单独的慢性时间点上测试父母治疗的影响。我们还将使用生物材料基质在TBI损伤部位进行直接和连续VPA给药的方法进行试验。