Behavioral and Neural Plasticity in TBI and PTSD

 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。本研究的三个目标是：1）确定慢性TBI和PTSD对记忆和恐惧消退学习的影响。2)研究慢性TBI和PTSD对PFC、HIPP和BLA区域神经炎症、DAI、胶质反应性和树突棘形态的影响;研究大脑与行为变化之间的关系。3)研究丙戊酸盐（VPA）对慢性TBI/PTSD患者记忆和恐惧消退以及神经生物学变化的影响。 (2)背景-（a）科学原理- TBI和PTSD已成为创伤后应激障碍的标志性伤害， OEF/OIF战区。TBI可引起局灶性和弥漫性脑损伤，这种损伤导致相关的神经认知和行为缺陷。本研究综合探讨了创伤性脑损伤和创伤后应激障碍对轴突损伤、神经炎症和树突可塑性的影响。基于研究文献，我们假设VPA的药物治疗将增强TBI和PTSD模型中的恐惧消退学习和空间记忆，并促进神经恢复。(b)这项研究将如何推进康复研究的知识-通过增加我们对脑损伤的机制和后遗症以及动物模型中共存的恐惧条件反射的理解，我们可以检查潜在的生物标志物并筛选TBI/PTSD患者的候选治疗方法。(c)研究的意义及其与RR&D优先领域的关系-本研究涉及慢性创伤性脑损伤的RR&D优先领域。使用慢性TBI和PTSD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方法至关重要。(d)直接利益和服务质量-这项研究检查了许多OIF/OEF退伍军人所持续的TBI和PTSD的影响，并将检查这些条件的生物标志物，然后可以在人类中进行测试。在该模型中进行测试后，临床可用的药物VPA可以在 研究其对TBI和/或PTSD退伍军人的促认知和恐惧消退增强作用。 (3)预期结果或产物-本研究的第一个结果是证明小鼠中FPI和共存的恐惧条件反射（FC）损害长期记忆和消退学习;这些效应与PFC、HIPP和BLA中树突形态的减少相关。第二个结果是表明TBI/PTSD模型中的认知和恐惧消退障碍与PFC、HIPP和BLA中的轴突损伤、胶质反应性和神经炎症相关。第三个结果是证明VPA治疗逆转了该模型中的空间记忆和恐惧消退缺陷，并在损伤后6个月和12个月减少了这些神经生物学变化。此外，我们还将证明VPA注射明胶输送至FPI损伤部位可增强认知能力并逆转神经生物学效应。 (4)方法和研究-使用雄性C57 BL/6小鼠，因为它们在我们的FPI和FC模型中被证明是有用的。我们的FPI模型使用中等水平的挤压力来产生长期的脑损伤。FPI小鼠将经历提示FC程序以产生共病TBI/PTSD模型。使用Morris水迷宫记忆测试和恐惧消退程序在FPI/FC小鼠中进行行为测试。从小鼠收获脑以使用定量免疫组织化学测量PFC、HIPP和BLA的变化，用于轴突损伤（如通过β-APP测量）、神经炎症（如通过IL-6和GFAP测量）和树突可塑性（Golgi-Cox染色）。在我们的FPI/FC模型中，我们将在6个月和12个月的两个单独慢性时间点检测VPA肠外治疗的影响。我们还将试验一种方法，使用生物材料基质在TBI损伤部位直接和连续给予VPA。

 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.