Behavioral and Neural Plasticity in TBI and PTSD

 描述(由申请人提供)： (1)目的-本项目的目的是利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。本项目的三个目标是：1)确定慢性脑创伤和创伤后应激障碍对记忆和恐惧消退学习的影响。2)研究慢性脑创伤和创伤后应激障碍对大鼠PFC、HIPP和BLA区神经炎症、DAI、胶质细胞反应性和树突棘形态的影响，探讨脑与行为改变的关系。3)研究丙戊酸盐(VPA)对慢性脑损伤/创伤后应激障碍(PTSD)大鼠记忆和恐惧消退及神经生物学改变的影响。 (2)背景--(A)科学依据--创伤性脑损伤和创伤后应激障碍已成为 OEF/OIF战区。颅脑损伤时会出现局灶性和弥漫性脑损伤，这种损伤会导致相关的神经认知和行为缺陷。这项拟议的研究全面考察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。在文献研究的基础上，我们假设VPA的药物治疗可以增强脑创伤和创伤后应激障碍模型的恐惧消退学习和空间记忆，并促进神经功能的恢复。(B)这项研究将如何促进康复研究方面的知识-通过增加我们对脑损伤和动物模型中共存的恐惧条件作用的机制和后遗症的了解，我们可以检查潜在的生物标记物，并筛选适用于患有脑创伤/创伤后应激障碍的人类的候选治疗方法。(C)研究的意义及其与RR&D优先领域的关系--该研究与慢性创伤性脑损伤的RR&D优先领域有关。使用慢性创伤性脑损伤和创伤后应激障碍的模型对于了解脑和行为机制以及为退伍军人开发有效的治疗方法至关重要。(D)直接益处和服务质量--这项研究考察了许多OIF/OEF退伍军人遭受的创伤性脑损伤和创伤后应激障碍的影响，并将检查这些疾病的生物标记物，然后可以在人体上进行测试。在此模型中进行测试后，临床上可用的试剂VPA可以在 对患有脑外伤和/或创伤后应激障碍的退伍军人的前认知和恐惧消退增强作用的研究。 (3)预期结果或产物-本研究的第一个结果是证明在小鼠中，FPI和共存的恐惧条件反射(FC)会损害长期记忆和消亡学习；这些影响与PFC、HIPP和BLA中树突形态的减少有关。第二个结果表明，在TBI/PTSD模型中，认知和恐惧消退损害与PFC、HIPP和BLA的轴突损伤、神经胶质细胞反应性和神经炎症有关。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，从注射明胶输送到FPI损伤部位的VPA可以增强认知并逆转神经生物学效应。 (4)方法和研究计划--使用雄性C57BL/6小鼠是因为它们在我们的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冲击力来产生长期的脑损伤。FPI小鼠将接受提示的FC程序，以产生一种TBI/PTSD共病模型。行为学测试是使用Morris水迷宫记忆测试和恐惧消退程序在FPI/FC小鼠身上进行的。取小鼠脑，用定量免疫组织化学方法检测轴突损伤(-APP)、神经炎症(IL-6和胶质纤维酸性蛋白)和树突可塑性(高尔基-考克斯染色)的变化。在我们的FPI/FC模型中，我们将在6个月和12个月的两个不同的慢性时间点测试静脉注射VPA的效果。我们还将试验一种使用生物材料基质在颅脑损伤部位直接和持续给予VPA的方法。

 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.