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。该项目的三个目标是： 1) 确定慢性创伤性脑损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TBI和PTSD对PFC、HIPP和BLA区域神经炎症、DAI、神经胶质反应性和树突棘形态的影响；检查大脑和行为变化之间的关系。 3) 研究丙戊酸 (VPA) 对慢性 TBI/PTSD 患者的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 已成为标志性伤害 OEF/OIF 战区。 TBI 中会发生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研究了 TBI 和 PTSD 联合对轴突损伤、神经炎症和树突可塑性的影响。根据研究文献，我们假设 VPA 药物治疗将增强恐惧消退学习和空间记忆，并促进 TBI 和 PTSD 模型的神经恢复。 (b) 这项研究将如何推进康复研究的知识——通过增加我们对动物模型中脑损伤和共存恐惧调节的机制和后遗症的理解，我们可以检查潜在的生物标志物并筛选患有 TBI/PTSD 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 优先领域相关。使用慢性创伤性脑损伤和创伤后应激障碍模型对于理解大脑和行为机制以及开发退伍军人的有效治疗方法至关重要。 (d) 直接效益和服务质量——这项研究调查了许多 OIF/OEF 退伍军人所遭受的 TBI 和 PTSD 的影响，并将检查这些疾病的生物标志物，然后在人体中进行测试。在此模型中进行测试后，可以在以下环境中仔细开发临床可用的 VPA 剂 研究其对患有 TBI 和/或 PTSD 的退伍军人的促认知和恐惧消退增强作用。 (3) 预期结果或产品——本研究的第一个结果是证明小鼠的 FPI 和共存的恐惧条件反射 (FC) 会损害长期记忆和消退学习；这些效应与 PFC、HIPP 和 BLA 中树突形态的减少有关。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、神经胶质反应性和神经炎症相关。第三个结果是证明 VPA 治疗可逆转该模型中的空间记忆和恐惧消退缺陷，并减少受伤后 6 个月和 12 个月时的这些神经生物学变化。此外，我们将证明将可注射明胶注射到 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，因为它们在我们的 FPI 和 FC 模型中表现出实用性。我们的 FPI 模型使用中等水平的撞击力来产生长期脑损伤。 FPI 小鼠将接受提示 FC 程序以产生共病 TBI/PTSD 模型。使用莫里斯水迷宫记忆测试和恐惧消退程序对 FPI/FC 小鼠进行行为测试。从小鼠身上采集大脑，使用定量免疫组织化学测量轴突损伤（通过 -APP 测量）、神经炎症（通过 IL-6 和 GFAP 测量）和树突可塑性（高尔基-考克斯染色）来测量 PFC、HIPP 和 BLA 的变化。在我们的 FPI/FC 模型中，我们将在 6 个月和 12 个月的两个独立的慢性时间点测试 VPA 肠外治疗的效果。我们还将试点一种使用生物材料基质在 TBI 损伤部位直接、连续施用 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.