Neurotrophic factor mechanisms in treatments in TBI and PTSD

描述(由申请人提供)： (1)目的-本项目的目的是利用啮齿动物模型评价神经营养因子在冲击性脑损伤(TBI)和创伤后应激障碍(PTSD)中的作用机制和相关治疗。该项目的三个目标是：1)测量冲击性脑损伤对认知和恐惧条件反射的影响；2)了解冲击性脑损伤对脑源性神经营养因子(BDNF)蛋白水平和前额叶皮质、海马区和杏仁核神经退行性变的影响；3)在这些模型中尝试一种新的治疗方法来增强认知和BDNF水平。我们假设，脑外伤通过降低可塑性和脑源性神经营养因子来损害空间学习和恐惧消退。我们假设，提高脑源性神经营养因子水平的药理学方法将减轻脑损伤所致的学习障碍。BDNF的表观遗传调节使用组蛋白脱乙酰酶(HDAC)抑制剂，被假设为增强学习。(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持久自由行动和伊拉克自由行动中的标志性战区创伤。人们对这些共同发生疾病的病理生理学知之甚少。创伤性脑损伤及其相关的创伤后应激障碍的机制涉及BDNF等神经营养因子的改变。BDNF通过促进轴突和树突的萌发，促进现有神经元的存活并产生突触重塑。初步研究表明，在颅脑损伤条件下，神经BDNF水平降低。调节行为和神经功能变化的一个重要机制是通过组蛋白的翻译后修饰来调节染色质结构。组蛋白脱乙酰酶(HDAC)抑制剂是神经精神疾病药物治疗的候选药物。HDAC抑制剂已被证明通过增强神经可塑性和BDNF活性来增加学习能力。(B)这项研究将如何促进康复研究方面的知识-通过增加我们对爆炸压力波在动物模型中造成脑损伤的机制和后遗症的了解，我们可以在临床前筛选候选的药理学方法。(C)研究的意义及其与RR&D优先领域的关系--研究与创伤性脑损伤的RR&D优先领域有关。建立一种标准化的小鼠压力波脑损伤和创伤后应激障碍模型，对于开发有效的治疗方法至关重要。(D)直接利益和服务质量--这项研究将调查许多退伍军人遭受的爆炸破坏和创伤后应激障碍的影响。重要的是，在将人类暴露于此类干预之前，在动物模型中测试治疗方法。(3)预期结果或产物-本研究的第一个结果是证明这种冲击性脑损伤小鼠的动物模型改变了学习和关联恐惧条件反射。第二个结果表明，冲击波导致的脑损伤和应激改变了前额叶皮质、海马体和杏仁核中BDNF的蛋白水平。第三个结果表明，一种HDAC抑制剂，一种可供人类使用的形式，通过增强脑源性神经营养因子增强脑损伤诱导的学习和消除恐惧。(4)方法和研究计划--雄性C57BL/6小鼠在脑创伤和创伤后应激障碍模型中被证明是有用的，因此被推荐使用。冲击波冲击伤(SWBI)模型使用了现场电液冲击波装置，其特性模拟了爆炸的特征。不同的SWBI队列分别评估认知和恐惧条件作用。在认知条件反射和恐惧消退学习的每一天之前，丁酸钠被用来检查效果。行为测试后，取小鼠大脑，用定量IHC切片测量神经可塑性标记物BDNF，交替切片进行尼氏染色以检查脑组织丢失。

DESCRIPTION (provided by applicant): (1) PURPOSE - The purpose of the project is to evaluate putative neurotrophic factor mechanisms and related treatments in blast induced traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) using rodent models. The three goals of this project are to: 1) measure the effects of blast induced TBI on cognition and on fear conditioning; 2) understand the effects of blast induced TBI on brain derived neurotrophic factor (BDNF) protein levels and on neurodegeneration in prefrontal cortex, hippocampus and amydala; and 3) pilot a novel treatment approach to enhance cognition and BDNF levels in these models. We hypothesize that TBI impairs both spatial learning and fear extinction by reducing plasticity and BDNF. We hypothesize that pharmacological approaches which enhance BDNF levels will attenuate TBI induced learning impairments. The epigenetic regulation of BDNF, using a histone deacetylase (HDAC) inhibitor, is hypothesized to enhance learning. (2) BACKGROUND- (a) Scientific Rationale- TBI and PTSD have become the signature war zone injuries in Operation Enduring Freedom and Operation Iraqi Freedom. Too little is known about the pathophysiology of these co-occurring conditions. The mechanisms of TBI and associated PTSD involve alterations in neurotrophic factors such as BDNF. BDNF promotes the survival of existing neurons and produces synaptic remodeling via its enhancement of axonal and dendritic sprouting. Preliminary research suggests that neural BDNF levels are reduced in TBI conditions. An important mechanism for mediating changes in behavior and neural function is through the regulation of chromatin structure via post-translational modifications of histones. Histone deacetylase (HDAC) inhibitors are promising candidates for the pharmacological treatment in neuropsychiatric conditions. HDAC inhibitors have been shown to increase learning via enhanced neuroplasticity and BDNF activity. (b) How this Research will Advance Knowledge in Rehabilitation Research - By increasing our understanding of the mechanisms and sequelae of brain injury caused by blast pressure waves in animal models, we can pre-clinically screen candidate pharmacological approaches. (c) Significance of the Research and How it Relates to RR&D Priority Areas -The research relates to the RR&D Priority Area of Traumatic Brain Injury. Developing a standardized mouse model for a pressure wave brain injury and PTSD is of critical importance for the development of effective treatments. (d) Direct Benefits and Quality of Services - This study will investigate the effects of blast damage and PTSD that have been sustained by many Veterans. It is important to test treatments in animal models before exposing humans to such interventions. (3) EXPECTED OUTCOMES OR PRODUCTS - The first outcome of this study is to demonstrate that this animal model of blast induced TBI in mice alters learning and associative fear conditioning. The second outcome is to show that blast induced TBI and stress alters BDNF protein levels in prefrontal cortex, hippocampus and amydala. The third outcome demonstrates that a HDAC inhibitor, with a form available for human use, enhances TBI induced learning and extinction of fear via BDNF enhancement. (4) METHODS AND RESEARCH PLAN - Male C57BL/6 mice are proposed for use because of their demonstrated utility in TBI and PTSD models. The shockwave blast injury (SWBI) model uses an on-site electrohydraulic shockwave apparatus with characteristics that simulate features of a blast. Different SWBI cohorts are separately assessed for cognition and fear conditioning. Prior to each day of the cognitive conditioning and fear extinction learning, sodium butyrate is administered to examine effects. After behavioral testing, brains are harvested from mice to measure neural plasticity marker BDNF in sections using quantitative IHC with alternate sections undergo Nissl staining to examine brain tissue loss.