Neurotrophic factor mechanisms in treatments in TBI and PTSD

描述（由申请人提供）： (1)本项目的目的是使用啮齿动物模型评估爆炸引起的创伤性脑损伤（TBI）和创伤后应激障碍（PTSD）中假定的神经营养因子机制和相关治疗。本项目的三个目标是：1）测量冲击波诱导的TBI对认知和恐惧条件反射的影响; 2）了解冲击波诱导的TBI对脑源性神经营养因子（BDNF）蛋白水平以及对前额叶皮层、海马和杏仁核中神经变性的影响; 3）试验一种新的治疗方法，以增强这些模型中的认知和BDNF水平。我们假设TBI通过降低可塑性和BDNF来损害空间学习和恐惧消退。我们推测，增强BDNF水平的药理学方法将减弱TBI诱导的学习障碍。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）科学原理- TBI和PTSD已成为持久自由行动和伊拉克自由行动中的标志性战区伤害。对这些并发症的病理生理学知之甚少。TBI和相关PTSD的机制涉及神经营养因子如BDNF的改变。BDNF促进现有神经元的存活，并通过其增强轴突和树突发芽来产生突触重塑。初步研究表明，神经BDNF水平在TBI条件下降低。介导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调节染色质结构。组蛋白去乙酰化酶（HDAC）抑制剂是神经精神疾病药理学治疗的有希望的候选药物。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。(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爆炸压力波引起的脑损伤机制和后遗症的理解，我们可以在临床前筛选候选药理学方法。(c)研究的意义及其与RR&D优先领域的关系-本研究涉及创伤性脑损伤的RR&D优先领域。建立标准化的压力波脑损伤和PTSD小鼠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-这项研究将调查爆炸伤害和创伤后应激障碍的影响，已持续由许多退伍军人。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。(3)预期的结果或产品-本研究的第一个结果是证明，这种动物模型的冲击波诱导TBI小鼠改变学习和联想恐惧条件反射。第二个结果是表明，爆炸引起的创伤性脑损伤和应激改变了前额叶皮层、海马和杏仁核中的BDNF蛋白水平。第三个结果表明，具有可供人类使用的形式的HDAC抑制剂通过BDNF增强来增强TBI诱导的学习和恐惧的消除。(4)方法和研究-雄性C57 BL/6小鼠被推荐使用，因为它们在TBI和PTSD模型中被证明是有用的。冲击波冲击伤（SWBI）模型使用现场电液冲击波装置，其特征模拟爆炸的特征。不同的SWBI组群分别评估认知和恐惧条件反射。在认知调节和恐惧消退学习的每一天之前，施用丁酸钠以检查效果。在行为测试后，从小鼠收获脑以使用定量IHC测量切片中的神经可塑性标记物BDNF，其中交替切片经历尼氏染色以检查脑组织损失。

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.