Neurotrophic factor mechanisms in treatments in TBI and PTSD

TBI 和 PTSD 治疗中的神经营养因子机制

• 批准号: 8466800
• 负责人: Gary B. Kaplan
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466800
• 关键词: Address; Afghanistan; Amnesia; Amygdaloid structure; Animal Model; Area; Arousal; Attenuated; Axon; Behavior; Behavior Therapy; Behavioral; Blast Cell; Blast Injuries; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; C57BL/6 Mouse; Cell Nucleus; Characteristics; Chromatin; Chromatin Structure; Clinical; Cognition; Cognitive; Cognitive deficits; Cortical Contusions; DNA; Data; Development; Devices; Diffuse; Diffuse Axonal Injury; Disease model; Dose; Emotional; Enzymes; Epigenetic Process; Event; Exposure to; Extinction (Psychology); Freedom; Fright; Functional disorder; Gene Expression; Genetic Transcription; Goals; Harvest; Health; Hippocampus (Brain); Histone Deacetylase Inhibitor; Histones; Human; Imagery; Impaired cognition; Impairment; Injury; Intervention; Iraq; Knowledge; Learning; Lesion; Long-Term Effects; Measures; Mediating; Memory; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Mus; Nerve Degeneration; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Outcome; Outcome Study; Pathology; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacotherapy; Post-Translational Protein Processing; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prosencephalon; Proteins; Psyche structure; Pulse Pressure; Regulation; Rehabilitation Research; Reporting; Research; Research Methodology; Risk; Rodent Model; Safety; Services; Simulate; Site; Sodium Butyrate; Staining method; Stains; Stress; Symptoms; Synapses; Tail; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Translations; Trauma; Traumatic Brain Injury; Veterans; War; axoplasm; base; behavior test; brain tissue; classical conditioning; cognitive change; cohort; combat; conditioned fear; design; effective therapy; experience; functional disability; histone modification; improved; injured; learning extinction; male; mortality; mouse model; neuropathology; neuropsychiatry; neuropsychological; neurotrophic factor; novel; operation; pre-clinical research; pressure; psychologic; relating to nervous system; response; treatment effect

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.

描述（由申请人提供）： （1）目的 - 该项目的目的是使用啮齿动物模型评估爆炸诱导的创伤性脑损伤（TBI）和创伤后应激障碍（PTSD）中推定的神经营养因子机制和相关治疗方法。该项目的三个目标是：1）测量爆炸引起的TBI对认知和恐惧条件的影响； 2）了解爆炸引起的TBI对脑衍生的神经营养因子（BDNF）蛋白水平以及前额叶皮层，海马和杏仁核的神经变性的影响； 3）在这些模型中，一种新型治疗方法，以增强认知和BDNF水平。我们假设TBI通过降低可塑性和BDNF损害了空间学习和恐惧灭绝。我们假设提高BDNF水平的药理学方法会减轻TBI诱导的学习障碍。假设使用组蛋白脱乙酰基酶（HDAC）抑制剂的BDNF的表观遗传调节以增强学习。 （2）背景 - （a）科学原理TBI和PTSD已成为持久自由和行动伊拉克自由行动中的签名战区伤害。对于这些同时发生条件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（例如BDNF）的改变。 BDNF促进现有神经元的生存，并通过增强轴突和树突发芽的增强而产生突触重塑。初步研究表明，在TBI条件下，神经BDNF水平降低。介导行为和神经功能变化的重要机制是通过组蛋白的翻译后修饰来调节染色质结构。组蛋白脱乙酰基酶（HDAC）抑制剂是在神经精神疾病下进行药理学治疗的有前途的候选者。已显示HDAC抑制剂通过增强的神经可塑性和BDNF活性增加了学习。 （b）这项研究将如何通过增加对动物模型中爆炸压力波引起的机制和后遗症的理解来提高康复研究的知识，我们可以在临床前筛选候选药理学方法。 （c）研究的重要性及其与RR＆D优先区域的关系 - 研究与创伤性脑损伤的RR＆D优先级有关。开发用于压力波脑损伤和PTSD的标准小鼠模型对于开发有效治疗至关重要。 （d）直接利益和服务质量 - 本研究将研究许多退伍军人所维持的爆炸损伤和PTSD的影响。在将人类暴露于这种干预措施之前，在动物模型中测试治疗很重要。 （3）预期的结果或产品 - 这项研究的第一个结果是证明，这种爆炸的动物模型在小鼠中诱导的TBI改变了学习和关联恐惧条件。第二个结果是表明爆炸诱导的TBI和应力改变了前额叶皮层，海马和杏仁核的BDNF蛋白水平。第三个结果表明，具有可用于人类使用的形式的HDAC抑制剂可以通过BDNF增强增强TBI引起的恐惧的学习和灭绝。 （4）方法和研究计划 - 由于在TBI和PTSD模型中证明了效用，因此建议使用雄性C57BL/6小鼠。冲击波爆炸损伤（SWBI）模型使用现场电解冲击器设备，具有模拟爆炸特征的特性。分别评估了不同的SWBI队列的认知和恐惧调节。在认知条件的每一天和恐惧灭绝学习之前，丁酸钠被施用以检查效果。行为测试后，从小鼠中收获大脑，以使用定量IHC在切片中测量神经可塑性标记BDNF，并进行替代切片进行NISSL染色，以检查脑组织损失。