The Neurobiology of Blast-Related Brain Injury in a Rat Model of mTBI

mTBI 大鼠模型中爆炸相关脑损伤的神经生物学

• 批准号: 8676382
• 负责人: Gregory A. Elder
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676382
• 关键词: Acoustics; Adverse effects; Afghanistan; Amygdaloid structure; Anatomy; Animal Model; Animal Testing; Anxiety; Behavioral; Biological Assay; Blast Cell; Blast Injuries; Brain; Brain Injuries; Cells; Chronic; Chronic stress; Clinical; Collaborations; Corticosterone; Cues; Dendritic Spines; Department of Defense; Development; Dexamethasone; Disease; Employee Strikes; Event; Exhibits; Exposure to; Glucocorticoid Receptor; Glucocorticoids; High Prevalence; Hippocampus (Brain); Hormonal; Injury; Iraq; Lead; Medial; Mediating; Mental Depression; Mifepristone; Modeling; Molecular; Morbidity - disease rate; Neurobiology; Neurosecretory Systems; Pattern; Plasma; Post-Traumatic Stress Disorders; Prefrontal Cortex; Protocols documentation; RU-486; Rattus; Reaction; Research Personnel; Stress; Structure; Symptoms; System; Testing; Time; Traumatic Brain Injury; Veterans; War; base; biological adaptation to stress; conditioned fear; design; hypothalamic-pituitary-adrenal axis; new therapeutic target; operation; prevent; psychological stressor; psychological trauma; public health relevance; response; stressor; trait; treatment strategy

DESCRIPTION (provided by applicant): Mild traumatic brain injury (mTBI) has been a major cause of morbidity in the wars in Iraq and Afghanistan. In both theatres of operation, blast exposure has been the most common cause of TBI. One striking feature of the clinical presentations of OIF/OEF veterans with mTBI is the prominence of post-traumatic stress disorder (PTSD). Indeed the high prevalence of PTSD and depression in returning OIF/OEF veterans with mTBI is well documented and distinction between the two disorders has proven clinically challenging. The association between PTSD and mTBI might be explained by co-incident exposures to TBI events and PTSD stressors. However, an alternative hypothesis that we have been exploring is that blast-related mTBI damages brain structures that are important in mediating responses to psychological stressors and thus enhances the likelihood of developing PTSD. In collaboration with a Department of Defense investigator, Dr. Stephen Ahlers, we have been studying a rat model of blast injury that mimics mTBI. We have found that animals tested several months post-exposure exhibit PTSD-related traits including increased acoustic startle, increased anxiety, an altered response to a predator scent challenge and an increased cued response in a fear conditioning paradigm. These observations suggest that blast exposure in the absence of any psychological trauma induces PTSD related traits that are chronic and persistent. Dr. Ahlers has found that plasma corticosterone levels become elevated after blast exposure and that these levels remain high for at least one month. PTSD is commonly thought to result from an abnormal and prolonged stress response with abundant evidence suggesting that abnormalities in the hypothalamic/pituitary/adrenal axis are chronically present. These observations have lead us to postulate that blast injury to the brain induces a chronic state of stress that even in the absence of any psychological trauma produces PTSD-related traits and exaggerated responses to subsequent PTSD-related stressors. Here we will examine whether stress responses in the brain are chronically altered by exposure to blast injury and determine whether treatment with a glucocorticoid receptor antagonist is able to block the development of or reverse PTSD-related behavioral traits. We will also examine whether blast injury induces structural effects in the medial prefrontal cortex, amygdala and hippocampus, the principal anatomic substrates that are thought to underlie the neurobiological basis of PTSD. These studies will further understanding of the relationship of blast injury to PTSD related traits and will have implications for designing treatment strategies for veterans who have suffered blast induced mTBIs.

描述(由申请人提供)： 在伊拉克和阿富汗战争中，轻度创伤性脑损伤(MTBI)一直是导致发病率的主要原因。在这两个手术区，冲击波暴露一直是导致脑外伤的最常见原因。患有mTBI的OIF/OEF退伍军人的临床表现的一个显著特征是突出的创伤后应激障碍(PTSD)。事实上，在患有mTBI的OIF/OEF退伍军人中，创伤后应激障碍和抑郁的高患病率是有充分证据的，这两种疾病之间的区别在临床上被证明是具有挑战性的。创伤后应激障碍和创伤后应激障碍之间的关系可以通过同时暴露于创伤后创伤事件和创伤后应激障碍来解释。然而，我们一直在探索的另一种假说是，与冲击波相关的mTBI损害了大脑结构，这些结构在调节对心理应激源的反应方面非常重要，从而增加了发生创伤后应激障碍的可能性。在国防部调查员斯蒂芬·阿莱斯博士的合作下，我们一直在研究模拟mTBI的爆炸伤大鼠模型。我们发现，暴露后几个月被测试的动物表现出与创伤后应激障碍相关的特征，包括声音惊吓增加，焦虑增加，对捕食者气味挑战的反应改变，以及恐惧条件反射范式中线索反应的增加。这些观察表明，在没有任何心理创伤的情况下，冲击波暴露会诱发与创伤后应激障碍相关的慢性和持久性特征。阿莱斯博士发现，在爆炸暴露后，血浆皮质酮水平会升高，而且这些水平至少会在一个月内保持在高位。创伤后应激障碍通常被认为是由异常和长期的应激反应引起的，大量证据表明，下丘脑/垂体/肾上腺轴的异常是慢性存在的。这些观察使我们假设，脑爆炸伤会导致慢性应激状态，即使在没有爆炸伤的情况下也是如此 任何心理创伤都会产生与创伤后应激障碍相关的特征，并对随后与创伤后应激障碍相关的压力源做出夸大的反应。在这里，我们将研究大脑中的应激反应是否会因冲击伤而慢性改变，并确定糖皮质激素受体拮抗剂的治疗是否能够阻止或逆转与创伤后应激障碍相关的行为特征的发展。我们还将研究冲击伤是否会在内侧前额叶皮质、杏仁核和海马区引起结构性影响，这些是被认为是创伤后应激障碍神经生物学基础的主要解剖底物。这些研究将进一步了解冲击伤与创伤后应激障碍相关特征的关系，并将对设计具有指导意义 遭受爆炸性MTBI的退伍军人的治疗策略。