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: 9261394
• 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 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261394
• 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; Pharmacology; Plasma; Post-Traumatic Stress Disorders; Prefrontal Cortex; Protocols documentation; Rattus; Reaction; Research Personnel; Stress; Structure; Symptoms; System; Testing; Time; Veterans; War; behavioral response; biological adaptation to stress; conditioned fear; glucocorticoid receptor alpha; hypothalamic-pituitary-adrenal axis; mild traumatic brain injury; new therapeutic target; operation; prevent; psychological stressor; psychological trauma; public health relevance; response; stressor; therapy design; 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）： 轻度创伤性脑损伤（mTBI）是伊拉克和阿富汗战争中发病的主要原因。在这两个手术区，爆炸暴露一直是 TBI 的最常见原因。患有 mTBI 的 OIF/OEF 退伍军人临床表现的一个显着特征是创伤后应激障碍 (PTSD) 的突出表现。事实上，在患有 mTBI 的 OIF/OEF 退伍军人中，PTSD 和抑郁症的患病率很高，这是有据可查的，而且这两种疾病之间的区别已被证明在临床上具有挑战性。 PTSD 和 mTBI 之间的关联可能是通过同时暴露于 TBI 事件和 PTSD 压力源来解释的。然而，我们一直在探索的另一种假设是，与爆炸相关的 mTBI 会损害大脑结构，而这些结构对于调节心理压力源的反应非常重要，从而增加了患 PTSD 的可能性。 我们与国防部调查员 Stephen Ahlers 博士合作，研究了模拟 mTBI 的大鼠爆炸损伤模型。我们发现，在暴露后几个月进行测试的动物表现出与创伤后应激障碍相关的特征，包括听觉惊吓增加、焦虑增加、对捕食者气味挑战的反应改变以及恐惧调节范式中的提示反应增加。这些观察结果表明，在没有任何心理创伤的情况下，爆炸暴露会诱发慢性且持续的 PTSD 相关特征。阿勒斯博士发现，爆炸暴露后血浆皮质酮水平升高，并且这些水平在至少一个月内保持较高水平。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/肾上腺轴的异常长期存在。 这些观察结果使我们推测，大脑的爆炸损伤会导致慢性压力状态，即使在没有压力的情况下， 任何心理创伤都会产生与 PTSD 相关的特征，并对随后的 PTSD 相关压力源产生过度反应。在这里，我们将检查大脑中的应激反应是否会因暴露于爆炸损伤而长期改变，并确定糖皮质激素受体拮抗剂治疗是否能够阻止或逆转 PTSD 相关行为特征的发展。我们还将研究爆炸损伤是否会引起内侧前额叶皮层、杏仁核和海马体的结构效应，这些主要的解剖基质被认为是 PTSD 的神经生物学基础。这些研究将进一步了解爆炸伤与 PTSD 相关特征的关系，并对设计具有重要意义。 遭受爆炸引起的 mTBIs 的退伍军人的治疗策略。