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）： 轻度创伤性脑损伤（MTBI）一直是伊拉克和阿富汗战争中发病率的主要原因。在两个运营剧院中，爆炸暴露一直是TBI的最常见原因。 MTBI的OIF/OEF退伍军人的临床表现的一个显着特征是创伤后应激障碍（PTSD）的突出。实际上，返回具有MTBI的OIF/OEF退伍军人的PTSD和抑郁症的高流行率已得到充分证明，两种疾病之间的区别已证明在临床上具有挑战性。 PTSD和MTBI之间的关联可以通过对TBI事件和PTSD压力源的共同暴露来解释。但是，我们一直在探索的另一种假设是，与爆炸相关的MTBI损害了在介导对心理压力源反应的脑结构，从而增强了开发PTSD的可能性。 在与国防部调查员斯蒂芬·艾尔斯（Stephen Ahlers）博士合作的情况下，我们一直在研究模仿MTBI的大鼠爆炸损伤模型。我们发现，在暴露后几个月测试的动物表现出与PTSD相关的特征，包括增加声音惊吓，增加焦虑，对捕食者气味挑战的反应改变以及恐惧条件范式中提示的反应增加。这些观察结果表明，在没有任何心理创伤的情况下，爆炸暴露会引起慢性和持久性PTSD相关的特征。 Ahlers博士发现，血浆皮质酮水平在爆炸暴露后升高，并且这些水平至少一个月保持较高。普遍认为PTSD是由于异常和延长的应力反应引起的，有大量证据表明下丘脑/垂体/肾上腺轴的异常是长期存在的。 这些观察结果使我们假设大脑的爆炸损伤会引起慢性压力状态，即使在不存在的情况下 在任何心理创伤中，都会产生与PTSD相关的性状，并对随后的PTSD相关压力源的反应夸大。在这里，我们将检查大脑中的压力反应是否会因暴露于爆炸损伤而长期改变，并确定用糖皮质激素受体拮抗剂治疗是否能够阻止与PTSD相关的行为性状的发展或反向。我们还将检查爆炸损伤在内侧前额叶皮层，杏仁核和海马中是否引起结构效应，杏仁核和海马是主要的解剖基质，被认为是PTSD神经生物学基础的基础。这些研究将进一步了解爆炸损伤与PTSD相关特征的关系，并将对设计产生影响 遭受爆炸引起的MTBI的退伍军人的治疗策略。