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: 9016450
• 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/9016450
• 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; Health; 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; Rattus; Reaction; Research Personnel; Stress; Structure; Symptoms; System; Testing; Time; Veterans; War; base; behavioral response; biological adaptation to stress; conditioned fear; design; hypothalamic-pituitary-adrenal axis; mild traumatic brain injury; new therapeutic target; operation; prevent; psychological stressor; psychological trauma; 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）是伊拉克和阿富汗战争中发病的主要原因。在这两个战区，爆炸暴露是TBI最常见的原因。OIF/OEF退伍军人mTBI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，创伤后应激障碍和抑郁症的高患病率返回OIF/OEF退伍军人与mTBI是有据可查的，这两种疾病之间的区别已被证明具有临床挑战性。PTSD和mTBI之间的关联可能被解释为同时暴露于TBI事件和PTSD应激源。然而，我们一直在探索的另一种假设是，爆炸相关的mTBI损害大脑结构，这些结构在介导对心理压力源的反应中非常重要，从而增加了发展PTSD的可能性。 在与国防部研究员Stephen Ahlers博士的合作中，我们一直在研究模拟mTBI的大鼠爆炸伤模型。我们发现，暴露后几个月测试的动物表现出PTSD相关的特征，包括增加的声音惊吓，增加的焦虑，对捕食者气味挑战的反应改变，以及恐惧条件反射范式中的线索反应增加。这些观察结果表明，在没有任何心理创伤的情况下，爆炸暴露会诱导慢性和持久的PTSD相关特征。Ahlers博士发现，血浆皮质酮水平在爆炸暴露后升高，并且这些水平至少在一个月内保持高水平。PTSD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/肾上腺轴的异常是长期存在的。 这些观察结果使我们假设，大脑的爆炸伤会引起一种慢性应激状态，即使没有 任何心理创伤都会产生与PTSD相关的特征，并对随后的PTSD相关压力源产生夸大的反应。在这里，我们将检查是否在大脑中的应激反应是长期改变暴露于冲击伤，并确定是否与糖皮质激素受体拮抗剂治疗能够阻止或逆转PTSD相关的行为特征的发展。我们还将研究爆炸伤是否会引起内侧前额叶皮层、杏仁核和海马的结构效应，这些结构被认为是PTSD神经生物学基础的主要解剖学基础。这些研究将进一步了解冲击伤与PTSD相关特征的关系，并将对设计 治疗策略的退伍军人遭受冲击波诱导的mTBI。