Psychological deficits after low level blast exposure: role of neurovascular disruption

许多退伍军人在正常的训练行动中经历了职业暴露于低水平爆炸（LLB）， 包括但不限于破坏活动。这些退伍军人坚持的风险增加 神经心理学损伤，由于在有限的时间内多次部署重复LLB暴露， 暴露之间的恢复。累积LLB暴露后的长期后果程度是 未知的，虽然报告显示赤字可以在生命的后期出现。此外，创伤后 与应激障碍（PTSD）相关的行为缺陷在有创伤史的士兵和退伍军人中更为明显。 长期暴露在爆炸中目前尚不清楚是哪些病理机制驱动了这种慢性 LLB暴露后的PTSD表型。已经建立了一些动物模型来解决这个不完整的问题。 了解LLB暴露的病理生物学机制。这些模型复制了 在退伍军人中观察到的慢性抑郁，焦虑和PTSD相关特征，尽管有许多 在造成这些长期缺陷的原因方面存在知识差距。一般来说，爆炸会导致急性血液- 脑屏障（BBB）和神经血管单位异常，可持续一段时间。本报告的总体目标 应用是确定LLB后急性神经血管功能障碍的时间以及如何重复LLB 导致慢性神经血管损伤和神经心理缺陷。我们的核心假设是， 在第一次LLB之后，以最大BBB损伤的时间间隔重复LLB将导致持续的PTSD- 比如行为特征此外，这些缺陷将与血清来源的抗体谱的变化有关。 外泌体miRNA和血小板生物能量学。这些假设是根据目前的文献制定的 以及我们自己发表的初步数据表明爆炸后焦虑和杏仁核血脑屏障破坏 exposure.通过利用肯塔基州大学的多模式爆炸模拟器，这些研究将能够 检查纵向行为概况，加上病理相关的生物标志物。这些假设 将在三个特定目标中进行测试：1）检查单次LLB暴露后的急性神经血管缺陷， 确定它们与纵向行为特征的关系，2）确定如何在不同时间重复LLB 根据急性神经血管特征， 行为特征和慢性神经血管损伤，3）确定是否调节急性或慢性 使用西地那非的神经血管健康将减轻长期PTSD样行为特征。这项研究将 极大地提高了我们对LLB影响的理解，并有可能发现新的临床- 相关生物标志物。这项研究具有重要意义，因为它将建立一个平台， 职业爆炸暴露的慢性影响，影响许多退伍军人。此外，这条线 研究可以导致更好的神经血管功能障碍的治疗靶向，以改善神经功能 结果是老退伍军人。除了通过本提案获得的研究成果外，申请人还将 从具有各种临床前、转化和临床观点的指导团队中受益匪浅， 这将有助于制定全面的职业发展计划。培训计划将增加额外的 技术哈伯德博士的剧目，不仅有助于这一建议，但他的退伍军人管理局的研究计划 继续前进。有了爆炸伤建模的先验知识，额外的行为和生物标志物测定将 大大提高了他的研究能力。在这一建议的后几年，哈伯德博士将继续扩大 资助写作，学生辅导，合作研究和独立所需的演讲技巧 研究人员总的来说，拟议的研究和多样化的指导计划将最终产生一个高度 成功的独立研究员。

Many Veterans experience occupational exposure to low-level blast (LLB) during normal training operations, including but not limited to breaching activity. These Veterans are at increased risk for persisting neuropsychological impairment due to repeated LLB exposure over several deployments with limited time for recovery between exposures. The extent of the long-term consequences after cumulative LLB exposure is unknown, though reports show that deficits can be present late in life. Furthermore, the resultant post-traumatic stress disorder (PTSD)-related behavioral deficits are more pronounced in soldiers and Veterans with a history of chronic blast exposure. There is no clear understanding of which pathological mechanisms drive this chronic PTSD phenotype after LLB exposure. A few animal models have been established to address this incomplete understanding of the pathobiological mechanisms underlying LLB exposure. These models replicate the chronic depressive, anxiogenic, and PTSD-related traits observed in Veterans, though there are many knowledge gaps in what contributes to these chronic deficits. In general, blast exposure causes acute blood- brain barrier (BBB) and neurovascular unit abnormalities that can persist over time. The overall objective of this application is to determine the timing of acute neurovascular dysfunction after LLB and how repeating LLB contributes to chronic neurovascular impairment and neuropsychological deficits. Our central hypothesis is that LLB repeated at a time interval of maximal BBB impairment, after the first LLB, will result in persistent PTSD- like behavioral traits. Additionally, these deficits will be associated with changes in the profile of serum-derived exosomal miRNAs and platelet bioenergetics. These hypotheses were formulated based on current literature and our own published and preliminary data demonstrating anxiety and amygdalar BBB disruption after blast exposure. By utilizing a multimodal blast simulator at the University of Kentucky, these studies will be able to examine the longitudinal behavioral profile, coupled with pathologically relevant biomarkers. These hypotheses will be tested in three specific aims: 1) examine acute neurovascular deficits after a single LLB exposure and determine their relationship to longitudinal behavioral traits, 2) determine how repeating LLB at various time intervals, based on the acute neurovascular profile, contributes to exacerbated or prolonged PTSD-like behavioral traits and chronic neurovascular impairment, 3) identify if modulating either acute or chronic neurovascular health using sildenafil will mitigate long-term PTSD-like behavioral traits. This research will drastically improve our understanding of the effects of LLB as well as potentially identify novel, clinically- relevant biomarkers. The proposed research is significant because it will establish a platform to understand the chronic effects of occupational blast exposure, which affects many Veterans. In addition, this line of investigation can lead to better therapeutic targeting of neurovascular dysfunction to improve neurological outcome in aging Veterans. In addition to the research products gained by this proposal, the applicant will greatly benefit from a mentoring team that has a variety of preclinical, translational, and clinical perspectives, which will contribute to a well-rounded career development plan. The training program will add additional techniques to Dr. Hubbard’s’ repertoire, contributing not only to this proposal but to his VA research program moving forward. With prior knowledge in blast injury modeling, additional behavioral and biomarker assays will greatly advance his research expertise. In the latter years of this proposal, Dr. Hubbard will continue to expand grant writing, student mentoring, collaborative research and presentation skills required of independent researchers. Overall, the proposed studies and diverse mentoring program will culminate in producing a highly successful independent VA researcher.