Neuroinflammation and abnormal behavior following combined chemical exposures and bacterial infection

海湾战争疾病(GWI)仍然是一些沙漠行动的挥之不去的疾病 1990-1991年，盾牌/风暴(Ods)老兵被部署到波斯湾。最近的报道 表明那些仍在经历症状的人的大脑发生了永久性的变化。沙林暴露 来自Khamisiyah的“神经毒气云”被认为是罪魁祸首，但GWI的症状 被部署到据信不在云下的地区的人员经历过。 神经炎可能会导致急性GWI症状，并最终导致长期的 由于白质轨迹的结构性变化而导致的认知问题。然而，沙林 暴露可能并不是导致这种神经炎症的唯一原因。 我们假设反复接触人员发放的化学用品组合 以及细菌感染足以导致持续性神经炎，最终 导致神经解剖学的结构变化，表现为白质轨迹减少。这个 I型拟除虫菊酯(PERM)是发放的喷雾剂、乳膏和 人类跳蚤项圈；反复接触烫发会导致啮齿类动物的神经炎症。 反复暴露于神经毒气预防性溴化吡斯的明(PB)导致急性 啮齿类动物出现神经炎症的迹象。细菌感染是部队面临的一个重大问题。 无论是在地面上，还是在公海上，脂多糖(LPS)都是细胞的一部分 引起急性外周炎症的革兰氏阴性细菌的膜，但它也可以 会引起神经炎。因此，这个试点项目的目标是建立一个 PERM/PB/LPS组合暴露，展示功能(行为)和结构 (组织学)啮齿动物大脑的变化。我们的工作假设是，一个时间 在相对较短的时间(一个月)内，PERM、PB和LPS的融合将导致 小鼠暴露后持续的神经炎症。这将导致行为 与认知功能相关的任务缺陷(GWI挥之不去的主要症状)。一个 一系列啮齿动物认知测试旨在辨别大脑功能的不同方面 暴露后：空间和非空间记忆、规则学习和灵活性， 疲劳性/动力和步态/平衡。在这些实验的同时，暴露于病毒的小鼠的大脑 将分析神经炎症的细胞迹象和白质轨迹的完整性。这些 分析将主要集中在海马体、下丘脑和内囊白色 物质轨迹。这些区域被证明参与了这些认知和行为 过程；从人类GWI脑扫描研究中暗示异常；或之前 在啮齿动物毒理学研究中证明了PERM、PB或LPS单独影响。 这项为期两年的试点计划将提供探索 非沙林来源可能导致神经炎症和GWI症状。这 将有助于实现了解这些暴露如何影响 长时间(老化)的大脑，识别增加或 降低对这些暴露的敏感性(使用基因操纵的小鼠)，而且，大多数 重要的是，开发治疗任何已发现的源于 这些化学/生物的多重暴露。

Gulf War Illness (GWI) continues to be a lingering condition for some Operation Desert Shield/Storm (ODS) veterans deployed to the Persian Gulf in 1990-1991. Recent reports suggest permanent changes in the brains of those still experiencing symptoms. Sarin exposure from the Khamisiyah “nerve-gas cloud” has been implicated as the cause, but GWI symptoms have been experienced by personnel deployed to areas, not believed to be under that cloud. Neuroinflammation could have caused acute GWI symptoms, and, eventually, long-term cognitive problems because of structural changes to the white matter tracks. Yet, sarin exposure may not have been the only cause of such neuroinflammation. We hypothesize that repeated exposure to a combination of personnel-issued chemical supplies along with bacterial infection is sufficient to cause persistent neuroinflammation, eventually leading to structural changes in neuroanatomy, in the form of reduced white matter tracks. The type I pyrethroid permethrin (PERM) was an active ingredient in the issued sprays, creams, and human flea collars; repeated exposure to PERM causes neuroinflammation in rodents. Repeated exposure to the nerve-gas prophylactic pyridostigmine bromide (PB) induces acute signs of neuroinflammation in rodents. Bacterial infection was a significant problem for troops both on the ground, as well as on the high seas; lipopolysaccharide (LPS) is part of the cell membrane of gram negative bacteria that causes acute peripheral inflammation, but it can also cause neuroinflammation. Thus, the goal of this pilot project is to establish a model of combined PERM/PB/LPS exposure, demonstrating functional (behavioral) and structural (histological) alterations in the rodent brain. Our working hypothesis is that a temporal confluence of PERM, PB, and LPS within a relatively short period of time (one month) will cause persistent neuroinflammation beyond the exposure period in mice. This will lead to behavioral deficits in tasks associated with cognitive functioning (a chief symptom of lingering GWI). A battery of rodent cognitive tests is designed to discern different aspects of brain functioning post-exposure: spatial and non-spatial memory, rule learning and flexibility, fatigability/motivation and gait/balance. In parallel to these experiments, brains of exposed mice will be analyzed for cellular signs of neuroinflammation and white matter track integrity. These analyses will primarily be focused in hippocampus, hypothalamus and the internal capsule white matter tracks. These are regions demonstrated to be involved in these cognitive and behavioral processes; implicated as abnormal from the human GWI brain scan studies; or previously demonstrated to be affected by PERM, PB, or LPS alone in the rodent toxicology studies. This 2-year pilot program will provide a foundation of knowledge needed to explore the possibility that non-sarin sources can induce neuroinflammation and symptoms of GWI. This will assist in achieving the long-term goals of understanding how those exposures affect the brain over long periods of time (aging), identifying individual vulnerabilities that increase or decrease susceptibility to these exposures (using genetically manipulated mice), and, most importantly, developing strategies for treating any identified neurodegeneration stemming from these multiple chemical/biological exposures.