Neuroinflammation and abnormal behavior following combined chemical exposures and bacterial infection

化学品暴露和细菌感染联合后的神经炎症和异常行为

• 批准号: 9351123
• 负责人: Kevin D. Beck
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351123
• 关键词: Acute; Address; Affect; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arthralgia; Axon; Bacterial Infections; Behavior; Behavior assessment; Behavioral; Biological; Brain; Brain scan; Bromides; C57BL/6 Mouse; Cell membrane; Chemical Exposure; Chemicals; Chronic; Chronic Disease; Cities; Clinical; Cognitive; Cream; Data; Dermal; Equilibrium; Event; Exhibits; Exposure to; Fatigue; Fleas; Foundations; Gait; Gated Ion Channel; Geography; Glucocorticoids; Goals; Gram-Negative Bacteria; Gulf War; Hippocampus (Brain); Histologic; Human; Human Resources; Hypothalamic structure; Immunologics; Impaired cognition; Incidence; Individual; Infection; Inflammation; Inflammatory; Insecticides; Interleukin-1 beta; Internal Capsule; Investigation; Ion Channel Gating; Knowledge; Lead; Learning; Lipopolysaccharides; Measures; Medical; Memory; Microglia; Modeling; Motivation; Mus; Myalgia; Myelin; Nerve Degeneration; Neuroanatomy; Neurons; Oral; Organophosphates; Patients; Peripheral; Permethrin; Persian Gulf; Pilot Projects; Predisposition; Process; Reporting; Resistance; Rodent; Rodent Model; Sarin; Sea; Services; Silicon Dioxide; Sleep disturbances; Sodium; Source; Stress; Structure; Symptoms; Time; Toxicology; Veterans; Work; astrogliosis; behavioral economics; brain behavior; brain dysfunction; cognitive function; cognitive testing; cytokine; design; experience; experimental study; flexibility; glial activation; imaging study; nerve gas; neuroinflammation; neuropathology; persistent symptom; programs; prophylactic; pyrethroid; pyridostigmine; relating to nervous system; response; social; stem; symptom cluster; theories; toxic organophosphate insecticide exposure; white matter; white matter damage

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.

海湾战争疾病（GWI）仍然是一些沙漠行动的挥之不去的条件 1990-1991年部署到波斯湾的盾牌/风暴（ODS）老兵。最近的报告 表明那些仍在经历症状的人的大脑会发生永久性变化。沙林毒气暴露 从哈米西亚“神经毒气云”已被牵连的原因，但GWI症状 部署到据信不在这片乌云之下的地区的人员经历了这种情况。 神经炎症可能会导致急性GWI症状，最终， 由于白色物质轨迹的结构变化而导致的认知问题。然而，沙林毒气 暴露可能不是这种神经炎症的唯一原因。 我们假设反复暴露于人员发放的化学品 沿着细菌感染足以导致持续的神经炎症，最终 导致神经解剖学的结构变化，其形式为减少的白色物质轨迹。的 I型拟除虫菊酯氯菊酯（PERM）是发布的喷雾剂，霜剂， 人类跳蚤项圈;反复暴露于PERM导致啮齿动物神经炎症。 反复暴露于预防性神经毒气的溴化吡啶斯的明（PB）诱导急性 啮齿类动物神经炎症的迹象。细菌感染是部队面临的一个重要问题 无论是在地面上，以及在公海上;脂多糖（LPS）是细胞的一部分， 革兰氏阴性菌膜，导致急性外周炎症，但它也可以 引起神经炎症。因此，该试点项目的目标是建立一个 组合PERM/PB/LPS暴露，证明功能（行为）和结构 （组织学）啮齿动物大脑的变化。我们的假设是 PERM、PB和LPS在相对较短的时间内（一个月）汇合， 在小鼠中暴露期后持续神经炎症。这将导致行为 与认知功能相关的任务缺陷（GWI延迟的主要症状）。一 一组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/动力和步态/平衡。在这些实验的同时， 将分析神经炎症的细胞体征和白色物质轨道完整性。这些 分析将主要集中在海马体、下丘脑和白色内囊 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脑扫描研究中推断为异常;或先前 在啮齿类动物毒理学研究中，证明仅受PERM、PB或LPS影响。 这个为期2年的试点计划将提供所需的知识基础，探索 非沙林来源可能会诱发神经炎症和GWI症状。这 将有助于实现长期目标，了解这些暴露如何影响 大脑在很长一段时间（老化），识别个人的脆弱性，增加或 降低对这些暴露的敏感性（使用基因操纵的小鼠）， 重要的是，开发治疗任何确定的神经变性的策略， 这些多重化学/生物暴露