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.

海湾战争病（​​GWI）仍然是一些沙漠行动中挥之不去的病症 1990-1991 年部署到波斯湾的盾牌/风暴 (ODS) 退伍军人。最近的报告 这表明那些仍然出现症状的人的大脑会发生永久性的变化。沙林暴露 来自 Khamisiyah 的“神经毒气云”被认为是病因，但 GWI 症状 部署到据信不在云层之下的地区的人员都经历过这种情况。 神经炎症可能导致急性 GWI 症状，并最终导致长期症状 由于白质轨迹的结构变化而导致的认知问题。然而，沙林 暴露可能不是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 加上细菌感染足以引起持续的神经炎症，最终 导致神经解剖学的结构变化，表现为白质轨迹减少。这 I 型拟除虫菊酯氯菊酯 (PERM) 是已发行的喷雾剂、霜剂和药物中的活性成分 人类除蚤项圈；反复接触 PERM 会导致啮齿类动物出现神经炎症。 反复接触神经毒气预防剂溴化吡斯的明 (PB) 可诱发急性 啮齿动物神经炎症的迹象。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）是细胞的一部分 革兰氏阴性菌的膜会引起急性外周炎症，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模型 结合 PERM/PB/LPS 暴露，展示功能（行为）和结构 啮齿动物大脑的（组织学）改变。我们的工作假设是时间 PERM、PB、LPS在较短的时间内（一个月）融合会导致 小鼠在暴露期后出现持续性神经炎症。这将导致行为 与认知功能相关的任务缺陷（挥之不去的 GWI 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/动机和步态/平衡。与这些实验同时进行的，暴露小鼠的大脑 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这些认知和行为 流程；人类 GWI 脑部扫描研究表明存在异常；或之前 啮齿动物毒理学研究表明，单独使用 PERM、PB 或 LPS 会对其产生影响。 这个为期 2 年的试点计划将为探索 非沙林源可能诱发神经炎症和 GWI 症状。这 将有助于实现了解这些风险如何影响的长期目标 大脑长期（老化），识别增加或增加的个人脆弱性 降低对这些暴露的敏感性（使用基因操纵的小鼠），并且，大多数 重要的是，制定治疗任何已发现的神经退行性疾病的策略 这些多重化学/生物暴露。