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）仍然是某些沙漠行动的挥之不去的状况 盾牌/风暴（ODS）退伍军人于1990 - 1991年在波斯湾部署。最近的报告 建议在仍有症状的人的大脑中永久变化。沙林暴露 从Khamisiyah的“神经气候云”被实施为原因，但GWI符号 已被部署到地区的人员经历，不认为在那云之下。 神经炎症可能导致急性GWI符号，并最终长期 认知问题是因为对白质轨道的结构变化。但是，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造化学物质的组合 与细菌感染一起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，以减少的白质轨迹的形式。这 I型拟甲虫素苄氯菊酯（PERM）是发放喷雾剂，面霜和 人跳蚤项圈；反复暴露于PERS会导致啮齿动物的神经炎症。 反复暴露于预防性吡啶基溴溴（PB）会诱发急性 啮齿动物中神经炎症的迹象。细菌感染是部队的重大问题 既在地面上，又在海洋上；脂多糖（LPS）是细胞的一部分 革兰氏阴性细菌的膜，导致急性周围炎症，但也可以 引起神经炎症。那个试点项目的目的是建立一个模型 合并的PERM/PB/LPS暴露，证明功能（行为）和结构 （组织学）啮齿动物大脑的改变。我们的工作假设是暂时的 在相对较短的时间内（一个月）内，PERM，PB和LP的汇合将导致 小鼠暴露期之后的持续性神经炎症。这将导致行为 与认知功能相关的任务缺陷（GWI挥之不去的主要症状）。 啮齿动物认知测试的电池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/动机和收集/平衡。与这些实验并行，暴露的小鼠的大脑 将分析神经炎症和白质轨道完整性的细胞迹象。这些 分析将主要集中在海马，下丘脑和内囊白色 物质轨道。这些是证明与这些认知和行为有关的区域 过程；与人类GWI脑扫描研究相关的异常；或以前 在啮齿动物毒理学研究中，仅受Perm，PB或LP的影响。 这个为期两年的试点计划将为探索所需的知识提供基础 非撒林源可以诱导神经炎症和GWI符号的可能性。这 将有助于实现理解这些暴露如何影响这些暴露的长期目标 长时间的大脑（衰老），确定增加或增加的个体漏洞 降低对这些暴露的敏感性（使用一般操纵的小鼠），并且大多数 重要的是，制定了治疗任何鉴定出的神经变性的策略 这些多重化学/生物学暴露。