Neuroinflammation and abnormal behavior following combined chemical exposures and bacterial infection

Va New Jersey Health Care System, East Orange NJ

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Abstract

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.