Abstract
Impairments in mood and cognitive function are the key brain abnormalities observed in Gulf war illness (GWI), a chronic multisymptom health problem afflicting ∼25% of veterans who served in the Persian Gulf War-1. Although the precise cause of GWI is still unknown, combined exposure to a nerve gas prophylaxis drug pyridostigmine bromide (PB) and pesticides DEET and permethrin during the war has been proposed as one of the foremost causes of GWI. We investigated the effect of 4 weeks of exposure to Gulf war illness-related (GWIR) chemicals in the absence or presence of mild stress on mood and cognitive function, dentate gyrus neurogenesis, and neurons, microglia, and astrocytes in the hippocampus. Combined exposure to low doses of GWIR chemicals PB, DEET, and permethrin induced depressive- and anxiety-like behavior and spatial learning and memory dysfunction. Application of mild stress in the period of exposure to chemicals exacerbated the extent of mood and cognitive dysfunction. Furthermore, these behavioral impairments were associated with reduced hippocampal volume and multiple cellular alterations such as chronic reductions in neural stem cell activity and neurogenesis, partial loss of principal neurons, and mild inflammation comprising sporadic occurrence of activated microglia and significant hypertrophy of astrocytes. The results show the first evidence of an association between mood and cognitive dysfunction and hippocampal pathology epitomized by decreased neurogenesis, partial loss of principal neurons, and mild inflammation in a model of GWI. Hence, treatment strategies that are efficacious for enhancing neurogenesis and suppressing inflammation may be helpful for alleviation of mood and cognitive dysfunction observed in GWI.
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Acknowledgements
This study was supported primarily by a grant for ‘Gulf War Illness Research’ from the Department of Veterans Affairs (Merit Review Award to AKS) and partly by a grant from the Texas A&M Health Science Center (Emerging Technology Funds to AKS).
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VKP, BH, and AKS contributed equally to this work. VKP performed chemical and stress exposures to animals, behavioral experiments, immunohistochemistry, stereological cell counts, collection, analyses, and interpretation of data and prepared an initial rough draft of the manuscript text. BH gave input to behavioral experiments, performed immunohistochemistry, stereological cell counts, confocal microscopy, and contributed to collection, analyses, and interpretation of behavioral data and assembly of figures. BS performed chemical and stress exposures to animals, tissue processing, histology, immunohistochemistry, and contributed to behavioral experiments and collection of data. AKS conceived the study, conceptualized the experimental design, analyzed, interpreted and assembled data, prepared all figures and wrote the manuscript. All authors gave input to the manuscript text and approved the final version of the manuscript.
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Parihar, V., Hattiangady, B., Shuai, B. et al. Mood and Memory Deficits in a Model of Gulf War Illness Are Linked with Reduced Neurogenesis, Partial Neuron Loss, and Mild Inflammation in the Hippocampus. Neuropsychopharmacol 38, 2348–2362 (2013). https://doi.org/10.1038/npp.2013.158
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DOI: https://doi.org/10.1038/npp.2013.158
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