Of the 700,000 military personnel deployed to the 1990-1991 Gulf War, 26%-32% developed chronic health problems that are ill-defined and in which it is difficult to pinpoint the etiologicl agents. The health problems include chronic fatigue, muscle and joint pains, gastrointestinal problems, sleep disturbances, mood disorders, persistent headaches, and attention and memory problems. Collectively, these multi-symptom health problems are called Gulf War illness. Twenty plus years after the Gulf War, many of the symptoms have not been resolved in Gulf War Veterans, and there is still not a reliable set of diagnostic criteria or effective treatments for Gulf War illness. Therefore, there is an urgent need for a better understanding of the stubborn nature of the illness and identify better approaches to improve the health of Gulf War Veterans. The etiology of the Gulf War illness is not known, but likely involves various chemicals and physical and psychological stresses unique to the Gulf War Theater. Several lines of clinical findings support defects in the hippocampus, the brain region that controls learning and memory, in Gulf War illness, and the defects include smaller hippocampal volume and hypometabolism, defects in working memory, and chronic hippocampal perfusion dysfunction. Increasing evidence suggests that neurological defects in Gulf War illness can be explained in part by exposure to acetylcholinesterase (AChE) inhibitors, including pyridostigmine bromide (PB), pesticides (permethrin), and nerve agents. A number of animal models have been established to simulate exposures to Gulf War chemicals and stress, and neurocognitive defects in these models again suggest the involvement of hippocampus. However, the cellular and molecular mechanism(s) underlying hippocampal defects is not entirely clear. Based on the biological properties of Gulf War agents, the known effects of stress hormones, and data from experimental animals exposed to GW agents, chronic inflammation and elevated levels of oxidative stress are likely to be intimately involved in Gulf War illness. We propose that chronic inflammation and increased oxidative stress play an important role in the persistent nature of Gulf War illness. Therefore, the goal of this applicatio is to carry out a pilot study to ascertain the delayed and persistent effects of various Gulf War agents on hippocampal functions and the involvement of neuroinflammation and oxidative stress We will use wild type mice and mice with higher levels of the antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), as the model system and expose the mice repeatedly to various Gulf War agents alone or in combination to simulate the condition during the Gulf War. The level of inflammatory cytokines and glucocorticoid hormone will be monitored to ascertain the level of acute and chronic inflammation and stress. Cognitive functions, together with pain sensitivity, anxiety, and motor functions, will be determined at various intervals following exposure to Gulf War agents. To identify cognitive defects at the tissue and cellular level, we will examine the dendritic system, which forms the infrastructure for neurotransmission during acquisition and formation of memory, in the hippocampal formation. Dendritic arbors, spine density and morphology, post-synaptic proteins, and the biochemical pathway important for the maintenance of the dendritic system will be investigated. Image analyses and immunological and molecular biological detection methods will be used to identify the structural, cellular, and biochemical changes in the synaptic system and how those changes may impact synaptic and cognitive functions.

Public Health Relevance

More than 25% of Veterans from the 1990-1991 Gulf War suffer from a multitude of ill-defined symptoms that are more prevalent and appear to be unique to the Gulf War Veterans. The multiple chronic symptoms afflicting the Gulf War Veterans include chronic fatigue, sleep disturbance, depression, joint and muscle pain, anxiety, and memory problems. As these symptoms persist 20 years later, the pathogenesis of Gulf War illness is still poorly understood. Exposure to nerve agents, such as sarin, remains a real threat in present day military conflicts, and exposure to environmental toxins with similar toxicity to that of nerve agents continue to exist. This proposal is designed to determine the delayed and persistent effects of Gulf War agents on the hippocampal functions to get a better handle on the pathogenic mechanism of memory defects in Gulf War illness. This proposal, therefore, is highly relevant to Veterans'health problems.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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Special Emphasis - Research on Gulf War Veterans' Illnesses (SPLD)
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Veterans Admin Palo Alto Health Care Sys
Palo Alto
United States
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Yang, Phillip; Leu, David; Ye, Keqiang et al. (2016) Cognitive impairments following cranial irradiation can be mitigated by treatment with a tropomyosin receptor kinase B agonist. Exp Neurol 279:178-186
Huang, Ting-Ting; Leu, David; Zou, Yani (2015) Oxidative stress and redox regulation on hippocampal-dependent cognitive functions. Arch Biochem Biophys 576:2-7