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Abstract
Gulf War Illness (GWI), a chronic, multisymptom disease including neurological and immune system deficits, affects a third of the military personnel deployed during the 1990-1991 Gulf War. In-theater overexposures to neurotoxicants, such as pesticides, prophylactic pyridostigmine bromide (PB) pills, and in some veterans, chemical nerve agents are implicated in GWI pathogenesis. Unfortunately, GWI therapeutics are limited and manage individual or a few symptoms. As GWI veterans age, a rise in symptom severity and risk of age-related co-morbidities are of concern. Thus, understanding the progressive pathobiology of GWI and developing efficacious treatments is imperative. This dissertation sought to investigate GWI-specific progressive neurological and pathological effects within two, chemically distinct rodent models of the disease and evaluate the efficacy of the immunotherapeutic, Lacto-N-fucopentaose III (LNFPIII). The GWI models utilized herein included the 1) PB + the pyrethroid insecticide permethrin (10 days; PB/PM model), and 2) PB + the insect repellent DEET + stress (corticosterone) + the nerve agent surrogate, diisopropylfluorophosphate (DFP) (15 days; PB/DEET/CORT/DFP model). Acutely, both models produced widespread brain monoaminergic disbalance and hippocampal neuroinflammation with these effects more pronounced in the PB/PM and PB/DEET/CORT/DFP model, respectively. LNFPIII co-administration restored this acute neurochemical dyshomeostasis and neuroinflammation. Long-term investigations with these models (6-10 months post GWI exposures) produced deficits in motor, mood, and cognitive functions, hippocampal neuroinflammation, and hippocampal synaptic plasticity. Delayed LNFPIII treatment (4-6 months post GWI exposure) ameliorated behavioral abnormalities (e.g. motor and cognitive function), alleviated hippocampal neuroinflammation, and enhanced hippocampal synaptic plasticity. Additionally, PB/PM exposure induced acute and lasting changes in the gut microbiota and inflammation; these effects were improved by LNFPIII. Further, structural brain alterations were characterized longitudinally (12 months) in both models. Both models led to enlarged ventricles and reductions in global brain and hippocampal volumes. However, model-specific alterations included reductions in cortical and brainstem volumes in the PB/PM and PB/DEET/CORT/DFP model, respectively. Collectively, these findings addressed substantial knowledge gaps in GWI preclinical research by characterizing the complex pathology and behavioral phenotypes produced by two, chemically distinct preclinical GWI models at varying stages of life and emphasized the potential for LNFPIII as a promising therapeutic for GWI pathology.