A Chronic Longitudinal Characterization of Neurobehavioral and Neuropathological Cognitive Impairment in a Mouse Model of Gulf War Agent Exposure
Open Access
- 12 January 2016
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Integrative Neuroscience
- Vol. 9, 71
- https://doi.org/10.3389/fnint.2015.00071
Abstract
Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component that includes memory impairment as well as neurological and musculoskeletal deficits. Previous studies have shown that in the First Persian Gulf War conflict (1990-1991) exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and permethrin (PER), were key contributors to the etiology of GWI. For this study, we used our previously established mouse model of GW agent exposure (10 days PB+PER) and undertook an extensive lifelong neurobehavioral characterization of the mice from 11 days to 22.5 months post exposure in order to address the persistence and chronicity of effects suffered by the current GWI patient population, 24 years post-exposure. Mice were evaluated using a battery of neurobehavioral testing paradigms, including Open Field Test, Elevated Plus Maze, Three Chamber Testing, Radial Arm Water Maze and Barnes Maze Test. We also carried out neuropathological analyses at 22.5 months post exposure to GW agents after the final behavioral testing. Our results demonstrate that PB+PER exposed mice exhibit neurobehavioral deficits beginning at the 13 months post exposure time point and continuing trends through the 22.5 month post exposure time point. Furthermore, neuropathological changes, including an increase in GFAP staining in the cerebral cortices of exposed mice, were noted 22.5 months post exposure. Thus, the persistent neuroinflammation evident in our model presents a platform with which to identify novel biological pathways, correlating with emergent outcomes that may be amenable to therapeutic targeting. Furthermore, in this work we confirmed our previous findings that GW agent exposure causes neuropathological changes, and have presented novel data which demonstrate increased disinhibition, and lack of social preference in PB+PER exposed mice at 13 months after exposure. We also extended upon our previous work to cover the lifespan of the laboratory mouse using a battery of neurobehavioral techniques.Keywords
This publication has 96 references indexed in Scilit:
- A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndromeBMC Immunology, 2013
- Altered immune pathway activity under exercise challenge in Gulf War Illness: An exploratory analysisBrain, Behavior, and Immunity, 2013
- Exploring the Diagnostic Potential of Immune Biomarker Coexpression in Gulf War IllnessMethods in molecular biology (Clifton, N.J.), 2012
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Hippocampal CA1 atrophy and synaptic loss during experimental autoimmune encephalomyelitis, EAELaboratory Investigation, 2010
- Differential effects and rates of normal aging in cerebellum and hippocampusProceedings of the National Academy of Sciences of the United States of America, 2010
- Gulf War illness: Effects of repeated stress and pyridostigmine treatment on blood–brain barrier permeability and cholinesterase activity in rat brainBehavioural Brain Research, 2009
- Repeated stress in combination with pyridostigmine: Part II: Changes in cerebral gene expressionBehavioural Brain Research, 2009
- From inflammation to sickness and depression: when the immune system subjugates the brainNature Reviews Neuroscience, 2008
- The use of the elevated plus maze as an assay of anxiety-related behavior in rodentsNature Protocols, 2007