title: A Chronic Longitudinal Characterization of Neurobehavioral and Neuropathological Cognitive Impairment in a Mouse Model of Gulf War Agent Exposure.
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 (OFT), Elevated Plus Maze (EPM), Three Chamber Testing, Radial Arm Water Maze (RAWM), and Barnes Maze (BM) 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.
authors.affiliation: The Roskamp InstituteSarasota, FL, USA; Life, Health and Chemical Sciences, The Open UniversityWalton Hall, Milton Keynes, UK; James A. Haley Veteran's HospitalTampa, FL, USA.
authors.forename: Zuchra
authors.initials: Z
authors.lastname: Zakirova
authors.affiliation: The Roskamp InstituteSarasota, FL, USA; Life, Health and Chemical Sciences, The Open UniversityWalton Hall, Milton Keynes, UK.
authors.forename: Gogce
authors.initials: G
authors.lastname: Crynen
authors.affiliation: The Roskamp Institute Sarasota, FL, USA.
authors.forename: Samira
authors.initials: S
authors.lastname: Hassan
authors.affiliation: The Roskamp InstituteSarasota, FL, USA; Life, Health and Chemical Sciences, The Open UniversityWalton Hall, Milton Keynes, UK; James A. Haley Veteran's HospitalTampa, FL, USA.
authors.forename: Laila
authors.initials: L
authors.lastname: Abdullah
authors.affiliation: The Roskamp Institute Sarasota, FL, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Horne
authors.affiliation: The Roskamp InstituteSarasota, FL, USA; Life, Health and Chemical Sciences, The Open UniversityWalton Hall, Milton Keynes, UK.
authors.forename: Venkatarajan
authors.initials: V
authors.lastname: Mathura
authors.affiliation: The Roskamp InstituteSarasota, FL, USA; Life, Health and Chemical Sciences, The Open UniversityWalton Hall, Milton Keynes, UK; James A. Haley Veteran's HospitalTampa, FL, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
authors.affiliation: The Roskamp InstituteSarasota, FL, USA; Life, Health and Chemical Sciences, The Open UniversityWalton Hall, Milton Keynes, UK; James A. Haley Veteran's HospitalTampa, FL, USA.
authors.forename: Ghania
authors.initials: G
authors.lastname: Ait-Ghezala
keywords: Gulf War; mouse model; neurobehavior; neuropathology; permethrin (PER); pyridostigmine bromide (PB)