Carpenter Jessica M, Hughes Sarah N, Filipov Nikolay M
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, United States.
Front Neurosci. 2024 Sep 6;18:1465701. doi: 10.3389/fnins.2024.1465701. eCollection 2024.
Gulf War Illness (GWI) affects nearly 30% of veterans from the 1990-1991 Gulf War (GW) and is a multi-symptom illness with many neurological effects attributed to in-theater wartime chemical overexposures. Brain-focused studies have revealed persistent structural and functional alterations in veterans with GWI, including reduced volumes, connectivity, and signaling that correlate with poor cognitive and motor performance. GWI symptomology components have been recapitulated in rodent models as behavioral, neurochemical, and neuroinflammatory aberrations. However, preclinical structural imaging studies remain limited. This study aimed to characterize the progression of brain structural alterations over the course of 12 months in two established preclinical models of GWI. In the PB/PM model, male C57BL/6 J mice (8-9 weeks) received daily exposure to the nerve agent prophylactic pyridostigmine bromide (PB) and the pyrethroid insecticide permethrin (PM) for 10 days. In the PB/DEET/CORT/DFP model, mice received daily exposure to PB and the insect repellent DEET (days 1-14) and corticosterone (CORT; days 7-14). On day 15, mice received a single injection of the sarin surrogate diisopropylfluorophosphate (DFP). Using a Varian 7 T Bore MRI System, structural (sagittal T2-weighted) scans were performed at 6-, 9-, and 12-months post GWI exposures. Regions of interest, including total brain, ventricles, cortex, hippocampus, cerebellum, and brainstem were delineated in the open source Aedes Toolbox in MATLAB, followed by brain volumetric and cortical thickness analyses in ImageJ. Limited behavioral testing 1 month after the last MRI was also performed. The results of this study compare similarities and distinctions between these exposure paradigms and aid in the understanding of GWI pathogenesis. Major similarities among the models include relative ventricular enlargement and reductions in hippocampal volumes with age. Key differences in the PB/DEET/CORT/DFP model included reduced brainstem volumes and an early and persistent loss of total brain volume, while the PB/PM model produced reductions in cortical thickness with age. Behaviorally, at 13 months, motor function was largely preserved in both models. However, the GWI mice in the PB/DEET/CORT/DFP model exhibited an elevation in anxiety-like behavior.
海湾战争综合症（GWI）影响了近30%的1990 - 1991年海湾战争（GW）退伍军人，这是一种多症状疾病，许多神经方面的影响归因于战区战时化学物质过度暴露。针对大脑的研究发现，患有GWI的退伍军人存在持续的结构和功能改变，包括体积减小、连接性降低以及信号传导异常，这些与认知和运动表现不佳相关。GWI的症状学组成部分在啮齿动物模型中表现为行为、神经化学和神经炎症异常。然而，临床前结构成像研究仍然有限。本研究旨在描述在两种已建立的GWI临床前模型中，大脑结构改变在12个月内的进展情况。在PB/PM模型中，8 - 9周龄的雄性C57BL/6J小鼠每天接受神经毒剂预防性溴化吡啶斯的明（PB）和拟除虫菊酯杀虫剂氯菊酯（PM）暴露，持续10天。在PB/DEET/CORT/DFP模型中，小鼠每天接受PB以及驱虫剂避蚊胺（第1 - 14天）和皮质酮（CORT；第7 - 14天）暴露。在第15天，小鼠接受一次沙林替代物二异丙基氟磷酸酯（DFP）注射。使用瓦里安7T孔径MRI系统，在GWI暴露后6个月、9个月和12个月进行结构（矢状面T2加权）扫描。在MATLAB中的开源伊蚊工具箱中勾勒出感兴趣区域，包括全脑、脑室、皮质、海马体、小脑和脑干，随后在ImageJ中进行脑体积和皮质厚度分析。在最后一次MRI检查1个月后还进行了有限的行为测试。本研究结果比较了这些暴露模式之间的异同，有助于理解GWI的发病机制。模型之间的主要相似之处包括随着年龄增长相对脑室扩大和海马体体积减小。PB/DEET/CORT/DFP模型的关键差异包括脑干体积减小以及全脑体积早期且持续的减少，而PB/PM模型随着年龄增长皮质厚度减小。行为学上，在13个月时，两种模型中的运动功能在很大程度上得以保留。然而，PB/DEET/CORT/DFP模型中的GWI小鼠表现出焦虑样行为增加。
