Immune basis for hippocampal cholinergic deficits in pyridostigmine-treated rats

吡斯的明治疗大鼠海马胆碱能缺陷的免疫基础

• 批准号: 9890168
• 负责人: LAWRENCE P REAGAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890168
• 关键词: Acetylcholinesterase Inhibitors; Acute; Address; Affect; Animal Model; Behavior; Behavioral; Brain; Bromides; Cardiovascular Physiology; Cardiovascular system; Cholinesterases; Chronic; Diagnosis; Disease; Etiology; Exhibits; Exposure to; Functional disorder; Funding; Goals; Gulf War; Hippocampus (Brain); Immune; Immune response; Inflammatory; Lead; Life Experience; Lipopolysaccharides; Measures; Microdialysis; Microglia; Modeling; Nature; Neuraxis; Neurocognitive Deficit; Neuroimmune; Neurosecretory Systems; Performance; Plasma; Prefrontal Cortex; Quick Test for Liver Function; Rattus; Recording of previous events; Rodent Model; Stimulus; Stress; Structure; Symptoms; Telemetry; Testing; Therapeutic Intervention; Veterans; associated symptom; base; behavior measurement; behavior test; behavioral response; cholinergic; cytokine; experience; heart rate variability; in vivo; neurochemistry; neuroinflammation; novel; physiologic stressor; pressure; pyridostigmine; response; restraint stress; social stress; social stressor; stress reactivity

Following return from the Gulf War (GW), veterans have experienced of a constellation of symptoms, designated Gulf War Illness (GWI), that cannot be associated with a single disease. In this regard, GW veterans exhibit structural and functional deficits in the central nervous system (CNS), along with cardiovascular complications. One of the more insidious aspects of GWI is that it is a chronic and progressive disorder; indeed, the number of veterans diagnosed with GWI continues to rise in the post- deployment period. Although the mechanisms underlying the myriad of symptoms associated with GWI remain to be elucidated, some studies have determined that GWI veterans exhibit exaggerated immune responses to physiological stressors, which when combined with other studies support the concept that neuroinflammation is a key component in the etiology and progression of GWI. During the previous funding period we developed a rodent model of GWI in which rats were administered the acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB) alone and in combination with repeated restraint stress (RRS). Our ongoing studies have revealed that PB and RRS elicit alterations in cardiovascular, neuroendocrine, neuroimmune and behavioral measures. Perhaps more importantly, our preliminary studies indicate that these PB+RRS-induced alterations are exacerbated by lipopolysaccharide (LPS) or acute exposure to heterogeneous social stressors. Such observations suggest that in addition to baseline differences, a prior history of PB and stress may predispose GWI veterans to exaggerated responses to immune challenges or stressful life experiences after deployment in the GW. Surprisingly, relatively few studies have directly tested this hypothesis to determine the underlying mechanisms responsible for exacerbated responses to stress or immune challenges after exposure to PB. Accordingly, the goal of this project is to directly test our overarching hypothesis that immune challenges and stressful stimuli lead to exacerbated neuroimmune, neurochemical, cardiovascular and behavioral deficits after exposure to cholinesterase inhibition in an animal model of Gulf War Illness. This hypothesis will be tested in the following Aims: • Aim 1 will examine whether immune or stress challenges lead to potentiated neuroimmune responses in PB+RRS rats • Aim 2 will determine whether LPS or to exposure social stress enhances cardiovascular complications in enhanced in PB+RRS rats. • Aim 3 will determined whether the performance of hippocampal and prefrontal cortex-dependent behaviors are adversely affected by LPS administration or acute social stress. Successful completion of these studies will demonstrate that PB treatment in combination with stress elicits fundamental alterations in brain and body responses that may be much more evident following immune and social stress challenges, which would be highly consistent with the progress nature of GWI pathophysiology. Most importantly, these studies will identify loci for therapeutic intervention that can be quickly tested in our model and implemented for the treatment of GWI in our veterans.

从海湾战争（GW）返回后，退伍军人经历了一系列症状， 指定的海湾战争疾病（GWI），这与单一疾病无关。在这方面，GW 退伍军人在中枢神经系统（CNS）中暴露了结构和功能缺陷， 心血管并发症。 GWI最阴险的方面之一是它是慢性和 进行性疾病；实际上，被诊断为GWI的退伍军人的数量在后继续增加 部署期。尽管与GWI相关的无数症状的基础机制 仍然有待阐明，一些研究确定GWI退伍军人暴露了夸张的免疫 对身体压力源的反应，当与其他研究结合使用时，该概念是 神经炎症是GWI病因和进展的关键组成部分。 在上一个资金期间，我们开发了一种GWI的啮齿动物模型，在该模型中施用大鼠 单独并与 重复的约束应力（RRS）。我们正在进行的研究表明，PB和RRS引起了变化 心血管，神经内分泌，神经免疫和行为措施。也许更重要的是，我们 初步研究表明，这些PB+RRS诱导的改变会因脂多糖加剧 （LP）或急性暴露于异质社会压力源。这样的观察表明，除了 基线差异，PB和压力的先前历史可能会使GWI退伍军人夸大 在GW部署后，对免疫挑战或压力的生活经历的反应。出奇， 相关的研究很少直接检验该假设以确定基本机制 暴露于PB后，负责加剧对压力或免疫挑战的反应。因此， 该项目的目的是直接检验我们的总体假设，即免疫挑战和压力很大 刺激导致神经免疫性，神经化学，心血管和行为不足之后加剧 在海湾战争疾病的动物模型中，暴露于胆碱酯酶抑制。该假设将进行检验 在以下目的中： •AIM 1将检查免疫或压力挑战是否导致潜在的神经免疫反应 PB+RRS大鼠 •AIM 2将确定LP或暴露社会压力是否会增强心血管并发症 PB+RRS大鼠增强。 •AIM 3将确定海马和前额叶皮层的性能是否依赖 行为受到LPS管理或急性社会压力的不利影响。 这些研究的成功完成将证明PB治疗与压力引起的结合 在免疫和身体反应中的根本改变可能是更多证据和免疫后的证据 社会压力挑战，这将与GWI的进步性质一致 病理生理学。最重要的是，这些研究将确定可以进行治疗干预的本地 在我们的模型中迅速进行了测试，并在我们的退伍军人中进行了治疗GWI。