Immune basis for hippocampal cholinergic deficits in pyridostigmine-treated rats

从海湾战争归来后，退伍军人经历了一系列症状， 被指定为海湾战争疾病(GWI)，不能与单一疾病相关。在这方面，GW 退伍军人表现出中枢神经系统(CNS)的结构和功能缺陷，以及 心血管并发症。GWI的一个更隐秘的方面是它是一种慢性和 进行性精神障碍；事实上，被诊断为退伍军人的退伍军人人数在后一年继续上升。 部署期间。尽管与GWI相关的众多症状背后的机制 仍有待阐明，一些研究已经确定，二战退伍军人表现出夸大的免疫力 对生理应激源的反应，当与其他研究相结合时，支持这一概念 神经炎症是GWI的病因和进展中的关键成分。 在之前的资助期间，我们开发了一种GWI啮齿动物模型，在该模型中给大鼠注射 乙酰胆碱酯酶(AChE)抑制剂溴化吡斯的明(PB)单独和联合应用 重复约束应力(RRS)。我们正在进行的研究表明，PB和RRS在 心血管、神经内分泌、神经免疫和行为测量。也许更重要的是，我们的 初步研究表明，这些PB+RRS诱导的改变会被内毒素加剧 (LP)或急性暴露于不同的社会压力源。这样的观察表明，除了 基线差异、既往PB病史和压力可能使退伍军人倾向于夸大 在GW部署后，对免疫挑战或应激生活经历的反应。令人惊讶的是， 相对较少的研究直接测试这一假说来确定潜在的机制 负责在暴露于PB后对压力或免疫挑战的加剧反应。因此， 这个项目的目标是直接测试我们的总体假设，即免疫挑战和压力 刺激导致严重的神经免疫、神经化学、心血管和行为障碍 在海湾战争疾病动物模型中暴露于胆碱酯酶抑制。这一假设将得到检验。 在以下目标中： ·目标1将研究免疫或应激挑战是否会导致增强的神经免疫反应 PB+RRS大鼠 ·Aim 2将确定暴露于内毒素或社会压力是否会增加 PB+RRS大鼠增强。 ·Aim 3将确定海马区和前额叶皮质的表现是否依赖 行为会受到脂多糖注射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治疗与应激相结合会产生 大脑和身体反应的根本性变化，在免疫和 社会压力挑战，这将与全球倡议的进步性质高度一致 病理生理学。最重要的是，这些研究将确定可用于治疗干预的基因座 在我们的模型中进行了快速测试，并在我们的退伍军人中实施了GWI治疗。

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.