Immune basis for hippocampal cholinerginc 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: 9058419
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058419
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Acute; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Area; Autonomic Dysfunction; Behavioral; Brain; Brain region; Bromides; Cell physiology; Characteristics; Chronic; Cognitive; Cognitive deficits; Complement; Coupled; Development; Disease; Exhibits; Exposure to; Functional disorder; Goals; Gulf War; Hippocampus (Brain); Immune; Impaired cognition; Inflammation; Inflammatory; Lead; Link; Macrophage Activation; Mediating; Memory Loss; Memory impairment; Mental disorders; Microdialysis; Microglia; Modeling; Modification; Morphology; Nerve Degeneration; Neuroanatomy; Neurocognitive Deficit; Neurons; Pathway interactions; Patients; Performance; Plasma; Pre-Clinical Model; Prophylactic treatment; Psychological Stress; Rattus; Reflex action; Site; Soldier; Spleen; Stress; Stressful Event; Symptoms; Synapses; System; Testing; Therapeutic Intervention; Time; Veterans; associated symptom; basal forebrain; base; chemokine; cholinergic; cytokine; experience; hypothalamic-pituitary-adrenal axis; immune function; in vivo; lymph nodes; macrophage; migration; nerve agent; neurochemistry; neuroinflammation; neuropsychological; novel; object recognition; operation; psychologic; psychological symptom; public health relevance; pyridostigmine; response; restraint stress; social stress; stressor

DESCRIPTION (provided by applicant): Following return from the Gulf War (GW), Veterans have exhibited of a constellation of symptoms - designated Gulf War Illness (GWI) - that cannot be associated with a single disease. GW Veterans also show increased rates of developing psychological symptoms and psychiatric disorders, along with alterations in hypothalamic-pituitary-adrenal (HPA) axis function and neuroanatomical changes. The precise cause for these symptoms remains unknown. The acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB) was used as prophylaxis against the deleterious effects of nerve agents during the GW. When combined with the operational stress experienced by soldiers, this PB exposure has been proposed as one of the causes of the late cognitive dysfunction in GWI. Other studies determined that PB is a causative factor in the development of impaired immune cell function in GW Veterans, which may contribute to the memory deficits observed in GWI. Since vagal cholinergic afferents and efferents control a reflex circuit that regulates inflammation, we propose to investigate the hypothesis that the combined effects of stress and PB exposure result in altered immune function, which then leads to modifications in cholinergic responses in key brain areas that lead to cognitive deficits. Using a preclinical model of combined repeated psychological stress and PB exposure, we will test our overarching hypothesis that the neurocognitive deficits in GWI are related to combined effects of PB and repeated stress on immune function that alters acetylcholine function in hippocampus. This hypothesis will be tested in the following Aims: "Aim 1 will examine whether the combination of PB + repeated stress induces HPA axis dysfunction, increases cytokine levels, reduces the activity of cholinergic projections to the hippocampus and modulates vagal medullary centers." "Aim 2 will examine hippocampal synaptic re-organization, neuronal and microglia dendritic architecture and neuronal degeneration, analyses which would provide a functional anatomical basis for cognitive deficits observed in RRS + PB rats." "Aim 3 will directly assess the combined effects of PB and stress exposure on acetylcholine release in the hippocampus. In vivo microdialysis will be used to examine basal and behaviorally-induced changes in hippocampal acetylcholine levels during the performance of a hippocampal-dependent task and during an exposure to an acute stressor." "Aim 4 will more directly assess how stress and PB affect immune function via immunological analyses performed in plasma, spleen, and lymph nodes, as well as microglia isolated from the hippocampus, after exposure to PB +/- repeated stress at early and delayed time points. Successful completion of these studies will demonstrate that the combination of PB + repeated stress exposure elicits peripherally-mediated changes in pro-inflammatory cytokines/chemokines that are mechanistically responsible for deficits in hippocampal cholinergic activity, thereby providing a neurochemical and anatomical basis for behavioral deficits following exposure to PB and stressful events. Most importantly, successful completion of the proposed studies will identify loci for therapeutic intervention that can be quickly implemented for the treatment of GWI in our Veterans.

描述（由申请人提供）： 从海湾战争 (GW) 归来后，退伍军人表现出一系列症状 - 称为海湾战争病 (GWI) - 这些症状与单一疾病无关。 GW 退伍军人还表现出心理症状和精神疾病发生率增加，以及下丘脑-垂体-肾上腺 (HPA) 轴功能和神经解剖学变化的改变。这些症状的确切原因仍不清楚。 乙酰胆碱酯酶 (AChE) 抑制剂溴化吡啶斯的明 (PB) 用于预防 GW 期间神经毒剂的有害影响。与士兵所经历的作战压力相结合，这种 PB 暴露被认为是 GWI 晚期认知功能障碍的原因之一。其他研究确定，PB 是 GW 退伍军人免疫细胞功能受损的一个致病因素，这可能导致 GWI 中观察到的记忆缺陷。由于迷走神经胆碱能传入和传出控制着调节炎症的反射回路，我们建议研究这样的假设：压力和PB暴露的综合影响会导致免疫功能改变，从而导致关键大脑区域胆碱能反应的改变，从而导致认知缺陷。使用反复心理应激和 PB 暴露相结合的临床前模型，我们将检验我们的总体假设，即 GWI 中的神经认知缺陷与 PB 和反复应激对免疫功能的综合影响有关，从而改变海马中的乙酰胆碱功能。这一假设将在以下目标中得到检验：“目标 1 将检查 PB + 重复应激的组合是否会诱发 HPA 轴功能障碍、增加细胞因子水平、降低海马胆碱能投射的活性并调节迷走神经髓质中心。” “目标 2 将检查海马突触重组、神经元和小胶质细胞树突结构以及神经元变性，这些分析将为在 RRS + PB 大鼠中观察到的认知缺陷提供功能解剖学基础。” “目标 3 将直接评估 PB 和压力暴露对海马乙酰胆碱释放的综合影响。体内微透析将用于检查在执行海马依赖性任务期间和在执行海马依赖性任务期间海马乙酰胆碱水平的基础和行为诱导的变化。暴露于急性压力源。” “目标 4 将在暴露于 PB +/- 早期和延迟时间的重复应激后，通过对血浆、脾脏和淋巴结以及从海马分离的小胶质细胞进行免疫分析，更直接地评估压力和 PB 如何影响免疫功能成功完成这些研究将证明，PB + 重复应激暴露的组合会引起外周介导的促炎细胞因子/趋化因子的变化，这些变化在机制上负责海马的缺陷。胆碱能活动，从而为暴露于 PB 和应激事件后的行为缺陷提供神经化学和解剖学基础。最重要的是，成功完成拟议的研究将确定可以快速实施治疗退伍军人 GWI 的治疗干预位点。