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）返回后，退伍军人表现出了一系列症状 - 指定的海湾战争疾病（GWI） - 与单一疾病无关。 GW退伍军人还表明，发展心理症状和精神疾病的发生率增加，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然未知。 乙酰胆碱酯酶（ACHE）抑制剂吡啶斯汀溴溴（PB）用作防止神经药物在GW期间的有害作用的预防作用。当结合士兵所经历的操作压力时，已经提出了这种PB暴露是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受损的原因，这可能有助于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调节炎症的反射回路，因此我们提出了这样的假设，即压力和PB暴露的综合作用会导致免疫功能改变，然后导致关键大脑区域中胆碱能反应的修饰，从而导致认知性缺陷。使用临床前重复的心理压力和PB暴露的临床前模型，我们将测试我们的总体假设，即GWI中的神经认知缺陷与PB的综合作用和对免疫功能的重复应激有关，从而改变了Hippocampus中乙酰胆碱功能。该假设将在以下目的中进行检验：“ AIM 1将检查PB +重复应力的组合是否会诱导HPA轴功能障碍，增加细胞因子水平，降低胆碱能预测到海马的活性，并调节迷失髓质中心。” “ AIM 2将检查海马突触重组，神经元和小胶质细胞树突状结构以及神经元变性，这将为RRS + PB大鼠观察到的认知缺陷提供功能解剖基础。” “ AIM 3将直接评估Hippocampus中PB和压力暴露对乙酰胆碱释放的综合作用。在体内微透析中，将用于检查海马乙酰胆碱水平的基础和行为诱发的在海马相关任务以及暴露于急性急性急性急性急性压力的过程中的基础和行为诱发的变化。” ”目标4将更直接地评估压力和PB如何通过在血浆，脾和淋巴结中进行的免疫学分析以及从海马群中分离出的小胶质细胞以及在暴露于PB +/-重复应力的早期和延迟时间的重复时间上的PB +重复曝光的结合Pb + eTIS-RECTIENS的结合后，如何通过海马体中分离出来。 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.