Mechanisms driving functional connectivity changes in a mouse model of acute septic encephalopathy

驱动急性脓毒性脑病小鼠模型功能连接变化的机制

• 批准号: 10456085
• 负责人: Lindsey Michelle Brier
• 金额: $ 4.3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2023-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456085
• 关键词: Accidents; Acute; Adult; Affect; Animal Model; Animals; Astrocytes; Attenuated; Automobile Driving; Behavior Control; Behavioral; Binding; Biological Markers; Blood - brain barrier anatomy; Brain; Brain region; Calcium; Cell Wall; Chronic; Complement; Complement 3a; Confusion; Consult; Data; Delirium; Deterioration; Development; Disease; Elderly; Encephalopathies; Fluorescence; Future; General Hospitals; Genetic Engineering; Gram-Negative Bacteria; Hospital Costs; Hospitals; Image; Immunohistochemistry; Impaired cognition; Incidence; Infection; Inflammation Mediators; Inflammatory; Injections; Injury; Intensive Care Units; Interleukin-1 beta; Intervention; Length; Length of Stay; Link; Lipopolysaccharides; Malaise; Maps; Measures; Mediating; Mediator of activation protein; Microglia; Minor; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neurologic; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Pathogenesis; Pathologic; Pathway interactions; Patients; Performance; Peripheral; Plant Roots; Population; Process; Proteins; Research Personnel; Resources; Role; Secondary to; Sedation procedure; Sepsis; Source; Synapses; System; Systemic infection; TNF gene; Testing; Time; Up-Regulation; Work; animal model development; antagonist; base; behavior test; brain tissue; calcium indicator; cognitive change; conditioned fear; density; experience; glial activation; imaging approach; improved; mental state; mouse model; neurobehavioral; neuroimaging; neuroimaging marker; neuroinflammation; novel; object recognition; optical imaging; receptor; relating to nervous system; response; septic; serial imaging; synaptic pruning; systemic inflammatory response; therapeutic target; tool

Project Summary/Abstract Acute mental status changes, classified as encephalopathy or delirium, affect a large proportion of hospital patients and increase morbidity, especially in elderly and/or patients with neurodegenerative diseases. In turn, increasing evidence shows that these acute insults potentially fuel long term neurodegeneration. Apart from increased morbidity, these mental status changes also increase length and cost of hospital stays by resulting in accidents and unnecessary neurological consults, propagating unnecessary delegations of hospital resources. Despite this major pathologic and monetary burden, little is understood about the underlying mechanisms leading to acute encephalopathy. This is largely due to the absence of a fully defined animal model and further, a quick and reliable read out of encephalopathic progression/delirium in an animal model. Many cases of delirium are triggered by systemic infection, even when the CNS is not directly involved, which leads to a cascade of inflammatory pathways from or across the blood brain barrier. Studies have shown systemic infectious insults resulting in an upregulation of common inflammatory mediators within brain tissue that likely contribute to glial activation and resultant synapse dysregulation. Here, we use lipopolysaccharide (LPS), a cell wall component on gram negative bacteria known to cause systemic as well as neuroinflammation, as a systemic agent to model acute septic encephalopathy (ASE) in mice. We follow the impact of this inflammatory insult in healthy, adult mice. Further, we propose neuroimaging, specifically, recently developed calcium neural functional connectivity (FC) monitoring, to establish an FC readout of delirium in this model of ASE. Preliminary data has shown acute degradation of neural functional networks 24Hrs post LPS injection. This project will use this biomarker as a means to develop a read out of ASE/delirium in an animal model and probe regional upregulation of inflammatory mediators and synapse integrity during periods of altered FC. I hypothesize that this acute degradation of FC will parallel behavioral deficits and reflect regional upregulation of inflammatory mediators resulting in synapse elimination. A battery of behavioral data will be collected and used to help interpret the model as a whole. Further, development of this animal model will allow for cellular and molecular studies of this disease to progress, specifically with my additional hypothesis that acute synapse elimination and microglial priming is complement-mediated. Many studies have pointed to complement, especially protein C3a, as an important regulator post LPS administration, and complement in general has been show to drive synaptic pruning during development and elimination in a variety of neuroinflammatory diseases. It will thus be important to understand the role of complement in acute encephalopathy. This work as a whole sets up a means to study the underlying mechanisms involved in delirium/ASE and future work will begin investigating long term impacts on neurodegeneration.

项目总结/摘要 急性精神状态的变化，分类为脑病或谵妄，影响了很大比例的医院 患者，并增加发病率，特别是在老年人和/或患有神经退行性疾病的患者中。反过来， 越来越多的证据表明这些急性损伤潜在地促进长期的神经变性。除了 发病率增加，这些精神状态的变化也增加了住院时间和费用，导致 事故和不必要的神经科会诊，宣传不必要的医院资源委托。 尽管有这种重大的病理和经济负担，但对潜在的机制知之甚少 导致急性脑病这主要是由于缺乏完全定义的动物模型， 在动物模型中快速可靠地读出脑病进展/谵妄。多例 谵妄是由全身感染引起的，即使CNS没有直接受累，也会导致 来自或穿过血脑屏障的炎性通路级联。研究表明， 感染性损伤导致脑组织内常见炎症介质的上调， 导致神经胶质活化和由此产生的突触失调。在这里，我们使用脂多糖（LPS）， 革兰氏阴性细菌的壁成分，已知引起全身性以及神经炎症，作为一种 全身性试剂以在小鼠中建立急性脓毒性脑病（ASE）模型。我们关注这场煽动性的 在健康成年小鼠中的损伤。此外，我们建议神经成像，特别是最近开发的钙神经 功能连接（FC）监测，以在该ASE模型中建立谵妄的FC读数。初步 数据显示LPS注射后24小时神经功能网络的急性退化。This project will use 该生物标志物作为在动物模型中产生ASE/谵妄的读出的手段，并探测区域性的 在FC改变期间炎症介质和突触完整性的上调。我假设 FC的这种急性降解将平行于行为缺陷，并反映了炎症反应的区域上调。 介质导致突触消除。一组行为数据将被收集并用于帮助 把模型作为一个整体来解释。此外，这种动物模型的开发将允许细胞和分子生物学的研究。 这种疾病的研究进展，特别是与我的额外假设，急性突触消除 而小胶质细胞启动是补体介导的。许多研究指出，补体，特别是蛋白质 C3 a作为LPS给药后的重要调节因子，和补体一般已显示驱动 多种神经炎症疾病发展和消除过程中的突触修剪。因此将 了解补体在急性脑病中的作用很重要。这项工作作为一个整体建立了一个 研究谵妄/ASE的潜在机制的方法和未来的工作将开始调查 对神经退化的长期影响。