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

项目摘要/摘要 急性精神状态变化，被归类为脑病或精神错乱，影响着医院的很大一部分 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，这些尖锐的侮辱可能会助长长期的神经退化。除了 发病率的增加，这些精神状态的变化也增加了住院时间和成本，导致 事故和不必要的神经学咨询，宣传不必要的医院资源分配。 尽管有这种重大的病理和货币负担，但人们对其潜在的机制知之甚少。 导致急性脑病。这在很大程度上是由于缺乏完全定义的动物模型，而且， 在动物模型中快速可靠地读出脑病进展/精神错乱。许多情况下 精神错乱是由全身感染引发的，即使在中枢神经系统没有直接参与的情况下也是如此，这会导致 从血脑屏障或穿过血脑屏障的一连串炎症途径。研究表明，系统性的 感染性侮辱导致脑组织中常见炎症介质的上调，这可能 导致神经胶质细胞激活和由此导致的突触失调。在这里，我们使用脂多糖(LPS)，一种细胞 已知可引起全身和神经性炎症的革兰氏阴性细菌上的壁组分，如 用于建立小鼠急性感染性脑病(ASE)模型的全身性制剂。我们关注这一煽动性事件的影响 侮辱健康的成年小鼠。此外，我们建议神经成像，特别是最近发展的钙神经。 功能连接性(FC)监测，以建立这种ASE模型中的妄想症的FC读数。初步 数据显示，在注射脂多糖24小时后，神经功能网络急剧退化。该项目将使用 该生物标记物作为一种手段，在动物模型和探测区域中发展ASE/妄想的读出 FC改变期间炎性介质的上调和突触的完整性。我假设 Fc的这种急剧降解将平行于行为缺陷，并反映出局部炎症的上调 导致突触消除的介体。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读。此外，这种动物模型的发展将允许细胞和分子 对这种疾病的研究取得进展，特别是我的补充假设急性突触消除 而小胶质细胞的启动是由补体介导的。许多研究都指出补体，尤其是蛋白质。 补体C3a作为脂多糖给药后的重要调节因子，已显示出推动作用。 多种神经炎症性疾病发生和消除过程中的突触修剪。因此，它将是 了解补体在急性脑病中的作用很重要。这部作品作为一个整体建立了一个 研究精神错乱/ASE的潜在机制的手段和未来的工作将开始调查 对神经退化的长期影响。

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.