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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

基本信息

批准号：
10223180
负责人：
Lindsey Michelle Brier
金额：
$ 5.1万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2023-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223180
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 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

项目摘要

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/文摘