Project 2 Title: The brain brush border and microglial activation in response to ethanol

项目 2 标题：乙醇反应中的脑刷状缘和小胶质细胞激活

基本信息

批准号：
10609541
负责人：
Dimitrios Davalos
金额：
$ 27.39万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609541
关键词：
3-Dimensional Acute Adaptor Signaling Protein Adolescent Adolescent and Young Adult Adult Affect Age Alcohol abuse Alcohol-Induced Neurotoxicity Alcohols Animal Behavior Behavior assessment Biological Process Blood - brain barrier anatomy Blood Proteins Blood brain barrier dysfunction Brain Brain region Brush Border Cell Nucleus Cells Central Nervous System Chronic Clinical Data Development Encephalitis Endothelial Cells Ethanol Fibrinogen Frequencies Future Genes Genetic Transcription Hemorrhage Hippocampus Histologic Human Immune Impairment Individual Inflammatory Knockout Mice Knowledge Macrophage Mediating Microglia Modeling Molecular Morphology Mus Mutation Nature Neurons Pathology Pathway interactions Patients Play Population Predisposition Prefrontal Cortex Prevention strategy Property Reactive Oxygen Species Signal Transduction Synapses TLR4 gene Technology Testing Time Tissues Visual Cortex alcohol behavior alcohol effect alcohol exposure alcohol prevention alcohol response behavioral impairment binge drinking blood-brain barrier disruption brain tissue cytokine design drinking glial activation human tissue imaging modality impaired brain development in vivo in vivo imaging monocyte mouse model neuroinflammation neuron loss neurotoxic novel pre-clinical preference prevent regional difference single nucleus RNA-sequencing tissue injury transcriptomics two photon microscopy

3-Dimensional Acute Adaptor Signaling Protein Adolescent Adolescent and Young Adult Adult Affect Age Alcohol abuse Alcohol-Induced Neurotoxicity Alcohols Animal Behavior Behavior assessment Biological Process Blood - brain barrier anatomy Blood Proteins Blood brain barrier dysfunction Brain Brain region Brush Border Cell Nucleus Cells Central Nervous System Chronic Clinical Data Development Encephalitis Endothelial Cells Ethanol Fibrinogen Frequencies Future Genes Genetic Transcription Hemorrhage Hippocampus Histologic Human Immune Impairment Individual Inflammatory Knockout Mice Knowledge Macrophage Mediating Microglia Modeling Molecular Morphology Mus Mutation Nature Neurons Pathology Pathway interactions Patients Play Population Predisposition Prefrontal Cortex Prevention strategy Property Reactive Oxygen Species Signal Transduction Synapses TLR4 gene Technology Testing Time Tissues Visual Cortex alcohol behavior alcohol effect alcohol exposure alcohol prevention alcohol response behavioral impairment binge drinking blood-brain barrier disruption brain tissue cytokine design drinking glial activation human tissue imaging modality impaired brain development in vivo in vivo imaging monocyte mouse model neuroinflammation neuron loss neurotoxic novel pre-clinical preference prevent regional difference single nucleus RNA-sequencing tissue injury transcriptomics two photon microscopy

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项目摘要

ABSTRACT Exposure to alcohol during development or adulthood may result in damage to the brain. Binge alcohol consumption is a growing problem in the US, particularly among adolescents and young adults whose brains are continuing to develop and are thus more susceptible to the harmful effects of binge drinking on brain function. Both clinical and preclinical evidence suggest that microglia –the brain’s resident immune cells– play a key role in modulating alcohol-induced neurotoxicity. Indeed, brain inflammation following alcohol binge can impair brain development and function. In addition, activation of microglia promotes drinking preference in mouse models of chronic alcohol exposure. However, the cellular or molecular mechanisms through which microglia could mediate neuronal damage and alter animal behavior in response to alcohol in the adult or the adolescent brain have not been identified. Moreover, the effects of alcohol on microglia-neuronal interactions at the structural or functional level have not been studied, mostly due to technological limitations. We previously performed in vivo imaging using two-photon microscopy and discovered the dynamic nature of microglia, providing the first real-time demonstration of their tissue surveillance function. We also revealed their previously unknown ability to rapidly respond to changes in their microenvironment. Following systemic inflammatory challenges microglia become activated, and increase their interactions with the surrounding brain tissue. Acute and chronic alcohol exposure increases pro-inflammatory cytokines systemically, which can in turn directly or indirectly affect blood-brain barrier (BBB) integrity, and promote neuro-inflammatory and neurotoxic effects in different brain regions. Our preliminary results in models of excessive ethanol exposure show microglial activation, BBB disruption, and neuronal loss in the prefrontal cortex (PFC) of mice, a brain region implicated in alcohol-induced impairments in humans. Also, monocyte-specific deletion of MyD88, a key adaptor protein downstream of Toll-like receptor 4, abrogated microglial activation, BBB damage, and neuronal loss following ethanol abuse, and prevented ethanol- induced impairments in mice. Based on these findings, our proposed studies will test the hypotheses that increasing ethanol exposure causes localized BBB damage and microglial activation, which is required for regional structural and functional disruption of neuronal networks, and for alcohol-induced behavioral impairments.

抽象的在发育或成年期间接触酒精可能会导致大脑损害。暴饮暴食在美国，消费量是一个日益增长的问题，尤其是在青少年和年轻人中继续发展，因此更容易受到暴饮暴食对脑功能的有害影响。临床和临床前证据都表明，小胶质细胞（大脑的居民免疫核管）起着关键作用确实，酒精后的大脑炎症会损害大脑发展和功能。此外，小胶质细胞的激活促进了小鼠模型中的饮酒偏好慢性酒精暴露。但是，小胶质细胞可以介导的细胞或分子机制成人或青春期大脑中对酒精的响应神经元损害和改变动物行为尚未被确定。此外，酒精对结构或功能上小胶质细胞 - 神经元相互作用的影响水平尚未研究，主要是由于技术限制。我们以前在体内成像进行了使用两光子显微镜并发现了小胶质细胞的动态性质，提供了第一个实时证明其组织监视功能。我们还揭示了他们以前未知的能力遵循系统性炎症挑战小胶质细胞成为激活，并增加与周围脑组织的相互作用。急性和慢性酒精暴露有系统地增加促炎性细胞因子，这反过来直接或间接影响血脑屏障（BBB）完整性，并促进不同大脑区域的神经炎症和神经毒性作用。我们的过度乙醇暴露模型的初步结果显示小胶质激活，BBB破坏和小鼠前额叶皮层（PFC）的神经元丧失，这是在酒精诱导的损伤中实施的大脑区域人类。另外，MyD88的单核细胞特异性缺失，Toll样受体4下游的关键衔接蛋白，滥用乙醇后，小胶质细胞激活，BBB损伤和神经元丧失，并防止乙醇诱导小鼠损伤。基于这些发现，我们提出的研究将检验以下假设增加乙醇暴露会导致局部BBB损伤和小胶质细胞激活，这是必需的神经元网络的区域结构和功能破坏以及酒精诱导的行为障碍。