Investigating the role of neuroinflammation in environmental exposure-induced anxiety disorders

项目摘要 这项R21提案测试了环境化学物质靶向小胶质细胞的假设， 大脑中的免疫细胞和小胶质细胞功能的改变有助于发展的风险 神经精神和神经退行性疾病。小胶质细胞在反应中起重要作用， 炎症和免疫系统的挑战。他们也被证明有一些 免疫反应以外的重要作用，包括发育和成年期间的突触修剪 神经发生小胶质细胞激活已被证明参与不同的进展， 神经退行性疾病以及几种神经精神病症。越来越多的证据 表明，环境化学品暴露增加了对发展的敏感性， 各种神经变性和神经精神疾病。大多数研究调查了 环境化学品暴露对小胶质细胞的影响已经使用体外细胞进行了研究， 然而，目前对培养系统的研究很少，对体内效应，特别是在生命早期的影响知之甚少。 这项拟议的研究旨在了解环境化学品暴露对 在使用成像的完善的发育模型系统中的体内小胶质细胞功能障碍， 分子和行为方法。它有两个具体目标。在具体目标1中，我们测试 斑马鱼暴露于多氯联苯（PCBs）导致小胶质细胞 activation.这些研究将使用一系列与环境相关的浓度进行 PCB126是一种类似二恶英的PCB，广泛分布于环境中。利用转基因 斑马鱼表达细胞特异性荧光标记和延时共聚焦成像，我们将 测量对暴露的反应的小胶质细胞形态。此外，小胶质细胞的潜在影响 神经元网络上的激活以及神经行为将被量化。具体目标2： 测试PCB诱导的小胶质细胞功能障碍是AHR依赖性的假设。使用AHR null 斑马鱼，我们将表征AHR在小胶质细胞活化中的作用。野生型和AHR null 斑马鱼将暴露于影响小胶质细胞的PCB126浓度， 在接触后立即和以后的生活中都有影响。我们将描述大脑的具体特征 使用单细胞RNA与这些变化相关的转录和表观遗传谱 测序和单细胞DNA甲基化分析。拟议研究的结果将 提供有关环境化学品对免疫细胞的作用的基本知识， 个脑袋

Project Summary This R21 proposal tests the hypothesis that environmental chemicals target microglia, the resident immune cells in the brain and alterations in microglial function contributes to the risk of development of neuropsychiatric and neurodegenerative disorders. Microglia play an important role in responding to inflammation and immune challenge in the brain. They also have been shown to have a number of important roles beyond immune response, including synaptic pruning during development and adult neurogenesis. Microglial activation has been shown to be involved in the progression of different neurodegenerative diseases as well as in several neuropsychiatric conditions. Accumulating evidence suggests that environmental chemical exposure increases the susceptibility to the development of various neurodegenerative and neuropsychiatric disorders. A majority of the studies investigating the impacts of environmental chemical exposure on microglia have been conducted using in vitro cell culture systems and very little is known about in vivo effects, especially during early life. The proposed research is aimed at understanding the role of environmental chemical exposure on microglial dysfunction in vivo in a well-established developmental model system using imaging, molecular and behavioral approaches. It has two specific aims. In specific aim 1, we test the hypothesis that exposure of zebrafish to polychlorinated biphenyls (PCBs) causes microglial activation. These studies will be conducted using a range of environmentally relevant concentrations of PCB126, a dioxin-like PCB that is ubiquitously distributed in the environment. Using transgenic zebrafish expressing cell-specific fluorescent markers and time-lapse confocal imaging, we will measure microglial morphology in response to exposure. In addition, the potential effects of microglial activation on neuronal network as well as neurobehaviors will be quantified. In specific aim 2, we will test the hypothesis that PCB-induced microglia dysfunction is AHR dependent. Using AHR null zebrafish, we will characterize the role of AHR in microglial activation. Wild type and AHR null zebrafish will be exposed to a concentration of PCB126 that affected microglia and characterize the effects both immediately after exposure and later in life. We will characterize the brain specific transcriptional and epigenetic profiles associated with these changes using single cell RNA sequencing and single cell DNA methylation profiling. The results from the proposed studies will provide fundamental knowledge about the role of environmental chemicals on immune cells in the brain.