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

研究神经炎症在环境暴露诱发的焦虑症中的作用

基本信息

批准号：
10573948
负责人：
NEELAKANTESWAR Aluru
金额：
$ 24.1万
依托单位：
WOODS HOLE OCEANOGRAPHIC INSTITUTION
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-09 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10573948
关键词：
Address Adolescent Adult Affect Agonist Animal Model Anxiety Anxiety Disorders Aryl Hydrocarbon Receptor Behavioral Biological Models Brain Cell Culture System Cell physiology Cells Cellular Morphology Central Nervous System Country DNA Methylation DNA methylation profiling Defect Development Dioxins Disease Embryo Emotional Stress Environment Environmental Exposure Environmental Impact Environmental Risk Factor Epigenetic Process Exposure to Foundations Functional disorder Future Gene Expression Genetic Genetic Predisposition to Disease Genetic Transcription Image Immune Immune response Immunity In Vitro Inflammation Inflammatory Knowledge Learning Life Ligands Macrophage Measures Memory Mental Depression Mental disorders Microglia Modeling Molecular Morbidity - disease rate Morphology Neurodegenerative Disorders Neuroglia Neurologic Neurons Pathogenesis Phagocytes Physiological Play Polychlorinated Biphenyls Predisposition Pregnancy Production Public Health RNA methylation Regulation Research Risk Risk Factors Role Schizophrenia Schools Stress Testing Time Transgenic Organisms United States Zebrafish adult neurogenesis anxiety-like behavior anxiety-related disorders behavioral phenotyping cognitive process confocal imaging early life exposure environmental chemical environmental chemical exposure experience glial activation immune function in vivo in vivo Model model organism nervous system disorder neurobehavior neurobehavioral neuroinflammation neuropsychiatric disorder neuropsychiatry physiologic stressor prevent response single-cell RNA sequencing synaptic pruning transcription factor

项目摘要

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.

项目摘要该R21提案检验了以下假设：环境化学物质针对居民小胶质细胞大脑中的免疫细胞和小胶质功能的改变有助于发展的风险神经精神病学和神经退行性疾病。小胶质细胞在反应中起重要作用大脑的炎症和免疫挑战。他们也已显示出许多超出免疫反应的重要作用，包括在发育过程中的突触修剪和成人神经发生。小胶质细胞激活已显示与不同的进展有关神经退行性疾病以及在几种神经精神疾病中。积累证据表明环境化学暴露增加了对发展的敏感性各种神经退行性和神经精神疾病。大多数研究使用体外细胞对环境化学暴露的影响对小胶质细胞进行了培养系统和对体内影响的知之甚少，尤其是在早期。拟议的研究旨在了解环境化学暴露在使用成像的良好发展模型系统的体内小胶质功能障碍，分子和行为方法。它有两个具体的目标。在特定目标1中，我们测试假设斑马鱼暴露于多氯联苯（PCB）会引起小胶质细胞激活。这些研究将使用一系列与环境相关的浓度进行 PCB126（一种二恶英状的PCB），它在环境中分布。使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小胶质形态。另外，小胶质细胞的潜在影响将量化神经元网络以及神经脱头的激活。在特定的目标2中，我们将测试PCB诱导的小胶质细胞功能障碍的假设取决于AHR。使用ahr null 斑马鱼，我们将表征AHR在小胶质细胞激活中的作用。野生型和ahr null 斑马鱼将暴露于影响小胶质细胞并表征的PCB126浓度曝光后以及生命之后的效果。我们将表征特定的大脑使用单细胞RNA与这些变化相关的转录和表观遗传曲线测序和单细胞DNA甲基化分析。拟议研究的结果将提供有关环境化学物质在免疫细胞中的作用的基本知识脑。