Environmental Toxins and Microglia-Synapse Interactions in Autism

自闭症中的环境毒素和小胶质细胞突触相互作用

基本信息

批准号：
10019548
负责人：
Staci D Bilbo
金额：
$ 46.35万
依托单位：
DUKE UNIVERSITY
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：
2016-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019548
关键词：
Adult Air Pollutants Allergens Animal Genetics Animal Model Anxiety Asthma Behavior Behavioral Brain Brain region Cells Chemicals Child Cognitive deficits Communication Corpus striatum structure Data Data Set Development Diesel Exhaust Disease Elderly Embryo Environmental Exposure Environmental Pollutants Environmental Risk Factor Exhibits Exposure to Fetus Functional disorder Genes Genetic Hippocampus (Brain)Human Immune Immune system Impairment Individual Infection Injury Intellectual functioning disability Knockout Mice Lead Life Link Maternal Exposure Mediating Microglia Modeling Molecular Morphology Mothers Mus Neurodevelopmental Disorder Neurologic Neurons Pathology Pathway Analysis Pathway interactions Phenotype Physiological Pollution Population Predisposition Prefrontal Cortex Pregnancy Research Resources Risk Risk Factors Signal Pathway Social Behavior Social support Stimulus Stress Structure Synapses System Testing Thalamic structure Third Pregnancy Trimester Toxic Environmental Substances Toxin autism spectrum disorder autistic children brain abnormalities brain cell environmental stressor experience immune activation male maternal stress mouse model neural circuit neurobehavioral neurodevelopment neurophysiology novel offspring particle particle exposure pollutant prenatal prenatal exposure prevent response social stressor stressor synaptic pruning synergism toxicant

项目摘要

Project Summary Environmental toxins and microglia-synapse interactions in autism. It is increasingly evident that diverse genes and environmental exposure(s) combine or synergize to produce a spectrum of autism phenotypes dependent upon critical developmental windows. Multiple prenatal/maternal environmental toxins and exposures have been linked to human ASDs, but the associations of single agents have been relatively weak. This suggests it is the combination of multiple maternal exposures that increases vulnerability in offspring. We now recognize that non-chemical stressors, such as limited resources or social support of the mother, can increase vulnerability of the fetus to chemical stressor exposures (e.g., pollution or toxins), which could explain why a single exposure or risk factor in isolation is a modest predictor of autism risk. Models aimed at deciphering the mechanisms that contribute to ASD suffer from oversimplification, using single agents. We breach this gap by using a new model that employs the combined effects of an ethologically relevant maternal stressor and environmentally relevant pollutant, diesel exhaust, both of which have been implicated in autism. We show that maternal diesel exhaust particle (DEP) exposure combined with maternal stress (MS) (but neither in isolation) produces early-life communication deficits, and long-term cognitive deficits and strikingly increased anxiety in male but not female offspring. We show evidence that DEP exposure significantly alters microglial colonization of the male but not female embryonic brain, and combined prenatal DEP and MS exposure leads to persistent changes in the function of microglia of the same brain regions of males. Beyond their functions in innate immune defense of the brain, microglia are important regulators of experience-dependent synaptic remodeling during development. It is proposed that microglia prune inappropriate or weak synapses while sparing appropriate or strong connections. Autism has been well described as a disease of synaptic dysfunction, and functional network analyses have nearly all pointed out the importance of molecular pathways that control activity-dependent synaptic remodeling in the pathology of ASDs. Importantly, impaired microglia-mediated pruning in mice disrupts functional brain connectivity and social behavior, strongly suggesting that microglia-synapse interactions may contribute to autism’s pathophysiology. Thus, the specific hypothesis to be tested here is that microglial activation by combined environmental factors will cause aberrant synaptic pruning by these cells, leading to neural circuit dysfunction and ASD-like behaviors.

项目摘要自闭症中的环境毒素和小胶质细胞 - 共生相互作用。越来越多的证据表明，潜水基因和环境暴露结合或协同作用以产生自闭症表型的频谱取决于关键的发育窗口。多个产前/产妇环境毒素和暴露与人类ASD相关，但单一代理的关联相对较弱。这表明正是多种母校暴露的组合增加了后代的脆弱性。现在，我们认识到非化学压力源，例如有限的资源或社会母亲的支持可以增加胎儿对化学胁迫暴露的脆弱性（例如，污染或），这可以解释为什么孤立的单一暴露或风险因素是自闭症的适度预测指标风险。旨在破译有助于ASD过度简化的机制的模型单代理。我们通过使用一种采用伦理学综合效应的新模型来违反了这一差距相关的母子压力源和与环境相关的污染物，柴油排气，它们都是在自闭症中实施。我们表明，母校柴油排气颗粒（DEP）暴露与母体结合压力（MS）（但两者都不孤立）会产生早期生活的沟通缺陷和长期认知缺陷并且在男性后代的动画大幅增加。我们显示了DEP暴露的证据显着改变了男性但不改变雌性胚胎大脑的小胶质殖民化，并结合产前 DEP和MS暴露会导致同一大脑区域的小胶质细胞功能的持续变化男性。除了它们在天生的免疫防御大脑防御方面的功能外，小胶质细胞是重要的调节剂在开发过程中依赖经验的突触重塑。建议小胶质细胞修剪不适当或弱突触，同时保留适当或牢固的连接。自闭症一直很好被描述为一种突触功能障碍的疾病，功能网络分析几乎全部指出了分子途径控制活性依赖性突触重塑的重要性 ASD。重要的是，小鼠中的小胶质细胞介导的修剪受损会破坏功能性脑连接性和社会行为，强烈表明小胶质细胞 - 共生的相互作用可能有助于自闭症病理生理学。这是，这里要检验的特定假设是通过组合的小胶质细胞激活环境因素将导致这些细胞异常的突触修剪，导致神经回路功能障碍和类似ASD的行为。