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

• 批准号: 9131441
• 负责人: Staci D Bilbo
• 金额: $ 39.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/9131441
• 关键词: Adult; Air Pollutants; Allergens; Animal Model; Anxiety; Asthma; Autistic Disorder; 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; Female; Fetus; Functional disorder; Genes; Genetic; Hippocampus (Brain); Human; Immune; Immune system; 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 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 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; synaptic function; toxicant

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.

项目概要 自闭症中的环境毒素和小胶质细胞突触相互作用。 越来越明显的是，不同的基因和环境暴露结合或协同产生了 自闭症表型谱取决于多个产前/孕产期。 环境毒素和暴露与人类自闭症谱系障碍有关，但单一因素的关联 相对较弱，这表明是多种母亲暴露的组合导致的。 我们现在认识到非化学压力源，例如有限的资源或社会。 母亲的支持可能会增加胎儿对化学应激源暴露（例如污染或环境）的脆弱性 毒素），这可以解释为什么单一暴露或孤立的风险因素是自闭症的适度预测因子 旨在破译自闭症谱系障碍机制的模型存在过度简单化的问题。 我们通过使用一种新的模型来打破这一差距，该模型利用了道德的综合效应。 相关的母体压力源和环境相关污染物、柴油机尾气，两者均已被 我们发现，母亲接触柴油机尾气颗粒（DEP）与母亲患有自闭症有关。 压力（MS）（但不是孤立的）会导致生命早期的沟通缺陷和长期的认知缺陷 我们有证据表明，暴露于 DEP 会显着增加男性后代的焦虑感，而女性后代则不会。 显着改变小胶质细胞在男性而非女性胚胎大脑中的定植，并结合产前 DEP 和 MS 暴露会导致相同大脑区域的小胶质细胞功能持续变化 除了其在大脑先天免疫防御中的功能外，小胶质细胞还是重要的调节因子。 发育过程中依赖于经验的突触重塑被认为是小胶质细胞的修剪。 不适当或弱的突触，同时保留适当或强的连接自闭症一直很好。 被描述为一种突触功能障碍疾病，功能网络分析几乎都指出了 控制活动依赖性突触重塑的分子途径在病理学中的重要性 重要的是，小鼠小胶质细胞介导的修剪受损会破坏功能性的大脑连接和 社会行为，强烈表明小胶质细胞-突触相互作用可能导致自闭症 因此，这里要检验的具体假设是小胶质细胞的激活是通过组合进行的。 环境因素会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。