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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：
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
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/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

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.

项目总结