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Effects of air pollution/maternal stress on microglial sculpting of social circuits

空气污染/母亲压力对社会回路小胶质细胞塑造的影响

基本信息

批准号：
10462810
负责人：
Caroline Jackson Smith
金额：
$ 9.53万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2023-01-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462810
关键词：
16S ribosomal RNA sequencing Adolescence Affect Air Pollution Animal Model Birth Brain Child Communication Data Development Diesel Exhaust Disease Dissection Dopamine Dopamine D1 Receptor Etiology Exposure to Fostering Foundations Funding Future Gene Expression Housing Human Immune Impairment Individual Learning Link Mediating Metagenomics Microglia Modeling Molecular Neuroimmune Neuroimmunomodulation Nucleus Accumbens Partner in relationship Pathway interactions Patients Phagocytosis Phase Physiology Play Pregnancy Psychosocial Stress Public Health Publishing Reporting Research Resources Rewards Risk Role Shapes Shotguns Signal Transduction Social Behavior Social Change Social Development Social Interaction Source Stress Structure Supplementation Support System Techniques Testing Toxic Environmental Substances Training United States Ursidae Family Ventral Tegmental Area Work autism spectrum disorder brain cell career development deprivation dopamine system experimental study gastrointestinal symptom gut dysbiosis gut microbiome gut-brain axis in vivo individuals with autism spectrum disorder male marginalized community maternal microbiome maternal stress metagenomic sequencing microbial microbiome mouse model neural circuit neural network neuropsychiatric disorder neuropsychiatry novel offspring optogenetics particle pollutant postnatal prenatal prenatal exposure prevent pup receptor density receptor expression sex social social deficits social disparities stressor

项目摘要

PROJECT SUMMARY Autism spectrum disorder (ASD) currently affects 1 in 59 children in the United States, 80% of whom are male, and is characterized primarily by impaired social interaction/communication. Prenatal exposure to air pollution has been implicated in the etiology of ASD, as well as many other neuropsychiatric disorders. However, the mechanisms by which air pollution alters the development of social circuits in the brain remains unknown. Importantly, there are large social disparities in environmental toxin exposure whereby marginalized communities bear the greatest burden of exposure. Using a novel mouse model that combines an environmental toxin (diesel exhaust particles; DEP) with an ethologically relevant maternal stressor (resource deprivation; MS), our preliminary data show that these exposures in combination, but neither alone, induce robust deficits in social interaction in male, but not female offspring. This is line with a model in which maternal psychosocial stress unmasks vulnerability to environmental toxins in offspring. ASD is increasingly recognized as a whole-body disorder. Gastrointestinal symptoms and changes in the composition of the gut microbiome are present in more than 50% of individuals with ASD. Studies using animal models suggest a causal link between the gut microbiome and social behavior, but this has not been studied in the context of environmental toxins. During the K99 phase of this proposal, in Aim 1, I propose to further my training in the analysis of the gut microbiome to ask whether cross-fostering of DEP/MS pups at birth can prevent shifts in the gut microbiome (assessed using metagenomic sequencing). The dopamine system supports social interaction, is sensitive to microbial signaling, and my preliminary data suggests is down-regulated following DEP/MS exposure. Thus, in Aim 2, I propose to learn in vivo optogenetic techniques to test whether activation of the mesolimbic dopamine reward pathway is sufficient to restore social behavior following DEP/MS. During the R00 phase, in Aim 3, I will use the techniques acquired during the K99 phase to determine whether changes in the gut microbiome are responsible for changes in social behavior and dopamine signaling in DEP/MS offspring. Moreover, I will use the preliminary data gathered in Aim 1 to ask what potential metabolites or molecular mechanisms might be altered following DEP/MS. Finally, I will ask whether microglia, the resident immune cells of the brain, play a key role in mediating these microbiome-driven changes. Together, these experiments will elucidate the ways in which pollutants and stress synergize to produce dysregulation of the gut-brain axis and deficits in social behavior. This proposal will significantly advance my career development by providing me with new training in cutting-edge techniques such as in vivo optogenetics and metagenomic sequencing. Thus, it will help me to establish my own independent line of work and the preliminary data obtained herein will serve as a foundation for future R01 funding.

项目总结