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

• 批准号: 10748065
• 负责人: Caroline Jackson Smith
• 金额: $ 20.1万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-16 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748065
• 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; Environmental Impact; Etiology; Exposure to; Fostering; Foundations; Funding; Future; Gene Expression; 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; 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; novel; offspring; optogenetics; particle; pollutant; postnatal; prenatal; prenatal exposure; prevent; pup; receptor density; receptor expression; sex; social; social deficits; social disparities; stressor; synergism; transmission process

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.

项目概要 目前，美国每 59 名儿童中就有 1 人患有自闭症谱系障碍 (ASD)，其中 80% 是男性， 主要特征是社交互动/沟通受损。产前暴露于空气污染 与 ASD 以及许多其他神经精神疾病的病因有关。然而， 空气污染改变大脑社交回路发育的机制仍不清楚。 重要的是，在环境毒素暴露方面存在巨大的社会差异，边缘化社区 承担最大的暴露负担。使用结合环境毒素（柴油 废气颗粒； DEP）与行为学相关的母亲应激源（资源剥夺；MS），我们的 初步数据显示，这些风险组合在一起（但单独使用）不会导致严重的社会赤字。 雄性后代有相互作用，但雌性后代没有相互作用。这与母亲心理社会压力的模型一致 揭示后代对环境毒素的脆弱性。自闭症谱系障碍 (ASD) 越来越被认为是一种全身性疾病 紊乱。胃肠道症状和肠道微生物组组成的变化存在于更多的情况 超过 50% 的 ASD 患者。使用动物模型的研究表明肠道之间存在因果关系 微生物组和社会行为，但这尚未在环境毒素的背景下进行研究。期间 该提案的 K99 阶段，在目标 1 中，我建议进一步开展肠道微生物组分析方面的培训，以 询问出生时 DEP/MS 幼崽的交叉寄养是否可以防止肠道微生物组的变化（使用 宏基因组测序）。多巴胺系统支持社交互动，对微生物信号敏感， 我的初步数据表明，在接触 DEP/MS 后，其浓度下调。因此，在目标 2 中，我建议 学习体内光遗传学技术来测试中脑边缘多巴胺奖赏通路的激活是否是 足以恢复 DEP/MS 后的社交行为。在 R00 阶段的目标 3 中，我将使用以下技术 在 K99 阶段获得，以确定肠道微生物组的变化是否是造成变化的原因 DEP/MS 后代的社会行为和多巴胺信号传导。此外，我将使用初步数据 在目标 1 中收集，询问以下可能会改变哪些潜在的代谢物或分子机制 DEP/MS。最后，我想问的是，大脑常驻免疫细胞小胶质细胞是否在介导免疫反应中发挥关键作用？ 这些微生物组驱动的变化。这些实验将共同阐明污染物和 压力协同作用会导致肠脑轴失调和社会行为缺陷。 该提案将通过为我提供新的培训来显着促进我的职业发展 体内光遗传学和宏基因组测序等尖端技术。因此，它将帮助我 建立自己的独立工作线，并以此获得的初步数据作为基础 用于未来的 R01 资金。