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:
  • 金额:
    $ 9.53万
  • 依托单位:
  • 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

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.
项目摘要 自闭症谱系障碍(ASD)目前影响美国59名儿童中有1个,其中80%是男性, 并主要取决于社会互动/交流受损。产前暴露于空气污染 与ASD的病因以及许多其他神经精神疾病有关。但是, 空气污染改变大脑社会回路发展的机制仍然未知。 重要的是,环境毒素暴露有很大的社会差异,边缘化社区 承担最大的曝光负担。使用结合环境毒素的新型鼠标模型(柴油 排气颗粒; DEP)具有与伦理学相关的母体压力源(资源剥夺; MS),我们的 初步数据表明,这些暴露结合起来,但都不会引起社会上的强大缺陷 男性的互动,但没有女性后代。这是与孕产妇的社会心理压力的模型 揭示了后代中对环境毒素的脆弱性。 ASD越来越被认为是全身 紊乱。胃肠道症状和肠道微生物组组成的变化存在于更多 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。在 本提案的K99阶段,在AIM 1中,我建议在分析肠道微生物组的分析中进一步培训 询问出生时DEP/MS幼崽的交叉促进是否可以防止肠道微生物组发生变化(使用 元基因组测序)。多巴胺系统支持社交互动,对微生物信号传导敏感, 并且我的初步数据表明在DEP/MS暴露后被下调。因此,在AIM 2中,我建议 学习体内光遗传学技术以测试中脱脂胺多巴胺奖励途径的激活是否为 足以恢复DEP/MS之后的社会行为。在R00阶段,在AIM 3中,我将使用这些技术 在K99阶段获取,以确定肠道微生物组的变化是否负责变化 在DEP/MS后代的社会行为和多巴胺信号中。此外,我将使用初步数据 聚集在目标1中,询问可能会改变哪些潜在代谢物或分子机制 DEP/MS。最后,我会问小胶质细胞(大脑的常驻免疫细胞)在介导中起关键作用 这些微生物组驱动的变化。这些实验将共同阐明污染物和 压力协同为导致肠道轴和社会行为缺陷的失调。 该建议将通过为我提供新的培训来大大提高我的职业发展 尖端技术,例如体内光遗传学和元基因组测序。因此,这将帮助我 建立我自己的独立工作线和本文获得的初步数据将作为基础 用于未来的R01资金。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Emerging roles for microglia and microbiota in the development of social circuits.
Sickness and the Social Brain: Love in the Time of COVID.
  • DOI:
    10.3389/fpsyt.2021.633664
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Smith CJ;Bilbo SD
  • 通讯作者:
    Bilbo SD
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Caroline Jackson Smith其他文献

Caroline Jackson Smith的其他文献

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{{ truncateString('Caroline Jackson Smith', 18)}}的其他基金

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
  • 财政年份:
    2023
  • 资助金额:
    $ 9.53万
  • 项目类别:
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:
    10283978
  • 财政年份:
    2021
  • 资助金额:
    $ 9.53万
  • 项目类别:
The Microglial Developmental Index: A Novel Framework for Understanding the Role of Microglia in the Etiology of Autism Spectrum Disorder
小胶质细胞发育指数:了解小胶质细胞在自闭症谱系障碍病因学中的作用的新框架
  • 批准号:
    9761008
  • 财政年份:
    2019
  • 资助金额:
    $ 9.53万
  • 项目类别:

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