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
- 来源:
- 关键词:16S ribosomal RNA sequencingAdolescenceAffectAir PollutionAnimal ModelBirthBrainChildCommunicationDataDevelopmentDiesel ExhaustDiseaseDissectionDopamineDopamine D1 ReceptorEtiologyExposure toFosteringFoundationsFundingFutureGene ExpressionHousingHumanImmuneImpairmentIndividualLearningLinkMediatingMetagenomicsMicrogliaModelingMolecularNeuroimmuneNeuroimmunomodulationNucleus AccumbensPartner in relationshipPathway interactionsPatientsPhagocytosisPhasePhysiologyPlayPregnancyPsychosocial StressPublic HealthPublishingReportingResearchResourcesRewardsRiskRoleShapesShotgunsSignal TransductionSocial BehaviorSocial ChangeSocial DevelopmentSocial InteractionSourceStressStructureSupplementationSupport SystemTechniquesTestingToxic Environmental SubstancesTrainingUnited StatesUrsidae FamilyVentral Tegmental AreaWorkautism spectrum disorderbrain cellcareer developmentdeprivationdopamine systemexperimental studygastrointestinal symptomgut dysbiosisgut microbiomegut-brain axisin vivoindividuals with autism spectrum disordermalemarginalized communitymaternal microbiomematernal stressmetagenomic sequencingmicrobialmicrobiomemouse modelneural circuitneural networkneuropsychiatric disorderneuropsychiatrynoveloffspringoptogeneticsparticlepollutantpostnatalprenatalprenatal exposurepreventpupreceptor densityreceptor expressionsexsocialsocial deficitssocial disparitiesstressor
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
自闭症谱系障碍(ASD)目前在美国每59名儿童中就有1名患病,其中80%是男性,
并且主要特征是社交交互/通信受损。产前空气污染暴露
与ASD的病因学以及许多其他神经精神疾病有关。然而,
空气污染改变大脑中社会回路发展的机制仍不清楚。
重要的是,在环境毒素暴露方面存在很大的社会差异,边缘化的社区
承担最大的曝光负担。使用一种结合了环境毒素(柴油)的新型小鼠模型
废气颗粒;DEP)与行为相关的母亲应激源(资源匮乏;MS),我们的
初步数据显示,这些暴露组合在一起,但不是单独的,会导致严重的社会赤字
雄性后代之间的相互作用,而不是雌性后代。这与母亲心理社会压力的模型是一致的
揭示了后代对环境毒素的脆弱性。ASD越来越被认为是一个整体
无序。胃肠道症状和肠道微生物群组成的变化更多地出现在
超过50%的自闭症患者。用动物模型进行的研究表明,肠道和肠道之间存在因果关系
微生物群和社会行为,但这还没有在环境毒素的背景下进行研究。在.期间
K99阶段的这项建议,在目标1中,我建议进一步培训我的肠道微生物群分析,以
询问在出生时交叉培养DEP/MS幼崽是否可以防止肠道微生物群的变化(使用
元基因组测序)。多巴胺系统支持社会互动,对微生物信号敏感,
我的初步数据显示,在接触DEP/MS后,基因表达下调。因此,在目标2中,我建议
学习体内光遗传技术,以测试中脑边缘多巴胺奖励通路的激活是否
足以在DEP/MS之后恢复社会行为。在R00阶段,在目标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导致变化
DEP/MS后代的社会行为和多巴胺信号。此外,我将使用初步数据
聚集在目标1中,询问以下哪些潜在代谢物或分子机制可能会发生变化
最后,我会问一下,小胶质细胞,大脑的常驻免疫细胞,是否在调节
这些由微生物群驱动的变化。总之,这些实验将阐明污染物和
压力协同作用导致肠道-脑轴的失调和社交行为的缺陷。
这项建议将为我提供新的培训,从而显著促进我的职业发展
体内光遗传学和元基因组测序等尖端技术。因此,它将帮助我
建立我自己独立的工作路线,这里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.
- DOI:10.1016/j.bbih.2021.100296
- 发表时间:2021-10
- 期刊:
- 影响因子:0
- 作者:Smith CJ
- 通讯作者:Smith CJ
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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{{ 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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