Delineating the effects of sex on microglia in neurodevelopmental disorders

描述性别对神经发育障碍中小胶质细胞的影响

基本信息

批准号：
9809266
负责人：
John R Lukens
金额：
$ 24.04万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-11 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9809266
关键词：
Ablation Adult Affect Behavioral Bioinformatics Biological Biological Factors Biological Markers Biology Brain CSF1R gene Cerebral Palsy Child Clinical Communicable Diseases Complex Data Development Disease Disease Outcome Disease Progression Disease model Environment Etiology Exhibits Exposure to Expression Profiling Female Gene Expression Genes Genetic Goals Hyperactive behavior Immune Immune response Immunohistochemistry In Situ Hybridization Incidence Inflammation Inflammatory Life Link Literature Mediator of activation protein Microglia Modeling Molecular Molecular Profiling Morphology Myeloid Cells Neuraxis Neurodevelopmental Disorder Neurons Pathway interactions Perinatal Phenotype Population Predisposition Pregnancy Pregnant Women Regulation Reporting Research Schizophrenia Sex Bias Sex Differences Shapes Stress Structure Synapses Testing Therapeutic Time Tissues autism spectrum disorder autistic children axon guidance axonal guidance base cell type comparative contrast enhanced differential expression fetal high risk immune activation improved in utero inflammatory milieu insight knock-down macrophage male mouse model neurodevelopment neurogenesis novel offspring pathogen protective effect response sex sexual dimorphism synaptic pruning therapeutic target transcriptome transcriptome sequencing

项目摘要

ABSTRACT The incidence of many neurodevelopmental disorders including autism, schizophrenia, and cerebral palsy are considerably higher in males than females. In the case of autism spectrum disorder (ASD), recent estimates indicate that autism is 4 to 5 times more prevalent in males than females. The reason(s) for male vulnerability and female protection in autism currently remain poorly understood. Improved understanding of the molecular and cellular factors that underlie sex-bias in neurodevelopmental disorders will provide important new insights into the etiologies of these complex disorders and will ultimately help to reveal much-needed biomarkers and therapeutic targets for neurodevelopmental disease. In our preliminary studies, we have found that altering the extent of maternal immune activation (MIA) influences development of autism-related behavioral abnormalities in a sex-specific manner. More specifically, we demonstrate that low levels of gestational inflammation promotes the development of autism-related phenotypes in male but not female offspring. In contrast, enhancing MIA above a threshold promotes female-specific induction of neurodevelopmental disorders and fetal reabsorption of male offspring. Interestingly, in our male-biased model of neurodevelopmental disease, we observe that microglial pathways are hyperactivated in male offspring and not females. Moreover, we find that anti-CSF1R knockdown of microglia and other myeloid cells during early gestation provides substantial protection against the development of behavioral abnormalities in the MIA model. Microglia are tissue-resident macrophages of the central nervous system (CNS) that aid in the clearance of debris and pathogens, and also have been reported to participate in synaptic pruning, axon guidance, and neurogenesis. Recent studies have begun to reveal sex-based differences in microglia activity that can contribute to distinct disease outcomes in the adult brain. In contrast, little is currently known in regard to how sex modulates microglia responses in neurodevelopmental disorders. Given our preliminary findings, we hypothesize that MIA results in sex-specific alterations in microglia activities that can affect neurodevelopment. For this exploratory project, we propose two aims to define how sex shapes microglia dynamics and function (Aim 1), and gene expression (Aim 2) in a neurodevelopmental disorder model driven by MIA. Completion of the proposed studies will break new ground in our understanding of how gestational exposure to inflammation can alter microglia responses in a sex- specific manner and will provide new insights into the underpinnings of neurodevelopmental disorders.

抽象的许多神经发育障碍的发生率包括自闭症，精神分裂症和脑瘫男性比女性高得多。在自闭症谱系障碍（ASD）的情况下，最近的估计值表明自闭症在男性中比女性高4至5倍。男性脆弱性的原因目前，自闭症中的女性保护仍然知之甚少。提高了对分子的理解和神经发育障碍中性偏见的基础的细胞因素将提供重要的新见解进入这些复杂疾病的病因，最终将有助于揭示急需的生物标志物和神经发育疾病的治疗靶标。在我们的初步研究中，我们发现母体免疫激活（MIA）影响自闭症相关行为异常的发展以特定的方式。更具体地说，我们证明妊娠炎症水平较低促进男性后代自闭症相关表型的发展。相比之下，在阈值以上增强MIA可促进女性特定的神经发育障碍的诱导男性后代的胎儿重吸收。有趣的是，在我们男性偏见的神经发育疾病模型中，我们观察到小胶质细胞途径在男性后代而不是女性中被过度激活。而且，我们发现早期妊娠期间，小胶质细胞和其他髓样细胞的抗CSF1R敲低可提供大量保护MIA模型中行为异常的发展。小胶质细胞是组织居民中枢神经系统（CNS）有助于清除碎屑和病原体的巨噬细胞，也据报道，参与突触修剪，轴突引导和神经发生。最近的研究开始揭示小胶质细胞活动的基于性别的差异，这可能导致不同的疾病结果成人大脑。相比之下，关于性别如何调节小胶质细胞反应的目前知之甚少神经发育障碍。鉴于我们的初步发现，我们假设MIA会导致性别特定可能影响神经发育的小胶质细胞活动的改变。对于这个探索性项目，我们建议两个目的是定义性别形状如何塑造小胶质细胞动力学和功能（AIM 1）和基因表达（AIM 2）由MIA驱动的神经发育障碍模型。拟议研究的完成将破坏新的基础在我们了解妊娠暴露于炎症的情况下，可以改变性别中的小胶质细胞反应特定的方式，将为神经发育障碍的基础提供新的见解。