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首页> 外文学位 >Maternal immune activation alters the behavioral, cytokine, and gene expression profiles in rat offspring.
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Maternal immune activation alters the behavioral, cytokine, and gene expression profiles in rat offspring.

机译：母体免疫激活会改变大鼠后代的行为，细胞因子和基因表达谱。

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摘要

Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. The relationship between maternal infection and atypical fetal development is likely mediated by the activation of the maternal immune system, notably with elevated inflammatory cytokines in the fetal environment, but the intervening cellular and molecular links between infection and risk for neuropsychiatric disorders are unknown. The following dissertation addressed the behavioral, immunological, and molecular effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on embryonic day 15.;In Study 1, the consequences of maternal LPS on postnatal behavioral development were examined. Offspring born to LPS-dams exhibited reduced social preference and exploration behaviors as juveniles and adults. In Study 2, the effects of maternal LPS on cytokine, chemokine, and growth factor protein levels in maternal serum, amniotic fluid, and fetal brain at 4 and 24 h post injection were examined. Across the three compartments, LPS elevated pro-inflammatory cytokine and chemokine levels at 4 h, and levels decreased but remained elevated at 24 h. The greatest elevations were in serum, followed by amniotic fluid, then fetal brain. Treatment initially reduced anti-inflammatory cytokine levels at 4 h, which could partly explain the sustained cytokine response. Growth factor levels in the fetal brain were reduced at both time points. Study 2 could not address the source of inflammatory proteins in the fetal brain, but based on the failure to detect cytokine mRNA induction by microarray and quantitative real-time PCR performed in Study 3, the fetal brain cytokines are likely to be derived from maternal fluids or placenta. Study 3 was designed to elucidate the possible molecular mechanisms by which maternal LPS affects the fetal brain. Microarray analysis of mRNA expression levels in the whole fetal brain 4 h post maternal LPS injection revealed a significant up-regulation of hypoxia and cellular stress-responding genes and selective down-regulation of neurodevelopmental genes, specifically those that regulate neuronal migration. Genes controlling migration of gamma-amino butyric acid (GABA)ergic interneurons were specifically affected. These results offer a novel mechanism by which MIA can disrupt fetal CNS development.
机译：产妇的免疫激活（MIA）是精神分裂症和自闭症发展的危险因素。孕产妇感染与非典型胎儿发育之间的关系很可能是由孕产妇免疫系统的激活介导的，尤其是胎儿环境中炎性细胞因子的升高，但感染与神经精神疾病风险之间的介入性细胞和分子联系尚不清楚。以下论文讨论了MIA在怀孕的Sprague-Dawley大鼠的后代在胚胎第15天给予腹腔注射（0.25 mg / kg）脂多糖（LPS）的行为，免疫和分子作用；在研究1中，结果检查产妇LPS对产后行为发育的影响。 LPS水坝出生的后代在少年和成年时表现出降低的社会偏好和探索行为。在研究2中，检查了母体LPS对注射后4和24小时母体血清，羊水和胎儿脑中细胞因子，趋化因子和生长因子蛋白水平的影响。在三个隔室中，LPS在4 h时升高了促炎细胞因子和趋化因子的水平，在24 h时降低了水平，但仍然升高。最大的升高是血清，其次是羊水，然后是胎脑。治疗最初在4 h降低了抗炎细胞因子水平，这可以部分解释持续的细胞因子反应。胎儿脑中的生长因子水平在两个时间点均降低。研究2无法解决胎儿脑中炎性蛋白的来源，但是基于研究3中未能通过微阵列和定量实时PCR检测细胞因子mRNA诱导的失败，胎儿脑细胞因子可能源自母体液或胎盘。研究3旨在阐明母亲LPS影响胎儿大脑的可能分子机制。母体LPS注射后4 h，整个胎儿脑中mRNA表达水平的微阵列分析显示，缺氧和细胞应激反应基因显着上调，神经发育基因（尤其是调节神经元迁移的基因）选择性下调。控制γ-氨基丁酸（GABA）能的中间神经元迁移的基因受到特别影响。这些结果提供了一种新的机制，MIA可以通过该机制破坏胎儿中枢神经系统的发育。

著录项

  • 作者

    Oskvig, Devon Rene Brost.;

  • 作者单位

    Georgetown University.;

  • 授予单位 Georgetown University.;
  • 学科 Biology Neuroscience.;Biology Neurobiology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 138 p.
  • 总页数 138
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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