Functional Role of IL-6 in Fetal Brain Development and Abnormal Behavior

IL-6 在胎儿大脑发育和异常行为中的功能作用

• 批准号: 8255331
• 负责人: Elaine Hsiao
• 金额: $ 4.18万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255331
• 关键词: Adult; Animal Model; Autistic Disorder; Behavior; Behavioral; Biological Assay; Brain; Brain Pathology; Cells; Defect; Development; Disease; Double-Stranded RNA; Embryo; Endocrine; Environmental Risk Factor; Goals; Human; Immune system; Incidence; Infection; Inflammatory Response; Injection of therapeutic agent; Interleukin-6; Knock-out; Knockout Mice; Lead; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Mus; Neurons; Pathway interactions; Patients; Phosphorylation; Placenta; Poly I-C; Process; Recombinant Interleukins; Research; Research Project Grants; Respiratory Tract Infections; Risk; Risk Factors; Role; STAT1 gene; STAT3 gene; Schizophrenia; Signal Transduction; Site; Staging; Susceptibility Gene; Transgenes; Viral; beta-Galactosidase; cell type; cytokine; endophenotype; environmental agent; fetal; fetus cell; immune activation; insight; mouse model; neurodevelopment; neuropathology; non-genetic; offspring; postnatal; pregnant; promoter; relating to nervous system; response; transcription factor

Maternal infection is an environmental factor that can increase the incidence of autism and schizophrenia in the offspring. In an animal model of this risk factor, respiratory infection of pregnant mice yields offspring that develop behavioral abnormalities and neuropathology consistent with those observed in autistic and schizophrenic patients. These changes can be mimicked by maternal injection of the dsRNA, poly(I:C), which evokes an anti-viral inflammatory response. Recent studies have shown that the cytokine interleukin-6 (IL-6) is necessary and sufficient and necessary for mediating the development of behavioral and transcriptional changes in this maternal immune activation (MIA) model. While IL-6 is critical for mediating the effects of MIA, the mechanism by which IL-6 acts to alter neural development is unknown. We recently demonstrated that, shortly after MIA, maternally-derived IL-6 in the placenta mediates the activation of fetal cells in the placental, and subsequent changes levels of important endocrine factors. However, elucidating the mechanism of IL-6 action in altering fetal brain development is complicated by the fact that IL-6 is also upregulated in the fetal brain after MIA. This project will investigate the pathway of IL-6 action in mediating the development of abnormal behaviors in MIA offspring. We will identify the cells that are responsive to, and activated by, MIA-induced IL-6 in the placenta and embryonic brain. We will localize IL-6Ra promoter activity in mice carrying an IL-6Ra-beta-galactosidase transgene to determine where in the fetal brain and placenta IL-6Ra is expressed. We will then use immunohistochemical methods to detect downstream responses of IL-6Ra activation, including phosphorylation of the transcription factors, STAT3 and STAT1. Importantly, this project will pinpoint specific regions and cells for which IL-6 action is critical for the development of autistic and schizophrenic endophenotypes. We will knockout IL-6R in particular cell types and regions in the fetal brain and placenta and assay behavior to determine where IL-6 action acts to alter fetal brain development. The long-term goals are to elucidate the molecular mechanisms by which IL-6 causes behavioral abnormalities relevant for autism and schizophrenia.

母体感染是一种环境因素，可增加后代自闭症和精神分裂症的发病率。在这种危险因素的动物模型中，怀孕小鼠的呼吸道感染产生的后代出现行为异常和神经病理学，与自闭症和精神分裂症患者中观察到的情况一致。这些变化可以通过母体注射 dsRNA、poly(I:C) 来模拟，从而引发抗病毒炎症反应。最近的研究表明，细胞因子白介素 6 (IL-6) 对于介导这种母体免疫激活 (MIA) 模型中行为和转录变化的发展是必要的、充分的和必要的。虽然 IL-6 对于介导 MIA 的作用至关重要，但 IL-6 改变神经发育的机制尚不清楚。我们最近证明，MIA 后不久，胎盘中母体来源的 IL-6 介导胎盘中胎儿细胞的激活，并随后改变重要内分泌因子的水平。然而，由于 MIA 后胎儿大脑中 IL-6 的表达也上调，阐明 IL-6 改变胎儿大脑发育的作用机制变得复杂。该项目将研究 IL-6 在介导 MIA 后代异常行为发展中的作用途径。我们将鉴定胎盘和胚胎脑中对 MIA 诱导的 IL-6 做出反应并被其激活的细胞。我们将定位携带 IL-6Ra-β-半乳糖苷酶转基因的小鼠中的 IL-6Ra 启动子活性，以确定 IL-6Ra 在胎儿大脑和胎盘中的何处表达。然后，我们将使用免疫组织化学方法检测 IL-6Ra 激活的下游反应，包括转录因子 STAT3 和 STAT1 的磷酸化。重要的是，该项目将查明 IL-6 作用对于自闭症和精神分裂症内表型的发展至关重要的特定区域和细胞。我们将敲除胎儿大脑和胎盘中特定细胞类型和区域的 IL-6R，并分析行为以确定 IL-6 作用在何处发挥作用来改变胎儿大脑发育。长期目标是阐明 IL-6 导致与自闭症和精神分裂症相关的行为异常的分子机制。