Project 1: Maternal Immunity in MIA susceptibility

项目摘要-项目1 母体感染增加了后代对精神和神经发育障碍的易感性， 包括精神分裂症（SZ）。母体免疫激活（MIA）的动物模型支持这种联系，因为 妊娠中期注射poly（I：C）诱导成年后代的行为和神经病理学异常 在与深圳受影响的领域类似的领域。因此，poly（I：C）小鼠模型提供了鉴定 MIA易感性的分子和细胞基础，这可能导致早期诊断， 治疗人类脑部疾病然而，在知识方面仍然存在着重大差距， 这一人类疾病风险因素的重要方面：㈠大多数怀孕对母体感染具有复原力 和（ii）易感妊娠导致后代多种不同的疾病。我们最近发现了一个 在MIA小鼠模型中研究这两个问题的方法。迄今为止的结果显示， - 一种内在因素，雌性小鼠怀孕前的基线免疫反应性（BIR），与 用于诱导MIA的poly（I：C）剂量预测了恢复力以及对神经病理学和异常神经病理学的易感性。 在后代的行为。这些发现提供了一个独特的机会，以确定免疫签名之前， 在怀孕期间，这些因素是MIA的易感性和恢复力的基础，可以用作MIA的生物标志物。 易受感染的怀孕该项目的中心目标是确定免疫信号通路， 女性在怀孕前和怀孕期间，赋予敏感性或弹性的不同子集的MIA诱导 行为内在表型。我们将解决三个具体目标：（i）识别免疫生物标志物 和信号通路，这些通路是雌性小鼠怀孕前BIR范围的基础， 后代对MIA的易感性和恢复力，（ii）确定母体妊娠的进展如何 小鼠模型中的免疫应答决定了后代对MIA影响的易感性或恢复力， (iii)确定怀孕前的BIR和母体妊娠免疫反应是否与 在非人灵长类动物模型中对MIA的易感性或弹性。项目1直接针对中央 假设和所有3个目标，这个康特中心在机械的方式，通过识别免疫信号 在女性怀孕前和怀孕期间，赋予不同的子集的易感性或弹性的途径， MIA诱导的后代神经发育和行为表型。该项目的成果也 对于该中心其他项目的成功至关重要，这些项目揭示了免疫信号通路， 对神经回路中性别依赖性变化的敏感性和弹性（项目2、4和5）， 后代的神经发育和行为结果（项目2-5）。与项目2密切合作，我们 还将测试MIA诱导的纹状体DA释放和行为变化的两种免疫途径的因果关系， 开发一个管道，用于测试跨模型（项目2，3和5）的免疫途径（项目1，4）， 改善MIA影响的能力，从而提高我们中心的翻译相关性。

PROJECT SUMMARY – PROJECT 1 Maternal infection increases susceptibility of offspring to psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). Animal models of maternal immune activation (MIA) support this link, because mid-gestational injection of poly(I:C) induces behavioral and neuropathological abnormalities in adult offspring in domains similar to those affected in SZ. Thus, the poly(I:C) mouse model provides an opportunity to identify the molecular and cellular underpinnings of susceptibility to MIA, which could lead to earlier diagnosis and treatment of brain disease in humans. However, critical gaps in knowledge persist related to two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal infection and (ii) susceptible pregnancies lead to multiple distinct disorders in offspring. We have recently discovered a way to study both of these issues in the MIA mouse model. Results to date have revealed — for the first time — an intrinsic factor, baseline immunoreactivity (BIR) of female mice before pregnancy, that, together with the poly(I:C) dose used to induce MIA, predicts resilience as well susceptibility to neuropathology and aberrant behaviors in offspring. These discoveries provide a unique opportunity to identify immune signatures before and during pregnancy that underlie susceptibility and resilience to MIA, which can be used as biomarkers for susceptible pregnancies. The central goal of this project is to identify the immune signaling pathways in females before and during pregnancy that confer susceptibility or resilience to distinct subsets of MIA-induced behavioral endophenotypes in offspring. We will address three specific aims: (i) identify immune biomarkers and signaling pathways that underlie the range of BIR in female mice before pregnancy and that correlate with susceptibility and resilience to MIA in offspring, (ii) identify how the progression of the maternal gestational immune response in the mouse model dictates susceptibility or resilience to the effects of MIA in offspring, and (iii) determine if BIR before pregnancy, and the maternal gestational immune response, correlate with susceptibility or resilience to MIA in the non-human primate model. Project 1 directly addresses the central hypothesis and all 3 aims of this Conte Center in a mechanistic manner by identifying immune signaling pathways in females before and during pregnancy that confer susceptibility or resilience to distinct subsets of MIA-induced neurodevelopmental and behavioral phenotypes in offspring. Results from this project are also essential to the success of the other projects in the Center in revealing the immune signaling pathways that drive susceptibility and resilience to sex-dependent changes in neural circuits (Projects 2, 4 and 5) and neurodevelopmental and behavioral outcomes of offspring (Projects 2-5). Working closely with Project 2, we will also test causality of two immune pathways for MIA-induced changes in striatal DA release and behaviors, developing a pipeline for testing immune pathways (Projects 1, 4) across models (Projects 2, 3, and 5) for their ability to ameliorate the effects of MIA, thereby enhancing the translational relevance of our Center.