Implications of Maternal Baseline Immunoreactivity in the Susceptibility and Resilience to Behavioral and Circuit-wide Consequences of Maternal Immune Activation

项目概要/摘要 母亲感染和发烧会增加后代对包括自闭症在内的几种脑部疾病的易感性 (ASD)、精神分裂症（SZ）和重性抑郁症（MDD）。母体免疫激活（MIA）的动物模型 支持这一联系，因为妊娠中期注射病毒模拟物poly（I：C）会诱发多种疾病- 成年后代的相关行为和神经病理学异常。然而，目前使用这种方法的 该模型忽略了人类精神疾病的两个最重要的方面：（i）大多数怀孕是有弹性的 母亲病毒感染和（ii）易感妊娠可导致多种神经发育和 后代的精神疾病。我们的实验室最近发现了一种研究这两个问题的方法， MIA小鼠模型。我们最近发现，处女雌性C57/B6小鼠表现出广泛的基线 免疫反应性（BIR）决定了随后妊娠对MIA诱导的， 后代的疾病相关结果。令人惊讶的是，中等（但不是低和高）聚（I：C）剂量是有效的。 选择性有效地增加成年雄性后代和暴露于 妊娠期间相同的中间剂量表现出可重复的异常行为的不同子集 大坝的BIR预测。这些结果首次揭示了一个因素（BIR）， MIA后代的弹性以及对特定内表型组合的易感性。核心目标 我的项目的一部分是确定后代纹状体连接的变化和白细胞介素-6（IL-6）的作用， 在大坝信号，赋予弹性或敏感性的特定组合MIA诱导的行为 成果。在目标1中，我将确定MIA的大小是否预示着后代对以下疾病的恢复力和易感性： 行为缺陷，以及易感个体是否表现出明显的BIR驱动的行为特征。在Aim中 2，我将确定MIA是否会导致传入神经元，多巴胺能神经元， 利用阵列断层成像技术研究纹状体内兴奋性和抑制性突触的回路、突触密度和平衡 和逆向病毒追踪最后，在目标3中，我将采用利用IL-6的实验组合 补充和抑制，以揭示单独的IL-6是否是必要的和足够的，以决定易感性 以及对纹状体依赖行为和回路改变的适应力。最重要的是，我会决定 控制IL-6水平可以将易感妊娠转变为恢复性妊娠。如果成功，我的项目 可以确定生物标志物来预测怀孕的风险最大，并采取措施，以防止后代 发展成精神疾病

Project Summary/Abstract Maternal infection and fever increase susceptibility of offspring to several brain disorders including autism (ASD), schizophrenia (SZ), and major depression (MDD). Animal models of maternal immune activation (MIA) support this link, as mid-gestational injection of the viral mimic, poly(I:C), induces a wide range of disease- related behavioral and neuropathological abnormalities in adult offspring. Yet, current approaches using this model ignore two of the most important aspects of human psychiatric illness: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to multiple neurodevelopmental and psychiatric disorders in offspring. Our laboratory has recently discovered a way to study both of these issues in the MIA mouse model. We have recently found that virgin female C57/B6 mice exhibit a wide range of baseline immunoreactivity (BIR) that dictates susceptibility or resilience of subsequent pregnancies to MIA-induced, disease-related outcomes in offspring. Surprisingly, intermediate (but not low and high) poly(I:C) doses are selectively effective at increasing repetitive behaviors in adult male offspring and offspring exposed to the same intermediate dose during gestation exhibit distinct subsets of abnormal behaviors that are reproducibly predicted by the BIR of the dam. These results have revealed, for the first time, a factor (BIR) that confers resilience as well susceptibility to specific combinations of endophenotypes in MIA offspring. The central goals of my project are to identify the striatal connectivity changes in offspring and the role of interleukin-6 (IL-6) signaling in the dam that confer resilience or susceptibility to specific combinations of MIA-induced behavioral outcomes. In Aim 1, I will determine if the magnitude of MIA predicts resilience and susceptibility of offspring to behavioral deficits, and whether susceptible individuals show distinct, BIR-driven behavioral signatures. In Aim 2, I will determine whether MIA results in distinct connectivity changes in afferent neurons, dopaminergic circuits, synapse density and balance of excitatory and inhibitory synapses in striatum using array tomography and retrograde viral tracing. Finally, in Aim 3, I will employ a combination of experiments utilizing IL-6 supplementation and inhibition to reveal whether IL-6 alone is necessary and sufficient to dictate susceptibility and resilience to alterations in striatal dependent behaviors and circuitry. Most important, I will determine if manipulation of IL-6 levels can convert susceptible pregnancies into resilient ones. If successful, my project may identify biomarkers to predict pregnancies most at risk and approaches to prevent offspring from developing psychiatric disorders.