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

项目摘要/摘要 母体感染和发烧增加了子女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)和重度抑郁症(MDD)。母体免疫激活动物模型(MIA) 支持这一联系，因为孕中期注射病毒模拟物Poly(I：C)会导致广泛的疾病- 成年子代的相关行为和神经病理异常。然而，目前使用这种方法 模型忽略了人类精神疾病最重要的两个方面：(I)大多数怀孕是有弹性的 母体病毒感染和(Ii)易感妊娠可导致多神经发育和 子代的精神障碍。我们的实验室最近发现了一种方法来研究这两个问题 MIA小鼠模型。我们最近发现，处女C57/B6小鼠表现出广泛的基线范围 免疫反应性(BIR)，指示后续妊娠对MIA诱导的敏感性或弹性， 子代的疾病相关结局。令人惊讶的是，中等(但不是低和高)聚(I：C)剂量是 选择性有效地增加成年雄性子代和暴露于 妊娠期相同的中等剂量表现出不同的可重复的异常行为亚群 根据大坝的BIR预测。这些结果第一次揭示了一个因素(BIR) MIA后代的韧性以及对特定内表型组合的敏感性。中心目标 我的项目的重点是确定后代纹状体连通性的变化以及白细胞介素6(IL-6)的作用 水坝中的信号使人对MIA诱导的行为的特定组合具有弹性或敏感性 结果。在目标1中，我将确定MIA的大小是否可以预测后代的韧性和易感性 行为缺陷，以及易感个体是否表现出明显的、由BIR驱动的行为特征。在AIM 2，我将确定MIA是否导致传入神经元、多巴胺能 纹状体兴奋性和抑制性突触的环路、突触密度和平衡性的阵列断层扫描 和逆行病毒追踪。最后，在目标3中，我将使用一组使用IL-6的实验 补充和抑制以揭示IL-6是否单独决定易感性是必要的和充分的 以及对纹状体依赖行为和回路改变的适应能力。最重要的是，我会决定是否 控制IL-6水平可以将易感妊娠转变为有弹性的妊娠。如果成功，我的项目 可能会确定预测怀孕风险最高的生物标志物，以及预防后代感染的方法 发展成精神障碍。

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.