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

母体基线免疫反应性对母体免疫激活的行为和环路后果的易感性和恢复力的影响

• 批准号: 10450068
• 负责人: Kathryn Elizabeth Prendergast
• 金额: $ 3.97万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450068
• 关键词: Address; Adult; Adult Children; Afferent Neurons; Anatomy; Animal Model; Anxiety; Array tomography; Behavior; Behavioral; Behavioral Assay; Biological Assay; Biological Markers; Brain Diseases; Brain region; Corpus striatum structure; Data; Disease; Dose; Early Diagnosis; Early treatment; Environmental Risk Factor; Equilibrium; Excitatory Synapse; Exhibits; Exposure to; Female; Fever; Glutamates; Goals; Human; IL-6 inhibitor; Immune; Immunology procedure; Incidence; Individual; Infection; Inhibitory Synapse; Injections; Interleukin-6; Laboratories; Lead; Link; Major Depressive Disorder; Measures; Memory; Mental disorders; Modeling; Molecular Target; Mus; Neurodevelopmental Disorder; Neurons; Outcome; Partner in relationship; Pathway interactions; Poly I-C; Predisposition; Pregnancy; Prevention strategy; Rabies virus; Risk; Risk Factors; Role; Route; Schizophrenia; Signal Transduction; Social Behavior; Social Interaction; Supplementation; Synapses; Testing; Time; Viral; Virus Diseases; anxiety-related behavior; autism spectrum disorder; behavioral outcome; cognitive function; density; endophenotype; experimental study; immune activation; immunoreactivity; male; mouse model; neuropsychiatric disorder; offspring; prenatal exposure; prevent; relating to nervous system; repetitive behavior; resilience; social anxiety; stress reactivity; young adult

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.

项目概要/摘要 母亲感染和发烧会增加后代对多种脑部疾病（包括自闭症）的易感性 （ASD）、精神分裂症（SZ）和重度抑郁症（MDD）。母体免疫激活（MIA）动物模型 支持这种联系，因为妊娠中期注射病毒模拟物聚（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，当前使用此方法的方法 该模型忽略了人类精神疾病的两个最重要的方面：（i）大多数怀孕都是有弹性的 母体病毒感染和（ii）易感妊娠可导致多种神经发育和 后代精神疾病。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) 决定后续妊娠对 MIA 诱导的易感性或恢复力， 后代疾病相关的结果。令人惊讶的是，中间（但不是低和高）聚（I：C）剂量是 选择性地有效增加成年男性后代和暴露于该物质的后代的重复行为 妊娠期间相同的中间剂量表现出可重复的不同异常行为子集 由大坝的 BIR 预测。这些结果首次揭示了一个因素（BIR） MIA 后代的恢复力以及对特定内表型组合的易感性。中心目标 我的项目的目的是确定后代纹状体连接的变化以及白细胞介素 6 (IL-6) 的作用 母鼠中的信号传递赋予对 MIA 诱导的行为的特定组合的恢复力或敏感性 结果。在目标 1 中，我将确定 MIA 的大小是否可以预测后代的复原力和易感性 行为缺陷，以及易受影响的个体是否表现出独特的、由 BIR 驱动的行为特征。瞄准 2，我将确定 MIA 是否会导致传入神经元、多巴胺能神经元的明显连接变化 使用阵列断层扫描研究纹状体中的电路、突触密度以及兴奋性和抑制性突触的平衡 和逆行病毒追踪。最后，在目标 3 中，我将结合使用 IL-6 进行实验 补充和抑制以揭示单独的 IL-6 是否必要且足以决定易感性 以及对纹状体依赖性行为和电路变化的恢复能力。最重要的是，我会确定是否 控制 IL-6 水平可以将易感妊娠转变为恢复性妊娠。如果成功的话我的项目 可以识别生物标志物来预测最危险的怀孕以及预防后代的方法 出现精神疾病。