Project 2: Striatal circuits in MIA phenotypic heterogeneity

项目摘要--项目2 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 孕中期注射聚(I：C)诱导成年子代行为和神经病理异常 在与深圳受影响区域相似的区域。特别是，执行功能、奖励处理和 纹状体回路的多巴胺能(DA)输入在SZ和MIA后代中发生改变。因此，聚(I：C)小鼠 模型提供了在与SZ相关的特定神经回路中识别分子靶点的机会，这可能 有助于人类脑部疾病的早期诊断和治疗。然而，知识方面的关键差距依然存在。 与这一人类疾病风险因素中最重要的两个方面有关：(一)大多数怀孕是 对母亲感染的抵抗力和(2)易感怀孕会导致后代出现多种不同的疾病。我们 最近发现了一种在MIA小鼠模型中研究这两个问题的方法。到目前为止，结果有 首次揭示了雌性小鼠的内在因素，即基线免疫反应性(BIR) 妊娠，与用于诱发MIA的聚(I：C)剂量一起，预测韧性以及 纹状体依赖行为的特定组合的易感性和免疫蛋白的变化 子代的纹状体。这个项目的中心目标是确定纹状体回路和免疫系统的变化 后代中的分子和母体中赋予弹性或敏感性的细胞因子信号的变化 MIA诱导的行为结果的特定组合。为此，我们将解决三个具体目标： (I)描述易感男性和女性MIA后代在多个领域的行为变化 和弹性组，由孕前DAM的BIR定义；(Ii)确定MIA是否改变纹状体DA 释放以及D1和D2特异性通路如何塑造敏感和有弹性的纹状体依赖行为 男性和女性后代；以及(3)确定促炎症和调节性母体之间的平衡 细胞因子决定了对MIA诱导的皮质-纹状体依赖行为变化的敏感性和弹性， DA的释放，以及雄性和雌性后代的免疫蛋白。我们的项目直接面向主中心 假说，和所有3个中心的目标，以机械的方式，通过定义皮质纹状体环路的变化， 通过比较雄性和雌性后代的表型，了解其对MIA的易感性和韧性。 该项目的结果将提供母体免疫的表型读数和 项目1和4中确定的神经发育分子通路，以及基于电路和行为的 小鼠与非人类灵长类动物MIA后代比较的信息(项目3)，以及在患有 SZ，以及将连接物种的计算框架(项目5)。最终，这个项目可能会 确定可作为干预措施的神经回路组件，以防止后代发育 与人类SZ患者类似的区域和区域的电路和行为异常。

PROJECT SUMMARY- PROJECT 2 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. In particular, deficits in executive function, reward processing, and dopaminergic (DA) input to striatal circuits are altered in SZ and in MIA offspring. Thus, the poly(I:C) mouse model provides an opportunity to identify molecular targets in specific neural circuits related to SZ that 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 as susceptibility to specific combinations of striatal-dependent behaviors and changes in immune proteins in the striatum in offspring. The central goals of this project are to identify the changes in striatal circuits and immune molecules in offspring and the changes in cytokine signaling in the dam that confer resilience or susceptibility to specific combinations of MIA-induced behavioral outcomes. To that end, we will address three specific aims: (i) characterize behavioral changes across multiple domains in male and female MIA offspring from susceptible and resilient groups, defined by BIR of the dam before pregnancy; (ii) determine whether MIA alters striatal DA release and how D1- and D2-specific pathways shape striatal-dependent behaviors in susceptible and resilient male and female offspring; and (iii) determine whether the balance of pro-inflammatory and regulatory maternal cytokines dictate susceptibility and resilience to MIA-induced changes in cortico-striatal-dependent behaviors, DA release, and immune proteins in male and female offspring. Our project directly addresses the main Center hypothesis, and all 3 Center aims, in a mechanistic manner by defining changes in cortico-striatal circuits that underlie susceptibility and resilience to MIA and by comparing phenotypes between male and female offspring. Results from this project will provide a phenotypic read-out for the maternal immune and the neurodevelopmental molecular pathways identified in Projects 1 and 4, as well as circuit-based and behavioral information in the mouse for comparison to nonhuman primate MIA offspring (Project 3), and in humans with SZ, and for the computational framework that will bridge the species (Project 5). Ultimately, this project may identify neural circuit components that can be targeted for interventions to prevent offspring from developing circuit and behavioral abnormalities in regions and domains similar to those affected in humans with SZ.