Project 2: Striatal circuits in MIA phenotypic heterogeneity

项目概要 - 项目 2 母亲感染会增加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）动物模型支持这种联系，因为 妊娠中期注射聚（I:C）可诱导成年后代行为和神经病理学异常 与深圳受影响的领域类似。特别是执行功能、奖励处理和 在 SZ 和 MIA 后代中，纹状体回路的多巴胺能 (DA) 输入发生了改变。因此，poly(I:C) 小鼠 模型提供了一个机会来识别与 SZ 相关的特定神经回路中的分子靶标 导致人类脑部疾病的早期诊断和治疗。然而，知识方面的重大差距仍然存在 与人类疾病危险因素的两个最重要方面相关：(i) 大多数怀孕是 对母体感染具有抵抗力，并且（ii）易感妊娠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。迄今为止的结果有 首次揭示了雌性小鼠之前的一个内在因素——基线免疫反应性（BIR） 怀孕，与用于诱导 MIA 的聚 (I:C) 剂量一起，可以预测恢复力以及 对纹状体依赖性行为和免疫蛋白变化的特定组合的易感性 后代的纹状体。该项目的中心目标是确定纹状体回路和免疫的变化 后代中的分子以及母体中细胞因子信号传导的变化赋予了弹性或易感性 MIA 诱发的行为结果的特定组合。为此，我们将实现三个具体目标： (i) 描述易感人群中男性和女性 MIA 后代跨多个领域的行为变化特征 和弹性群体，由怀孕前母猪的 BIR 定义； (ii) 确定 MIA 是否改变纹状体 DA 释放以及 D1 和 D2 特异性途径如何塑造易感和恢复性纹状体依赖性行为 男性和女性后代； (iii) 确定促炎性和调节性母体之间的平衡是否 细胞因子决定了对 MIA 引起的皮质纹状体依赖性行为变化的易感性和恢复力， 雄性和雌性后代中的 DA 释放和免疫蛋白。我们的项目直接位于主中心 假设，以及所有 3 个中心的目标，以机械的方式定义皮质纹状体回路的变化， 通过比较男性和女性后代之间的表型，揭示了对 MIA 的易感性和恢复力。 该项目的结果将为母体免疫和母体免疫提供表型读数。 项目 1 和 4 中确定的神经发育分子途径，以及基于回路和行为的 小鼠的信息用于与非人类灵长类 MIA 后代进行比较（项目 3），以及人类的信息 SZ，以及连接物种的计算框架（项目 5）。最终，这个项目可能 确定可作为干预目标的神经回路组件，以防止后代发育 与精神分裂症患者受影响的区域和领域相似的回路和行为异常。

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.