Project 5: Systems and circuits in MIA and schizophrenia

项目概要-项目5 来自流行病学的证据表明，妊娠期母体免疫激活（MIA）与妊娠期高血压疾病的病理生理学有关。 精神分裂症（SZ）。这些数据，加上我们对免疫系统作用的理解的最新进展， 分子在正常大脑发育中的作用，导致了康特中心的总体假设： 母体免疫系统的激活改变了后代的大脑发育， 以及与精神病理学的出现相关的连接功能变化， 青春期和青年期。我们对一种独特的非人灵长类（NHP）MIA模型的初步初步研究 发现了在青春期出现的改变的社会，重复和自我伤害行为的证据， 与纹状体多巴胺（DA）增加有关。在上一个供资周期，我们发现 额叶皮质体积和细胞外自由水（FW）的增加，这是一种假定的测量方法， 神经炎症，使用弥散加权MRI（DWI）测量，在扣带回皮质灰质（GM）， 男性MIA NHP。NHP大脑发育中的这些变化早在出生后6个月就出现了， 在出现任何行为异常之前，并强调产后时期对 了解MIA对大脑发育的影响。在SZ患者的平行研究中，我们发现 GM FW增加，前扣带回差异最大，支持以下临床相关性： NHP MIA模型。在目前的项目中，我们建议集中在MIA在产后期间的影响 以及女性NHP的大脑发育，扫描6个月和18个月大的男性和女性。到 获得MIA和SZ对皮质发育的影响的综合跨物种理解， 纹状体功能回路，我们将追求以下三个目标：（i）纵向成像研究 MIA NHP的表型异质性，（ii）基于计算模型的额叶-纹状体回路分析 与SZ的动机和认知控制相关，以及（iii）性别相关表型的潜在机制 SZ异质性这些影像学研究的结果的解释将通过组织分析得到加强 在18个月大的NHP中（项目4），测量BIR和母亲的免疫反应性 （项目1）的后代，我们计划的形象。最后，除了在MIA NHP中的上述研究之外， 随着我们中心对MIA效应和SZ对皮质-纹状体回路的关注的扩大，我们将使用一种新的 基于计算模型的功能磁共振成像分析，以剖析动机和认知的神经回路 控制缺陷以及它们与皮质FW和中脑神经黑色素（NM）的关系， SZ中的高多巴胺能活性。这个计算模型将允许跨物种的比较的作用 在小鼠MIA模型和MIA NHP的类似行为测定中，最后我们 还将在神经系统水平上研究性别在SZ患者表型异质性中的作用 以及与症状和临床结果的关系。

PROJECT SUMMARY – PROJECT 5 Evidence from epidemiology implicates gestational maternal immune activation (MIA) in the pathophysiology of schizophrenia (SZ). These data, together with recent advances in our understanding of the role of immune molecules in normal brain development, have led to the overarching hypothesis of this Conte Center: that early activation of the maternal immune system alters brain development in offspring leading to structural and functional changes in connectivity that are associated with the emergence of psychopathology in adolescence and young adulthood. Our initial pilot studies of a unique nonhuman primate (NHP) MIA model found evidence of altered social, repetitive, and self-injurious behaviors that emerged during adolescence and were associated with increased striatal dopamine (DA). During the previous funding cycle, we found decreases in frontal cortical volumes and increases in extracellular free water (FW), a putative measure of neuroinflammation, measured using diffusion weighted MRI (DWI), in cingulate cortex gray matter (GM) in male MIA NHPs. These changes in the developing NHP brain were present as early as 6 months postnatally, prior to the emergence of any behavioral abnormalities, and highlight the importance of the postnatal period for understanding the effects of MIA on brain development. In a parallel study in patients with SZ, we showed increased GM FW, with maximal differences present in anterior cingulate, supporting the clinical relevance of the NHP MIA model. In the present project, we propose to focus on the effects of MIA in the postnatal period and on brain development in female NHPs, scanning both males and females at 6 and 18 months of age. To obtain an integrated cross-species understanding of the effects of MIA and SZ on the development of cortico- striatal functional circuitry, we will pursue the following three aims: (i) Longitudinal imaging studies of phenotypic heterogeneity in MIA NHPs, (ii) Computational model–based analysis of frontal-striatal circuitry associated with motivation and cognitive control in SZ, and (iii) Mechanisms underlying sex-related phenotypic heterogeneity in SZ. Interpretation of the results of these imaging studies will be enhanced by tissue analyses in the NHPs (Project 4) at age 18 months and measurement of the BIR and immunoreactivity of the mothers (Project 1) of the offspring we plan to image. Finally, in addition to the above study in MIA NHPs, and in line with our center’s expanded focus on MIA effects and of SZ on cortico-striatal circuitry, we will use a novel computational model–based fMRI analysis to dissect the neural circuitry underlying motivation and cognitive control deficits as well as their relationship to cortical FW and midbrain neuromelanin (NM), a novel proxy for hyperdopaminergic activity in SZ. This computational model will allow cross-species comparisons of the role for cortico-striatal circuitry in similar behavioral assays in the mouse MIA model and the MIA NHP. Finally, we will also examine the role of sex in the phenotypic heterogeneity in humans with SZ at the neural systems level and in relationship to symptoms and clinical outcomes.