Cytokine Regulation of Secondary Neural Progenitors

孕期母体感染、过敏、自身免疫性疾病、肥胖或污染会增加后代风险 患精神分裂症、自闭症、多动症、抽动障碍和双相情感障碍的能力提高2-4倍。无人接听 问题是，是什么提高了这些疾病的频率。临床研究已经测量到2-3倍的 后来发展为神经发育障碍的儿童血斑中IL-6水平的升高 例如ASD。其他研究表明，IL-6是少数几种细胞因子之一，可以通过 胎盘和血脑屏障以及早期胎儿IL-6水平的升高是必要的，也是充分的 导致与神经发育障碍相关的几种行为表型。然而，研究表明 缺乏确定IL-6是如何改变胎儿大脑发育的。因此，这项提案试图调查IL-6是如何 影响位于脑室下区内的人类和小鼠次级神经前体细胞 -一组复杂的祖先，但一直未得到充分研究。行为和生理结果都很高 依赖于对大脑的侮辱的发育时间，这与特定的神经直接相关 在胎儿生命的特定发育阶段进行分裂、迁移和分化的祖细胞。这个 大多数使用ASD和精神分裂症动物模型的研究都集中在小鼠与 人类妊娠第12周，放射状神经胶质细胞是主要的神经前体细胞。我们的 已公布的数据显示，从出生后第3天开始，每天注射两次IL-6(其水平比正常水平高2倍) 到6(与人类怀孕28-34周相关)会导致各种 行为任务。最近，我们发现IL-6特异性地影响一种子集的增殖 小鼠SVZ神经前体细胞，干扰其增殖和基因表达，从而减少产生 复杂脑中多个脑区的原浆星形胶质细胞和皮质下少突胶质细胞 精神错乱。因此，这一应用的中心前提是系统性升高的IL-6改变 次级神经前体细胞改变中间神经元和大胶质细胞的发生。在这里，我们建议生成 从男性和女性IPSCs中分离出人类次级神经前体细胞，以确定IL-6如何改变其 增殖、规范和基因表达。将在小鼠SVZ细胞上进行比较研究。 这些比较研究将使我们能够对这些人类次级神经前体细胞进行分类。此外， 我们将在发育阶段用IL-6处理的小鼠进行命运图谱分析，对应于 分析人类妊娠24周腹侧纹状体、杏仁核和前额叶皮质的组织发生 更全面地了解复杂神经发育障碍的组织病理学器官，如 ASD.我们的重点是对妊娠晚期的感染进行建模，对异常的中间神经元发生和 大胶质细胞的发生将证实IL-6是预防精神疾病干预的关键靶点。

Maternal infection, allergies, autoimmune disease, obesity or pollution during pregnancy increase offspring risk for developing schizophrenia, ASD, ADHD, Tourette disorder and bipolar disorder by 2-4x. An unanswered question is what is enhancing the frequency of these disorders. Clinical studies have measured a 2-3 fold increase in IL-6 plasma levels in blood-spots from children who later develop neurodevelopmental disorders such as ASD. Other studies have shown that IL-6 is one of the few cytokines that is transported across the placenta and blood-brain barrier and that elevated early fetal levels of IL-6 are both necessary and sufficient to cause several behavioral phenotypes associated with neurodevelopmental disorders. However, studies are lacking to establish how IL-6 alters fetal brain development. Thus, this proposal seeks to investigate how IL-6 affects those human and mouse secondary neural progenitors that reside within the inner subventricular zone – a complex set of progenitors that have been understudied. Behavioral and physiological outcomes are highly dependent on the developmental timing of insults to the brain, which are directly related to the particular neural progenitors that are dividing, migrating and differentiating at specific developmental stages during fetal life. The majority of studies using animal models for ASD and schizophrenia have focused on the mouse correlate to the 12th week of human gestation where radial glial cells are the predominant neural progenitors. Our published data show that twice daily injections of IL-6 (that raise levels 2-fold over normal) from postnatal day 3 to 6 (correlating to 28-34 weeks of gestation in humans) leads to compromised performance on a variety of behavioral tasks. Most recently we have found that IL-6 specifically affects the proliferation of a subset of mouse SVZ neural progenitors, perturbing their proliferation and gene expression that reduces production of protoplasmic astrocytes and subcortical oligodendrocytes in several brain regions implicated in complex brain disorders. Thus, the central premise of this application is that systemically elevated IL-6 alters secondary neural progenitors to alter interneuron and macroglial genesis. Here we propose to generate human secondary neural progenitors from male and female iPSCs to determine how IL-6 alters their proliferation, specification and gene expression. Comparative studies will be performed on mouse SVZ cells. These comparative studies will enable us to catalog these human secondary neural progenitors. Furthermore, we will perform fate mapping analyses in mice treated with IL-6 at the stage of development corresponding to 24 weeks of human gestation to analyze histogenesis of the ventral striatum, amygdala and prefrontal cortex to more completely understand the histopathlogical orgins of complex neurodevelopmental disorders such as ASD. Our focus on modeling infections late in pregnancy, on aberrant interneuron genesis and macrogliogenesis will substantiate IL-6 as a key target for intervention to prevent psychiatric disorders.