Elucidating neural substrates that mediate autism-like behaviors

摘要 在母体子宫中发育的胎儿会暴露在环境压力下，这可能会导致 与长期的神经和行为变化的发展有关。不受控制 子宫中遇到的炎症及其对后代行为的影响已经被模拟 在啮齿动物身上，后来被称为母体免疫激活(MIA)。然而，它仍然是 尚不清楚在怀孕的水坝中发生的免疫激活是如何转化为 后代的神经和行为变化。 使用缺乏促炎免疫细胞特定子集的基因突变体和 阻断针对其活性的抗体，我们最近发现促炎T细胞 母亲表达IL-17a的辅助性细胞(Th17细胞)诱导MIA依赖 子代的行为改变和异常的皮质表型。我们还观察到， IL-17a受体(IL-17ra)在胎脑中表达，其表达在 MIA上的皮质板。这些观察结果综合起来表明了一种令人兴奋的 胎脑中表达的IL-17ra不受控制的激活可能导致 异常的皮质斑块和这些结构异常最终导致MIA- 相关的行为表型。因此，在本申请中，我们建议1)确定是否 皮质异常可以预测MIA后代的行为表型，2)特征 成年MIA子代的皮质异常，以及3)功能决定皮质是否 表型是MIA行为异常的根本原因。

ABSTRACT Developing fetus in maternal womb can be exposed to environmental stress, and this may lead to the development of long-lasting neurological and behavioral changes. Uncontrolled Inflammation encountered in utero and its effects on behaviors of offspring have been modeled in rodents and subsequently coined as maternal immune activation (MIA). However, it is still unknown how the immune activation, which takes place in pregnant dams, is translated into neurological and behavioral changes in offspring. Using both genetic mutants lacking a particular subset of pro-inflammatory immune cells and blocking antibodies targeting their activities, we have recently found that pro-inflammatory T helper cells (Th17 cells) expressing intereukin-17a (IL-17a) in mothers induce MIA-dependent behavioral changes and abnormal cortical phenotypes in offspring. We also observed that the receptor for IL-17a (IL-17Ra) is expressed in the fetal brain and its expression is increased in the cortical plate upon MIA. These observations taken together suggest an exciting hypothesis that uncontrolled activation of IL-17Ra expressed in fetal brain induces abnormal cortical patches and these structural abnormalities eventually lead to the MIA- associated behavioral phenotypes. Thus, in this application, we propose 1) to determine if cortical abnormalities could predict behavioral phenotypes in MIA offspring, 2) to characterize cortical abnormalities in adult MIA offspring, and 3) functionally determine if the cortical phenotype is the underlying cause of the MIA behavioral abnormalities.