Prenatal striatal morphogenesis: maternal and placental contributions and behavioral consequences

自闭症谱系障碍（ASD）与纹状体扩大和学习过程缺陷有关， 取决于纹状体的功能我们发现纹状体体积增加，纹状体神经元生成增多， 暴露于产前母体重复束缚应激的小鼠纹状体依赖性学习的变化。产前 包括母亲压力在内的干扰是儿童不良发育结果的风险因素（例如， ASD）。关于纹状体扩大是否是ASD相关问题的原因， 以及产前发育过程中的母体、胎盘和大脑因素对学习的影响 纹状体形态发生增加。我们的初步数据显示，产前压力会增加 母体白细胞介素-6，一种与ASD有关的促炎细胞因子， 神经元生成我们还表明，胎盘和胚胎大脑之间IGF信号的增加， 与我们的产前应激模型有关，并独立增加纹状体神经元的产生。我们假设纹状体形态发生的增加在产前神经发育问题的风险中起着核心作用，这些变化是由母体白细胞介素-6和IGF信号介导的。我们专注于胚胎脑中的纹状体形态发生是特别新颖和重要的，我们将研究多个层次的调节和后果时，纹状体的增长增加。我们也将测试相同的机制，在多个母亲的压力模型约束，脚电击，和慢性变量压力-概括这些压力的发现超出了一个单一的范例。首先在目标1中，我们将评估母体白细胞介素-6升高作为产前应激效应的一个组成部分增加纹状体神经元生成的必要性和充分性。我们还将确定曝光时间的重要性， 在胚胎快速发育过程中。其次，在目标2中，我们将评估以下方面的必要性和充分性： 增加IGF信号传导对纹状体祖细胞的产前应激作用。我们还将评估增长因素 母体应激模型中母体循环和胎盘的变化。最后，在目标3中，我们将检查 在动物学习和纹状体神经元的变化中，体内纹状体神经元产生的增加是足够的。 physiology.我们将使用一种新的策略来增加子宫内纹状体神经元的产生：脑室内 注射选择性代谢型谷氨酸受体激动剂CHPG，其具有增加细胞增殖的特异性， 纹状体祖细胞的增殖。在这种暴露的后代中，我们将测试纹状体依赖型的 学习-程序，习惯，逆转，并通过操作性训练的间隔时间。我们还将测量纹状体 学习间隔计时期间的神经元斜坡活动。以我们对产前压力的专业知识， 胚胎脑形态发生，生长因子和啮齿动物的学习，我们很好地解决如何 拟议的机制可以成为预防和治疗的目标。

Autism spectrum disorder (ASD) is linked with enlargement of striatum and deficits in learning processes that depend on striatal function. We have found increased striatal volume, greater striatal neuron generation, and changes in striatal-dependent learning in mice exposed to prenatal maternal repetitive restraint stress. Prenatal disruptions including maternal stress are risk factors for negative developmental outcomes in children (e.g. ASD). There are gaps in knowledge about whether enlarged striatum is causative of ASD-related problems with learning and what maternal, placental and brain factors during prenatal development contribute to increased striatal morphogenesis. We have preliminary data showing that prenatal stress increases levels of maternal interleukin-6, a proinflammatory cytokine implicated in ASD, which independently increases striatal neuron generation. We also show that increased IGF signaling between placenta and embryonic brain is implicated in our prenatal stress model and independently increases striatal neuron generation. We hypothesize that increased striatal morphogenesis plays a central role in prenatal risk for neurodevelopmental problems and that these changes are mediated by maternal interleukin-6 and IGF signaling. Our focus on striatal morphogenesis in embryonic brain is particularly novel and significant; we will examine multiple levels of its regulation and consequences when striatal growth is increased. We also will test the same mechanisms across multiple maternal stress models—restraint, foot-shock, and chronic variable stress--to generalize these stress findings beyond a single paradigm. First in Aim 1, we will assess the necessity and sufficiency of elevated maternal interleukin-6 for increased striatal neuron generation as a component of prenatal stress effects. We will also determine the importance of exposure timing, a critical question during rapid embryonic development. Second in Aim 2, we will assess the necessity and sufficiency of increased IGF signaling for prenatal stress effects on striatal progenitors. We will also assess growth factor changes in maternal circulation and placenta across maternal stress models. Lastly in Aim 3, we will examine the sufficiency of increased striatal neuron generation in vivo for changes in animal learning and striatal physiology. We will use a novel strategy to increase striatal neuron generation in utero: intracerebroventricular injection of a selective metabotropic glutamate receptor agonist, CHPG, with specificity for increasing cell proliferation in striatal progenitors. In offspring with this exposure, we will test striatal dependent types of learning—procedural, habit, reversal, and interval timing through operant training. We will also measure striatal neuronal ramping activity during learned interval timing. With our expertise in understanding prenatal stress, embryonic brain morphogenesis, growth factors, and rodent learning, we are well-situated to address how the proposed mechanisms could be targets for prevention and treatment.