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中的缺陷有关， 取决于纹状体功能。我们发现纹状体体积增加，纹状体神经元生成增加， 孕期母体重复束缚应激暴露下小鼠纹状体依赖学习的变化。产前 包括母亲压力在内的干扰是儿童负面发展结局的危险因素(例如 ASD)。对于纹状体肥大是否是引起自闭症相关问题的原因，人们的认识还存在差距。 与学习以及母体、胎盘和大脑因素在产前发育中的作用 纹状体形态发生增加。我们有初步数据显示，产前压力会增加 母体白介素6，一种与ASD有关的促炎细胞因子，可独立增加纹状体 神经元的产生。我们还表明，胎盘和胚胎大脑之间IGF信号的增加是 与我们的产前应激模型有关，并独立地增加纹状体神经元的生成。我们假设纹状体形态发生增加在神经发育问题的产前风险中起核心作用，并且这些变化是由母体白介素6和IGF信号介导的。我们对胚胎脑中纹状体形态发生的关注是特别新颖和重要的；我们将研究它的多个水平的调节和当纹状体生长增加时的后果。我们还将在多种母体应激模型上测试相同的机制--束缚、足部电击和慢性可变应激--以将这些应激发现推广到单一范式之外。首先，在目标1中，我们将评估作为产前应激效应的一个组成部分，提高母体白介素6水平对于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机的重要性，这是一个关键 在快速胚胎发育过程中的问题。第二，在目标2中，我们将评估以下各项的必要性和充分性 胎儿期应激对纹状体祖细胞影响的IGF信号增强。我们还将评估增长因素 不同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 体内纹状体神经元生成增加对动物学习和纹状体改变的充分性 生理学。我们将使用一种新的策略来增加子宫中纹状体神经元的生成：脑室内 选择性代谢型谷氨酸受体激动剂CHPG的注射 纹状体前体细胞的增殖。在有这种接触的后代中，我们将测试纹状体依赖类型的 学习--通过操作训练进行程序性、习惯性、反转和间歇计时。我们还将测量纹状体 在习得的间期计时中神经元的斜波活动。凭借我们在理解产前压力方面的专业知识， 胚胎脑形态发生、生长因子和啮齿动物学习，我们很好地解决了 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.