Prenatal striatal morphogenesis: maternal and placental contributions and behavioral consequences

产前纹状体形态发生：母体和胎盘的贡献和行为后果

基本信息

批准号：
10117283
负责人：
HANNA E STEVENS
金额：
$ 38.63万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10117283
关键词：
Address Adolescent Adult Affect Age Agonist Animals Antibodies Behavioral Biological Models Blood Circulation Brain Cell Cycle Cell Proliferation Cell physiology Child Chronic Corpus striatum structure Data Development Dorsal Electrophysiology (science)Embryo Embryonic Development Etiology Exposure to Family Ganglia Generations Goals Growth Growth Factor Habits Immunohistochemistry Impairment Injections Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Interleukin-6 Intervention Knock-out Knowledge Lateral Learning Link Maternal Physiology Measures Mediating Metabotropic Glutamate Receptors Methods Modeling Molecular Morphogenesis Mus Neurodevelopmental Deficit Neurodevelopmental Problem Neurons Outcome Outcome Measure Physiology Placenta Placental Biology Play Population Prevention Process Ramp Regulation Risk Risk Factors Rodent Role Series Signal Transduction Specificity Stress Stress Tests Structure Testing Tissues Training Work autism spectrum disorder autistic children clinically significant cytokine disorder risk experimental study fetal in utero in vivo innovation juvenile animal learned behavior maternal serum maternal stress mature animal mouse model nerve stem cell novel novel strategies offspring postnatal prenatal prenatal stress prevent progenitor restraint restraint stress single-cell RNA sequencing stem cells

项目摘要

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.

自闭症谱系障碍（ASD）与纹状体的扩展有关，并在学习过程中定义取决于纹状体功能。我们发现纹状体体积增加，纹状体神经元的产生更大，并且暴露于产前母亲重复约束应力的小鼠中纹状体依赖性学习的变化。产前包括母子压力在内的破坏是儿童负面发育结果的危险因素（例如 ASD）。关于扩大纹状体是否是与ASD相关问题的结构的知识差距在产前发展期间的学习以及什么材料，胎盘和大脑因素对纹状体形态发生增加。我们有初步数据，表明产前应力增加母体白介素6，一种在ASD中实施的促炎细胞因子，它独立增加纹状体神经元产生。我们还表明，pleceta和胚胎大脑之间的IGF信号增加是在我们的产前压力模型中实施，并独立增加纹状体神经元的产生。我们假设增加的纹状体形态发生在神经发育问题的产前风险中起着核心作用，并且这些变化是由Mater Interleukin-6和IGF信号传导介导的。我们对胚胎大脑中纹状体形态发生的关注尤其是新颖而重要。当我们还将在多个成熟的应力模型中测试相同的机制时，我们将检查其调节的多个级别和后果，例如延伸，脚打和慢性变化应力 - 将这些应力发现超出了一个范式。首先，在AIM 1中，我们将评估成熟的白介素-6的必要和安全性，以增加纹状体神经元的产生，这是产前应激效应的一部分。我们还将确定暴露时间的重要性，这是一个关键快速胚胎发育过程中的问题。第二位于AIM 2，我们将评估必要和充分性增加IGF信号传导对纹状体祖细胞的产前应力影响。我们还将评估生长因子跨母校应力模型的孕产妇循环和片剂的变化。最后在AIM 3中，我们将检查体内纹状体神经元产生增加的充分性，用于动物学习和纹状体的变化生理。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：脑室室内选择性代谢性谷氨酸受体激动剂CHPG注射具有特异性的细胞纹状体祖细胞增殖。在这种曝光的后代，我们将测试纹状体依赖类型学习 - 通过操作培训进行培训，习惯，逆转和间隔时间。我们还将测量纹状体在学习间隔时间内，神经元横斜活动。凭借我们了解产前压力的专业知识，胚胎脑的形态发生，生长因子和啮齿动物学习，我们非常适合解决如何解决建议的机制可能是预防和治疗的目标。