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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) 与纹状体增大和学习过程缺陷有关，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多，并且暴露于产前母亲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负面发育结果的危险因素（例如，自闭症谱系障碍）。关于纹状体增大是否导致 ASD 相关问题的认识存在空白与学习以及产前发育过程中母亲、胎盘和大脑因素的贡献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细胞介素 6，一种与 ASD 相关的促炎细胞因子，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 信号传导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的增加在神经发育问题的产前风险中发挥着核心作用，并且这些变化是由母体白细胞介素 6 和 IGF 信号传导介导的。我们对胚胎大脑纹状体形态发生的关注尤其新颖且意义重大。我们将研究纹状体生长增加时其调节的多个层面和后果。我们还将在多种母亲压力模型（约束、足部冲击和慢性可变压力）中测试相同的机制，以将这些压力发现推广到单一范式之外。首先，在目标 1 中，我们将评估母体白细胞介素 6 升高对于增加纹状体神经元生成（作为产前应激影响的一个组成部分）的必要性和充分性。我们还将确定曝光时间的重要性，这是一个关键因素胚胎快速发育过程中的问题。第二个目标 2，我们将评估以下内容的必要性和充分性：产前应激对纹状体祖细胞影响的 IGF 信号增加。我们还将评估生长因子孕产妇应激模型中孕产妇循环和胎盘的变化。最后在目标 3 中，我们将检查体内增加纹状体神经元生成足以改变动物学习和纹状体生理。我们将使用一种新策略来增加子宫内纹状体神经元的生成：脑室内注射选择性代谢型谷氨酸受体激动剂 CHPG，具有增加细胞特异性的作用纹状体祖细胞的增殖。在具有这种暴露的后代中，我们将测试纹状体依赖性类型学习——通过操作训练进行程序、习惯、逆转和间隔计时。我们还将测量纹状体在学习的间隔时间期间神经元的斜坡活动。凭借我们在了解产前压力方面的专业知识，胚胎大脑形态发生、生长因子和啮齿动物学习，我们有能力解决如何拟议的机制可以作为预防和治疗的目标。