Gyrencephalic Model for Neurodevelopmental Disease and Postnatal Cortical Therapeutic Interventions

项目摘要 皮质抑制性神经元（CIN）是一种神经元亚群，其强烈地牵涉到神经元的生长。 神经发育障碍（NDD）的发病机制，例如自闭症谱系障碍（ASD）1。我们 最近发表的证据表明，在出生后的人类大脑中，CIN迁移很强， 弧，这有助于在前额叶皮层和扣带皮层网络在生命的第一个月。 这种迁移人群的存在表明，人类大脑皮层在大脑中仍然是动态的。 围产期，出生前后的时间，并提出了需要寻找方法，询问 “晚期迁移”神经元的功能重要性。然而，围产期人类皮质发育， 在无脑（无脑）啮齿类动物的大脑和脑组织中， 稀少。这在人类发育神经科学中留下了一个根本性的空白。我的长期目标是 研究的目的是了解在围产期，几周， 出生前后，以及在此期间的中断如何导致神经精神疾病 如ASD。我们的中心假设是CIN继续在围产期向多个皮质区域传播， 这种迁移的中断会导致异常的社会行为，这是ASD的标志性表型。测试 为此，我们将开发与人类新皮层非常相似的小猪皮层，作为研究 围产期脑内CIN迁移的分子多样性。我们还将进行出生日期实验， 确定出生后干细胞分裂是否在出生后继续产生CIN。最后，我们将生成一个 特异性去除Reelin受体表达的条件性仔猪模型（极低密度 脂蛋白受体）VLDLR，涉及ASD病因学3，4，在一个亚群的“晚期迁移”CIN。的 将检查中断Reelin信号传导的细胞和行为后果。拟议的研究 将确定迁移性CIN的独特特性，旨在建立一种新的方法来研究ASD。 通过建立一个更忠实的人类大脑皮层模型，我们可以建立所需的细胞过程， 在大脑皮层发育的后期，并确定新的方法来治疗影响神经细胞，甚至在出生后。

PROJECT SUMMARY Cortical inhibitory neurons (CIN) are a neuronal subpopulation that have been strongly implicated in the pathogenesis of neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD)1. We recently published evidence of robust CIN migration in the postnatal human brain2, in a population called the Arc, that contributes to the cortical network in the prefrontal cortex and cingulate during the first months of life. The presence of this migratory population demonstrates that the human cortex remains dynamic in the perinatal period, the time before and after birth, and raised the need to find methods to interrogate the functional importance of “late-migrating” neurons. Perinatal human cortical development, however, is incompletely represented in the lissencephalic (agyric) rodent brain and brain tissues from this period are scarce. This has left a fundamental gap in human developmental neuroscience. The long-term goal of my research is to understand the development of the gyrated neocortex during the perinatal period, the weeks immediately before and after birth, and how disruption during that time can lead to neuropsychiatric conditions such as ASD. Our central hypothesis is that CIN continue to travel perinatally to multiple cortical regions, and that disruption of this migration contributes to abnormal social behaviors, a hallmark phenotype in ASD. To test this, we will develop the piglet cortex, which closely mimics the human neocortex, as a model to investigate the molecular diversity of CIN migrating in the perinatal brain. We will also perform birthdating experiments to determine if postnatal stem cell divisions continue to generate CIN after birth. Lastly, we will generate a conditional piglet model that specifically removes expression of the Reelin receptor, (very low density lipoprotein receptor) VLDLR, implicated in ASD etiology3,4, within a subpopulation of “late-migrating” CIN. The cellular and behavioral consequences of interrupting Reelin signaling will be examined. The proposed studies will identify distinctive properties of migratory CIN and aim to establish a novel approach to investigate ASD. By creating a more faithful model of the human cortex, we can establish the cellular processes that are needed late in cortical development and identify new ways to therapeutically influence nerve cells, even after birth.