Gyrencephalic Model for Neurodevelopmental Disease and Postnatal Cortical Therapeutic Interventions

项目总结 皮质抑制神经元(CIN)是一类神经元亚群，与脑出血密切相关。 神经发育障碍(NDDS)的发病机制，如自闭症谱系障碍(ASD) 最近发表的证据表明，CIN在出生后的人脑中发生了强劲的迁移，这一群体被称为 弧形，在生命的最初几个月，它构成了前额叶皮质和扣带回的皮质网络。 这种迁徙人口的存在表明，人类的大脑皮层在 围产期，出生前后的时间，并提出了需要寻找方法来审问 “晚迁移”神经元的功能重要性。然而，围产期人类皮质发育 在无脑啮齿类动物的脑和脑组织中不完全表现为这一时期 少之又少。这在人类发育神经科学领域留下了一个根本性的空白。我的长期目标是 研究是为了了解围产期新皮质旋转的发育。 出生前和出生后的瞬间，以及在这段时间内精神分裂如何导致神经精神疾病 例如ASD。我们的中心假设是CIN继续通过围产期传播到多个皮质区域，并且 这种迁移的中断导致了不正常的社会行为，这是ASD的一个标志性表型。为了测试 为此，我们将开发仔猪皮质，它与人类的新大脑皮层非常相似，作为研究 CIN在围产期脑内迁移的分子多样性。我们还将进行出生测定实验，以 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)极低密度脂蛋白受体，与ASD的病因有关，3，4，在CIN的一个亚群中。这个 本课程将研究中断Reelin信号的细胞和行为后果。建议进行的研究 将鉴定移行性CIN的独特特性，并旨在建立一种新的方法来研究ASD。 通过建立一个更真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，找出治疗影响神经细胞的新方法，甚至在出生后也是如此。

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.