Project 1: The Origin and Diversity of Human GABAergic Interneurons

项目总结 皮质中间神经元是一组不同的局部抑制细胞，对适当平衡 兴奋和抑制是大脑功能的关键。中间神经元的异常发育可以 导致严重的神经精神障碍(神经间性疾病)。分子鉴定 这些疾病中涉及的通路和细胞群对于了解它们的 并提高我们预测哪些人处于危险之中的能力。根据我们的原创作品 格兰特证明，婴儿的额叶维持着大量的迁徙人口 出生后几个月的中间神经元。这组迁移的年轻神经元(Arc) 目标是婴儿额叶的许多区域。这些细胞对期末考试有重要的贡献 人脑的中间神经元组成(如扣带回)。人类大脑皮层， 因此，在出生后的几个月里，特别是在 较高的认知能力与神经发育障碍有关。同样，我们最近的证据 显示人类杏仁核在出生后继续接收许多年轻的神经元。这些 观察显著地改变了我们看待婴儿大脑发育的方式，并提高了 需要更好地了解人类皮质中间神经元的起源，包括那些 出生后在弧形中迁移。人脑弓状核和杏仁核中的年轻神经元是有丝分裂后的 (Ki67-)，支持它们不是在这些区域内产生的假设。这个 区域转录因子在Arc中的表达模式表明它们来自于 发育中的人腹侧前脑；内侧和尾侧神经节隆起(hMGE和 HCGE)。该项目的总体目标是了解人类GE是如何产生大量 大脑皮层中间神经元的数量和不同类型的发育 妊娠晚期和出生后早期生活。我们将确定其遗传和分子特性 人死后脑hMGE、hLGE和hCGE中的增殖群 新生儿和婴儿(出生后6个月)的样本，定义中间神经元是如何 亚型出现在围产期的人脑中。拟议的研究将确定独特的和 人类抑制性神经元发育的持续性。通过使用多学科 方法(包括转录、组织学和急性切片培养)，我们的目标是建立 人脑中的中间神经元是如何形成的，并提供所需的基本知识 以了解它们在疾病中的作用。

PROJECT SUMMARY Cortical interneurons are a diverse set of local inhibitory cells essential for proper balance of excitation and inhibition and key to brain function. Abnormal development of interneurons can lead to severe neuropsychiatric disorders (interneuropathies). Identification of the molecular pathways and cellular populations implicated in these disorders is necessary to understand their etiology and to improve our ability to predict which individuals are at risk. Work from our original grant demonstrated that the infant frontal lobe maintains a large population of migratory interneurons for several months after birth. This collection of migrating young neurons (Arc) targets many areas of the infant frontal lobe. These cells contribute importantly to the final interneuron composition of the human brain (e.g. cingulate gyrus). The human cortex, therefore, continues to receive interneurons for several months after birth, especially in areas of higher cognition implicated in neurodevelopmental disorders. Similarly, our recent evidence shows that the human amygdala continues to receive many young neurons postnatally. These observations significantly change how we view the development of the infant brain and raise the need to better understand the origins of human cortical interneurons, including those that migrate postnatally in the Arc. Young neurons in the human Arc and amygdala are postmitotic (Ki67-), supporting the hypothesis that they are not generated within these regions. The expression pattern of regional transcription factors in the Arc, suggests that they come from the developing human ventral forebrain; the Medial and Caudal Ganglionic Eminences (hMGE and hCGE). The project's overall goal is to understand how the human GE generates large numbers and diverse types of cortical interneurons by studying its development during the mid- late gestation and early postnatal life. We will determine the genetic and molecular properties of proliferative populations in the hMGE, hLGE, and hCGE using human postmortem brain samples from neonatal and infant cases (up to 6 months after birth), define how interneuron subtypes arise in the perinatal human brain. The proposed studies will identify the unique and sustained properties of human inhibitory neuron development. By using a multi-disciplinary approach (including transcriptomic, histological, and acute slice cultures), we aim to establish how interneurons are made in the human brain and provide the fundamental knowledge needed to understand their role in disease.