Project 1: The Origin and Diversity of Human GABAergic Interneurons

项目摘要 皮质中间神经元是一组不同的局部抑制细胞，对于适当的平衡至关重要。 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 导致严重神经精神障碍（神经间病变）。分子鉴别 与这些疾病有关的通路和细胞群是了解它们的必要条件。 病因学，并提高我们预测哪些人处于危险之中的能力。从我们最初的作品 格兰特证明，婴儿的额叶维持着大量的迁移， 在出生后的几个月里，这些迁移的年轻神经元（Arc） 针对婴儿额叶的很多区域这些细胞对最终的 人类大脑的中间神经元组成（例如扣带回）。人类大脑皮层， 因此，在出生后的几个月里，它继续接受中间神经元，特别是在 与神经发育障碍有关的高级认知。同样，我们最近的证据表明， 表明人类杏仁核在出生后继续接收许多年轻的神经元。这些 观察结果显著改变了我们对婴儿大脑发育的看法， 需要更好地了解人类皮层中间神经元的起源，包括那些 出生后迁移到弧区人类Arc和杏仁核中的年轻神经元是有丝分裂后的 （Ki 67-），支持它们不在这些区域内产生的假设。的 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基因组如何产生大量的 数量和不同类型的皮层中间神经元，通过研究其发展中期， 妊娠晚期和产后早期。我们将确定的遗传和分子特性， 使用人死后脑的hMGE、hLGE和hCGE中的增殖群体 新生儿和婴儿病例（出生后6个月）的样本，定义了中间神经元 亚型出现在围产期人脑中。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特性。通过使用多学科 方法（包括转录组学，组织学和急性切片培养），我们的目标是建立 中间神经元是如何在人脑中产生的，并提供了所需的基本知识。 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.