Project 1: The Origin and Diversity of Human GABAergic Interneurons

项目1：人类GABA能中间神经元的起源和多样性

基本信息

批准号：
10221061
负责人：
Arturo Alvarez-Buylla
金额：
$ 26.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10221061
关键词：
3-Dimensional Acute Amygdaloid structure Anatomy Architecture Area Autopsy Behavior Birth Brain Cells Chain Migrations Cognition Collection Development Disease Dorsal Epilepsy Equilibrium Etiology Evolution Funding Ganglia Gene Expression Genetic Goals Grant Growth Histologic Human Human Characteristics Image Individual Infant Infant Development Interneurons Knowledge Lead Life Medial Molecular Molecular Profiling Neonatal Neurodevelopmental Disorder Neurons Output Pathway interactions Pattern Perinatal Population Pregnancy Property Prosencephalon Risk Role Route Sampling Site Slice Source Stream Structure Testing Third Pregnancy Trimester Work autism spectrum disorder cell growth regulation cingulate gyrus frontal lobe improved inhibitory neuron interdisciplinary approach migration migratory population neonatal human nerve stem cell neurogenesis neuron development neuropsychiatric disorder novel postnatal postnatal human progenitor reconstruction single-cell RNA sequencing stem cells time use transcription factor transcriptomics

项目摘要

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.

项目摘要皮质中间神经元是一套多样化的局部抑制细胞，对于适当平衡激发和抑制和大脑功能的关键。中间神经元的异常发展可以导致严重的神经精神疾病（神经间病中）。鉴定分子与这些疾病有关的途径和细胞种群对于了解它们病因并提高我们预测哪些人有危险的能力。我们原始的工作格兰特证明，婴儿额叶维持大量迁徙出生后几个月中的中间神经元。迁移的年轻神经元（ARC）的集合针对婴儿额叶的许多区域。这些细胞对最终的重要贡献人脑的间神经元组成（例如扣带回）。人皮质，因此，出生后几个月继续接受中间神经元，尤其是在较高的认知与神经发育障碍有关。同样，我们最近的证据表明，人类杏仁核在产后继续接受许多年轻神经元。这些观察显着改变了我们如何看待婴儿大脑的发展并提高需要更好地了解人皮质中间神经元的起源，包括在弧后出生后迁移。人弧和杏仁核中的年轻神经元是有丝分裂的（ki67-），支持以下假设，即它们不是在这些区域内产生的。这区域转录因子在ARC中的表达模式表明它们来自发展人类腹前脑；内侧和尾神经节的隆起（HMGE和 HCGE）。该项目的总体目标是了解人类通用电气如何产生大型数量和多种类型的皮质中间神经元通过研究其在中期中的发育晚期妊娠和早期产后生活。我们将确定 HMGE，HLGE和HCGE的增生种群使用人类后脑大脑来自新生儿和婴儿病例（出生后6个月后最多）的样品，定义中间神经元如何亚型在围产期的人脑中出现。拟议的研究将确定独特的和人类抑制神经元发展的持续特性。通过使用多学科方法（包括转录组，组织学和急性切片培养物），我们旨在建立中间神经元如何在人脑中制造并提供所需的基本知识了解他们在疾病中的作用。