The Development and Diversity of Forebrain Cholinergic Neurons

项目摘要/摘要 纹状体胆碱能中间神经元(SCI)和基底前脑胆碱能投射神经元(BFCN)， 它们共同包含了所有的前脑胆碱能神经元，是神经调节所必需的 前脑。然而，人们对这些神经元的特性和多样性知之甚少。前兆 因为所有的前脑胆碱能神经元都是在胚胎大脑的同一区域出生的，目前还不知道是如何产生的 这些胆碱能前体最终发育成不同的中间神经元和投射神经元群体。 尽管在SCI和BFCN中存在表型多样性，但这种多样性的发育起源 也没有分子标记来定义胆碱能神经元的亚类 体现了这种多样性。该项目旨在解决这些问题。该项目有两个主要目标： 1)将成熟的前脑胆碱能神经元的特性与其前体细胞的特性联系起来，并 利用这些信息来理解它们是如何产生不同类别的前脑胆碱能神经元的； 为了描述导致前脑胆碱能神经元多样性的转录级联， 尤其是那些区分胆碱能中间神经元和投射神经元的神经元。这些目标将是 通过组合遗传命运图谱、转录图谱和评估 体外和体内的候选转录因子。在这项研究的结论中，分类的框架 超出其解剖位置和形态的前脑胆碱能神经元将被发育，并 这一分类方案将与它们的发展挂钩。此外，转录中的关键基因 在发育过程中区分胆碱能中间神经元和投射神经元的级联将被识别。 这将提高我们对前脑正常发育所需条件的理解。 胆碱能系统，并为我们提供了基因工具来专门研究和操纵离散的种群 这个系统内的细胞。

PROJECT SUMMARY/ABSTRACT Striatal cholinergic interneurons (SCIs) and basal forebrain cholinergic projection neurons (BFCNs), which together encompass all forebrain cholinergic neurons, are required for neuromodulation throughout the forebrain. However, both the specification and diversity of these neurons are poorly understood. The precursors for all forebrain cholinergic neurons are born in the same region of the embryonic brain, and it is not known how these cholinergic precursors ultimately develop into diverse populations of interneurons and projection neurons. Although there is phenotypic diversity within SCIs and BFCNs, the developmental origins of this diversity has not been characterized, nor are there molecular markers to define the subclasses of cholinergic neurons that embody this diversity. This project aims to address these questions. There are two primary goals of this project: 1) to link the properties of mature forebrain cholinergic neurons with properties of their precursor cells, and to use this information to understand how they give rise to distinct classes of forebrain cholinergic neurons; and 2) to characterize the transcriptional cascades that give rise to the diversity of forebrain cholinergic neurons, particularly those that distinguish cholinergic interneurons and projection neurons. These goals will be accomplished through a combination of genetic fate mapping, transcriptional profiling, and assessment of candidate transcription factors in vitro and in vivo. At the conclusion of this study, a framework for classifying forebrain cholinergic neurons beyond their anatomical location and morphology will have been developed, and this classification scheme will be linked to their development. Furthermore, key genes in the transcriptional cascades during development that distinguish cholinergic interneurons and projection neurons will be identified. This will both improve our understanding of what is required for the normal development of the forebrain cholinergic system and provide us with genetic tools to specifically study and manipulate discrete populations of cells within this system.