A Molecular and Cellular Atlas of the Marmoset Brain

项目摘要/摘要 哺乳动物大脑的复杂性是任何其他器官都无法比拟的，而且理解它的 细胞的组成对于理解它如何引起认知和行为是至关重要的。很明显，大脑 包含比迄今所描述的更多的单元格类型。现在可以通过以下方式区分许多细胞类型 它们的基因表达模式，以及对这些模式的了解，可以为特定的基因提供访问 成群的神经元。操纵和测量基因定义的细胞类型和活性的能力 电路将允许我们从静态的解剖学描述转向对大脑功能的动态理解。 尽管基因工具极大地提高了我们对大脑功能的理解，但它们 在很大程度上仅限于老鼠。虽然小鼠是神经科学许多领域的基本模型，但也有 高级大脑功能的许多方面不能在啮齿类动物身上充分建模。同样，许多大脑 紊乱会影响高级认知功能，而这些功能在啮齿类动物中没有明显的相似之处。因此，迫切需要 寻找在系统进化上与人类更接近的新遗传模型。 一个很有前途的新兴灵长类模型是普通的绒猴，一种小型的新世界灵长类动物，它有 为神经科学和基因研究提供了许多优势。在过去的三年里，我们建立了一个大型的 绒猴群体和麻省理工学院的基因工程平台为各种不同物种生成绒猴遗传模型 大脑紊乱。我们已经成功地展示了高效的基因敲除和敲除技术 绒猴胚胎。我们还生成并组装了高质量的绒猴基因组序列。在……里面 此外，我们正在开发用于自动行为分析的硬件和软件以及 电生理记录和多光子成像方法。我们的目标是使这成为一个全国性的 利用绒猴研究大脑功能和功能障碍的技术和资源中心。在此建议 将另一个重要的数据集添加到这个潜在的变革性模型中-使用单细胞RNAseq 系统地定义细胞类型、它们的位置和形态。这些数据对于生成像元至关重要 特定类型的遗传工具以及用于监控和操作特定类型的细胞中的电路活动 方式，了解大脑功能和功能障碍的关键方法。

PROJECT SUMMARY/ABSTRACT The complexity of the mammalian brain is unparalleled by any other organ, and understanding its cellular composition is essential to understand how it gives rise to cognition and behavior. It is clear that brain contains many more cell types than have been described to date. Many cell types can now be distinguished by their patterns of gene expression, and knowledge of these patterns can provide genetic access to specific populations of neurons. The ability to manipulate and measure activity in genetically defined cell types and circuits will allow us to move from a static anatomical description to a dynamic understanding of brain function. Although genetic tools have dramatically advanced our understanding of brain function, they have largely been confined to mice. While mice are essential models for many areas of neuroscience, there are also many aspects of higher brain function that cannot be adequately modeled in rodents. Similarly, many brain disorders affect higher cognitive functions that have no clear parallels in rodents. There is thus an urgent need for new genetic models that are phylogenetically closer to humans. A promising emerging primate model is the common marmoset, a small new world primate that has many advantages for neuroscience and genetic research. In the past three years, we have established a large marmoset colony and a genetic engineering platform at MIT to generate marmoset genetic models for various brain disorders. We have successfully demonstrated efficient gene knockout and knockin techniques in marmoset embryos. We have also generated and assembled high quality marmoset genome sequence. In addition, we are developing hardware and software for automated behavioral analysis as well as electrophysiological recording and multi-photon imaging approaches. Our goal is to make this a national technology and resource center for using marmosets to study brain function and dysfunction. Here propose to add another important dataset to this potentially transformative model—using single cell RNAseq to systematically define cell types, their location and morphology. These data will be critical for generating cell type-specific genetic tools as well as for monitoring and manipulating circuit activity in a cell type-specific manner, key approaches to understand brain function and dysfunction.