A Molecular and Cellular Atlas of the Marmoset Brain

项目概要/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，了解它的复杂性， 细胞组成对于理解它如何产生认知和行为至关重要。很明显，大脑 含有比迄今为止所描述的更多的细胞类型。许多细胞类型现在可以通过 他们的基因表达模式，这些模式的知识可以提供遗传访问特定的 神经元群体。操纵和测量遗传定义的细胞类型中的活性的能力， 电路将使我们从静态的解剖学描述转向对大脑功能的动态理解。 尽管遗传工具极大地促进了我们对大脑功能的理解， 主要局限于小鼠。虽然小鼠是神经科学许多领域的基本模型，但也有一些研究。 高级大脑功能的许多方面无法在啮齿动物中充分建模。同样，许多大脑 这些疾病影响高级认知功能，在啮齿类动物中没有明显的相似之处。因此，迫切需要 寻找在遗传学上更接近人类的新遗传模型。 一种有希望的新兴灵长类动物模型是普通的绒猴，一种新世界的小型灵长类动物， 对神经科学和遗传学研究有很多好处。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遗传工程平台，以生成绒猴遗传模型， 大脑紊乱我们已经成功地证明了有效的基因敲除和敲入技术， 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 此外，我们正在开发用于自动行为分析的硬件和软件， 电生理记录和多光子成像方法。我们的目标是让它成为全国性的 利用绒猴研究大脑功能和功能障碍的技术和资源中心。在此提议， 为这个潜在的变革性模型添加了另一个重要的数据集-使用单细胞RNAseq， 系统地定义细胞类型、它们的位置和形态。这些数据对于生成细胞至关重要 类型特异性遗传工具以及用于监测和操纵细胞类型特异性 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.