A Molecular and Cellular Atlas of the Marmoset Brain

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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.