Developing cell type-specific enhancers and connectivity mapping pipelines for marmosets

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PROJECT SUMMARY 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. Furthermore, recent large- scale single cell transcriptomic analyses have revealed many neuron types, connections and gene expression patterns that are unique to primates. Thus, there is an urgent need for new genetic models that have brain structure and function closer to humans. Non-human primates (NHP) are much more closely related to humans than are rodents, and this is reflected in their brain development, structure and physiology. Hence, it is increasingly recognized that they provide an attractive model to study higher brain function and brain disorders. A promising emerging NHP model is the common marmoset, a small new world primate that has many advantages for neuroscience and genetic research. However, lack of tools with cell type specificity has been a major obstacle in advancing structural and functional studies in NHP. With the combined single cell RNA-seq and single cell ATAC-seq, it is now possible to nominate short cell type-specific enhancer sequences. If validated, these enhancers will provide an effective tool to map connectivity and interrogate function using virus mediated expression. The difficulty lies in the identification of functional enhancers from the hundreds or thousands of nominated potential enhancer sequences in NHP. Here we propose (1) to use a novel high throughput in vivo approach to identify functional enhancers, and (2) to establish a whole-brain circuit mapping pipeline for use striatal circuitry to validate our approach for cell type-specific connectivity mapping in marmosets. When completed, these studies will provide much needed essential tools, methods and computational pipelines for cell type-specific mapping and functional interrogation of the marmoset brain in healthy and disease models.