SUMMARY This ambitious proposal will establish an integrated experimental-computational platform to create the first comprehensive brain-wide mesoscale connectivity map in a non-human primate, the common marmoset (Callithrix jacchus),. It will do so by tracing axonal projections of RNA barcode-identified neurons brain-wide in the marmoset, utilizing a sequencing-based imaging method that also permits simultaneous transcriptomic cell typing of the identified neurons. This will help bridge the gap between brain-wide mesoscale connectivity data available for the mouse from a decade of mapping efforts using modern techniques and the absence of comparable data in humans and NHP. The proposal will bring together new viral barcode-based approaches with established tracer-injection based methods to collect an unprecedented data set which will permit comprehensive mapping of region-to-region axonal projections in the marmoset brain with cell-type specificity, apply this data to scientific questions regarding how brain connectivity differs between primates and rodents, address the relation between MRI-derived measures to ground-truth connectivity, and utilize web-based tools to engage the research community in annotating and using the resulting data. A diverse team of world-leading experts and pioneers in the problem domain who are already collaborating, spanning diverse institutions and disciplines, and equipped with outstanding facilities and resources, will come together to assemble the enabling platform. There are five specific aims to achieve stated goals. Aim 1 is to establish data acquisition platform for mesoscale projection mapping in marmoset using barcoded + fluorescent AAV/AAV-retro. Aim 2 is to develop brain-wide single-axon projection maps using systemic injections with simultaneous transcriptomic cell-typing. Aim 3 is to develop data management and analysis pipelines. Aim 4 is to perform comparative studies of the mesoscale connectivity in marmoset and mouse, comparing MRI-based connectivity with ground truth. Aim 5 is to develop platforms for data dissemination, community engagement through web portal, collaborative proofreading and annotations. Such a data set will have profound scientific significance, comparable to the first whole genome map of a primate. As genomes encode the blueprint for understanding an organism’s phenotype, so does the architecture of brain circuitry contain the blueprint for explaining an animal’s behavior and holds the key to many open questions.

NARRATIVE A major obstacle in basic and translational neuroscience is the lack of animal models that have brain structure and function closely related to the human brain. Such models are critical to our understanding to higher brain function as well as developing therapeutics for brain disorders. The goal of this proposal is to establish an integrated experimental-computational platform to create the first comprehensive brain-wide mesoscale connectivity map in a non-human primate. This will help bridge the gap between brain-wide mesoscale connectivity data available for the mouse from a decade of mapping efforts using modern techniques and the absence of comparable data in humans and NHP.