Cellular resolution multi-omics of white matter tracts in developing human and non-human primate brain for cell atlases-Diversity

Project Summary The molecular evolution underlying cell type diversity and function has facilitated the increased cognitive capacity of humans. While significant progress has been made to uncover cell type specific gene expression programs in the brains of rodents, only a modest amount of progress has been made in human brains. Moreover, the majority of the existing cell type genomic datasets focus on gray matter. Our recent work has identified important human-specific gene expression patterns relevant to non-neurons, especially oligodendrocytes. Human brain imaging studies in disorders such as autism spectrum disorders and schizophrenia have identified alterations in white matter tracts that are primarily comprised of oligodendrocytes. We therefore propose to profile white matter tracts that are anatomically comparable across primates: pyramidal tract, optic chiasm, cerebellar white matter, and corpus callosum. Because oligodendrocyte maturation varies between gray and white matter, we will profile tissue across development. This comparative cell type profiling between human and non-human primate brain will provide spatially defined epigenomic and transcriptomic data through the following four Aims: 1) Profile single cell level transcriptional maps and chromatin states of white matter tracts and functionally associated gray matter in human brain across development; 2) Profile single cell level transcriptional maps and chromatin states of white matter tracts and functionally associated gray matter across development in two non-human primates: rhesus macaque and the common marmoset; 3) Profile single cell level transcriptional maps and chromatin states of white matter tracts and functionally associated gray matter in additional tissue from adult great ape and monkey brains; and 4) Validate observed differences in white matter composition at the cell type level in human and non- human primates. Together, these aims will molecularly define understudied cell types from human and non- human primate brains. Finally, the training plan that we have described in this proposal will provide Mr. Outland with a cutting-edge skill set in neurogenomics.