Single-nucleus multi-omics analyses reveal cellular and molecular innovations in the anterior cingulate cortex during primate evolution

The anterior cingulate cortex (ACC) of the human brain is involved in higher-level cognitive functions such as emotion and self-awareness. We generated profiles of human and macaque ACC gene expression and chromatin accessibility at single-nucleus resolution. We characterized the conserved patterns of gene expression, chromatin accessibility, and transcription factor binding in different cell types. Combining the published mouse data, we discovered the molecular identities and cell-lineage origin of the primate von Economo neurons (VENs). Our in vitro and in vivo experiments identified a group of primate-shared and human-specific VEN marker genes, such as PCSK6, ADAMTSL3, and CDHR3, potentially contributing to VEN morphogenesis. We demonstrated that the human-specific sequence changes account for the cellular and functional innovations in the ACC during primate evolution and human origin. These findings provide new insights into understanding the cellular composition and molecular regulation of ACC and its evolutionary role in shaping human-owned higher cognitive skills.