Multiregion Cross-species Single-cell Multimodal Study of Prefrontal Cortex Reveals Cell-type Divergence and PTSD-associated Regulatory Landscapes

Abstract The prefrontal cortex subregions—particularly the prelimbic (PLPFC) and infralimbic (ILPFC) cortices in rodents and dorsal anterior cingulate (dACC) and ventromedial prefrontal cortex (vmPFC) in humans—exhibit functionally specialized yet interconnected roles in PTSD pathogenesis. While PLPFC/dACC are implicated in fear memory, ILPFC/vmPFC are associated with fear extinction. However, the inherent difference and cross-species molecular signatures underlying these functional parallels remain unresolved. To bridge the gap, we integrate single-nucleus RNA-seq, ATAC-seq, and spatial transcriptomics across mouse PLPFC/ILPFC and human dACC/vmPFC to construct a cross-species, multi-omic atlas. We then delineate conserved/divergent gene regulatory networks (GRNs), with emphasis on excitatory neuron evolution. By incorporating PTSD GWAS data and gene expression changes from vmPFC of PTSD patients, we identify cell-type-specific PTSD risks, SNP-anchored GRNs linked to PTSD heritability, and stress-induced chromatin-primed genes. This work provides a multiregion atlas and advances translational understanding of PTSD-related gene regulation divergence from mouse transition to human and complement the present multi-omic research of PTSD.