Cross-species Multimodal Single-cell Profiling of Dorsal and Ventral Prefrontal Cortex Reveals Cell-type Divergence and PTSD-associated Regulatory Landscapes

Abstract The prefrontal cortex subregions—particularly the prelimbic (PL) and infralimbic (IL) 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 PL/dACC are implicated in fear acquisition, IL/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 PL/IL and human dACC/vmPFC to construct a cross-species, multi-omic atlas. We 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 risk enrichment, SNP-anchored GRNs linked to PTSD heritability, and stress-primed chromatin states in candidate neurons. This work provides a molecularly resolved subregional atlas and advances translational understanding of PTSD-related gene regulation divergence and complement the present multi-omic research of PTSD.