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.