Cannabidiol modulates spontaneous recovery through distinct and conserved transcriptomic signatures in mPFC subregions.

Cannabidiol (CBD) has shown therapeutic potential for post-traumatic stress disorder (PTSD) by reducing spontaneous recovery (SR), yet the underlying mechanisms remain unclear. We examined the effects of CBD on SR in male and female mice and found greater behavioral efficacy in males. To uncover the molecular basis of these effects, we performed transcriptomic profiling of the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC). We identified distinct and overlapping SR-associated gene sets in each subregion, and CBD shifted the expression of a significant subset of these genes toward non-stressed control levels, including genes involved in retrograde endocannabinoid signaling. Cross-species comparisons with human PTSD transcriptomic datasets revealed conserved gene alterations within each subregion, suggesting shared molecular signatures between mouse SR and human PTSD. These findings highlight region-specific and conserved pathways through which CBD may exert therapeutic effects and provide mechanistic insight to advance CBD-based interventions for PTSD-associated spontaneous recovery.