Behavioral and transcriptomic profiling of PTSD-like susceptible and resilient rat lines

After a traumatic event, dysfunctional stress coping can lead to psychiatric disorders such as post-traumatic stress disorder (PTSD). However, only a subset of trauma-exposed individual develops PTSD, and the factors driving vulnerability or resilience remain largely unknown. The aim of this study was to generate distinct SUS and RES lines and perform bulk RNA sequencing in PTSD-related brain regions (basolateral amygdala, BLA; dorsal and ventral hippocampus, dHipp and vHipp; prefrontal cortex; PFC) to identify markers of susceptibility and resilience. We have previously developed a rat model allowing early post-trauma behavioral differentiation between susceptible (SUS) and resilient (RES) PTSD-like phenotypes in both sexes, and through selective breeding, we established two lines of SUS and RES animals. Data collected on the 11th generation, show a clear phenotypic distinction with SUS rats exhibiting fear memory deficits (i.e., enhanced traumatic memory consolidation, recall, and impaired extinction) and socio-emotional alterations compared to RES rats. Transcriptomic profiling revealed marked baseline differences between the two phenotypes, with a greater number of differentially expressed genes in females. Notably, SUS vs RES comparisons in males identified 627 downregulated and 489 upregulated genes in the BLA, 96 down and 85 up in the dHipp, 111 down and 78 up in the vHipp, and 153 down and 119 up in the PFC. In females: 1408 down and 1166 up in the BLA, 152 down and 248 up in the dHipp, 130 down and 183 up in the vHipp, and 119 down and 129 up in the PFC. Gene ontology enrichment analysis highlighted sex- and brain region- specific alterations in pathways related to stress, memory, and neuroinflammation processes. These findings provide novel insights into the molecular basis of PTSD vulnerability/resilience and support the use of these SUS/RES rat lines as a translational model for identifying preventive or therapeutic targets for trauma-related disorders.