“Memory of Pain”: Hippocampal correlates and translational data on early life adversity and risk for posttraumatic pain in humans and rodents

Early-life adversity (ELA) affects approximately 50% of children worldwide and heightens vulnerability to chronic musculoskeletal pain (CPMP) following adult traumatic stress exposure (TSE), yet underlying neurobiological mechanisms remain unclear. The hippocampus is known for its role in memory retrieval, stress regulation, and pain modulation, showing functional alterations after both ELA and trauma, making it a compelling target for investigation. We hypothesized that ELA dysregulates hippocampal expression of Nr3c1, a glucocorticoid receptor, NF-kB, an inflammatory transcription factor, and Htr1a, a serotonin 1A receptor, conferring CPMP risk. We used a translational model in humans, with the AURORA cohort (>1,000 TSE survivors; CTQ predicting CPMP trajectories via latent class analysis) and reverse-translated rodents, with neonatal limited bedding for ELA, single prolonged stress for TSE, mechanical hypersensitivity for pain representation and raw CQ qPCR (n=47) for hippocampal gene expression. We found higher human CTQ associated with physical and emotional neglect (Spearman’s ρ=0.83, p<0.001) and physical and emotional abuse (Spearman’s ρ=0.72, p<0.001). In rodents, NLB extended hypersensitivity on days 6 (p-adj.=0.022), 7 (p-adj.=0.003), 9 (p-adj.<0.001), 12 (p-adj.=0.012), and 14 (p-adj.=0.002) following SPS. Hippocampal analyses revealed sex differences in Htr1a expression (Welch ***p<0.0001, lower female expression), robust upregulation in NLB+SPS females (interaction F=14.22, **p=0.0014; Fisher LSD ***p=0.0003 vs -NLB+SPS), and a modest NFKB decrease in NLB vs -NLB males under baseline conditions (Fisher LSD *p=0.039; omnibus ANOVA ns); Nr3c1 unchanged. These findings identify ELA-induced increases in CPMP in both humans and rodents, as well as sex-specific hippocampal Htr1a plasticity as a molecular signature of ELA-induced CPMP.