Early life stress modulates neonatal somatosensation and the transcriptional profile of immature sensory neurons
Early life stress (ELS) is associated with an increased risk of experiencing chronic pain during adulthood, but surprisingly little is known about the short-term influence of ELS on nociceptive processing in the immature nervous system and the concomitant effects on somatosensation in the neonate.  Here we investigate how ELS modulates pain in neonatal mice as well as the transcriptional and electrophysiological signatures of immature dorsal root ganglia (DRG). Shortly after the administration of a neonatal limiting bedding (NLB) paradigm from postnatal days (P)2 to P9, both male and female pups exhibited robust hyperalgesia in response to mechanical, pressure and noxious cold stimuli compared to a control group housed under standard conditions, with no change in their sensitivity to noxious heat. Bulk RNA-seq analysis of L3-L5 DRGs at P9 revealed significant alterations in the transcription of pain- and itch-related genes following ELS, highlighted by a marked downregulation in Sst, Nppb, Chrna6, Trpa1 and Il31ra. Nonetheless, ex vivo whole cell patch-clamp recordings from putative A- and C-fiber sensory neurons in the neonatal DRG found no significant changes in their intrinsic membrane excitability following NLB. Overall, these findings suggest that ELS triggers hyperalgesia in neonates across multiple pain modalities that is accompanied by transcriptional plasticity within developing sensory neurons. A better understanding of the mechanisms governing the interactions between chronic stress and pain during the neonatal period could inform the future development of novel interventional strategies to relieve pain in infants and children who have experienced trauma. Overall design: Neonatal mouse pups underwent neonatal limited bedding protocol (stress) or control bedding protocol (control) from postnatal day (P)2-9 Lumbar L3-L5 DRG were harvested at P9, and total RNA was extracted for sequencing. Differential gene analysis was performed to identify stress-induced transcriptional changes.