Enriched environment rescues neonatal pain induced cognitive deficits and the impaired hippocampal synaptic plasticity later in life.

Although extensive and untreated pain that occurs during a critical developmental window may impair cognition later in life, environmental interventions early in life might promote cognition. However, the underlying mechanism is poorly understood. Our current study utilized a rat model of "repetitive needle pricks" from the day of birth (P0) to postnatal day 7 (P7) to mimic the painful experience of preterm neonates in the neonatal intensive care unit. Enriched environment (EE) during development period (from P15 to P70) was implemented as a nonpharmacological intervention approach. Electrophysiological recording, behavioral tests, and biochemical analysis were performed after the end of EE (between P71 and P80). The results showed neonatal repetitive pain resulted in a reduction in mechanical withdrawal thresholds by the von Frey test in P70 (p < .001). Furthermore, neonatal repetitive pain impaired spatial learning and memory (p < .05) and even led to dysfunction in fear memory (p < .01). In contrast, EE rescued neonatal pain-induced cognitive deficits and normalized hippocampal long-term potentiation in rats exposed to neonatal pain (p << .05). The beneficial effect of EE might be the improvements in hippocampal synaptic plasticity via upregulating neurotrophic factors and N-methyl-d-aspartate (NMDA) receptors in the hippocampus. Our findings provide evidence that early environmental intervention might be a safe strategy to overcome neurodevelopmental abnormalities in preterm infants who experienced multiple procedural painful events during the early critical period.