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.

中文翻译：

---

丰富的环境可以挽救新生儿疼痛引起的认知缺陷和生命后期海马突触可塑性受损

尽管在关键的发育窗口期间发生的广泛且未经治疗的疼痛可能会损害以后生命中的认知，但生命早期的环境干预可能会促进认知。然而，人们对底层机制知之甚少。我们目前的研究利用从出生当天 (P0) 到产后第 7 天 (P7) 的“重复针刺”大鼠模型来模拟早产儿在新生儿重症监护病房中的痛苦经历。开发期间（从 P15 到 P70）的丰富环境（EE）作为一种非药物干预方法实施。在 EE 结束后（P71 和 P80 之间）进行电生理记录、行为测试和生化分析。结果表明，新生儿重复性疼痛导致 P70 中 von Frey 试验的机械退缩阈值降低（p  <.001）。此外，新生儿重复性疼痛会损害空间学习和记忆 ( p  < .05)，甚至导致恐惧记忆功能障碍 ( p  < .01)。相比之下，EE 挽救了暴露于新生儿疼痛的大鼠的新生儿疼痛引起的认知缺陷和正常化的海马长时程增强 ( p << .05)。EE 的有益作用可能是通过上调神经营养因子和 N-甲基-d来改善海马突触可塑性- 海马体中的天冬氨酸 (NMDA) 受体。我们的研究结果提供的证据表明，早期环境干预可能是克服在早期关键时期经历多次程序性疼痛事件的早产儿神经发育异常的安全策略。