Table_1_Repetitive Pain in Neonatal Male Rats Impairs Hippocampus-Dependent Fear Memory Later in Life.docx

Preterm infants in neonatal intensive care units are inevitably subjected to numerous painful procedures. However, little is known about the consequences of early pain experience on fear memory formation later in life. We hypothesized that exposure to repetitive pain in early life triggered hippocampal synaptic plasticity and resulted in memory deficiency in prepubertal and adult rats. From the day of birth (P0) to postnatal day 7 (P7), neonatal male rat pups were randomly assigned to either needle pricks or tactile touches repetitively every 6 h. Trace fear conditioning was performed on rats on P24–P26 and P87–P89. On P24 and P87, rats were sacrificed for molecular and electrophysiological studies. On P24–26 and P87–89, rats that experienced neonatal needle treatment showed a significant reduction in freezing time in the contextual fear conditioning (P < 0.05) and trace fear conditioning tests (P < 0.05). Moreover, repetitive neonatal procedural pain caused a significant decrease in the magnitude of hippocampal long-term potentiation induced by high-frequency stimulation. Furthermore, rats that experienced neonatal needle treatment demonstrated sustained downregulation of NR1, NR2A, NR2B, and GluR1 expression in the hippocampus. Therefore, neonatal pain is related to deficits in hippocampus-related fear memory later in life and might be caused by impairments in hippocampal synaptic plasticity.

新生儿重症监护病房（Neonatal Intensive Care Unit, NICU）中的早产婴儿不可避免地会经历大量疼痛性操作。然而，学界对早期疼痛经历对日后恐惧记忆形成的影响尚不明晰。本研究假设，生命早期反复暴露于疼痛刺激会触发海马突触可塑性（hippocampal synaptic plasticity）改变，并导致青春期前及成年大鼠出现记忆缺陷。本研究从新生大鼠出生当日（P0）至出生后第7天（P7），将雄性新生幼鼠随机分为针刺刺激组与触觉对照组，每6小时重复施加对应处理一次。分别于出生后第24~26天（P24~P26）及第87~89天（P87~P89）对大鼠实施痕迹恐惧条件反射（trace fear conditioning）测试。于P24及P87天处死大鼠，开展分子生物学与电生理学检测。在对应检测时段中，接受过新生期针刺刺激的大鼠，其情境恐惧条件反射（contextual fear conditioning）与痕迹恐惧条件反射测试中的冻结时间均显著缩短（P < 0.05）。此外，新生期反复的操作性疼痛会显著降低高频刺激诱导的海马长时程增强（long-term potentiation, LTP）幅度。进一步研究显示，新生期接受针刺刺激的大鼠，其海马组织中NR1、NR2A、NR2B及GluR1的表达均持续下调。综上，新生期疼痛与日后海马依赖的恐惧记忆缺陷密切相关，其潜在机制可能与海马突触可塑性受损有关。