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

Dongqing Xia,Yinhua Chen,Cuiting Min,Xiaonan Li,Mengying Chen,Ru Ling

doi:10.3389/fnins.2020.00722

Abstract

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.

Highlights

Premature infants worldwide, especially those hospitalized in neonatal intensive care units (NICUs), underwent many painful procedures every day because of medical necessity (Chen et al, 2012; Cruz et al, 2016)
Life is a critical period of brain development due to its plasticity and vulnerability
We found that neonatal pain impaired contextual and trace fear conditioning, causing sustained deficits in synaptic plasticity related to glutamate signaling from early life to adulthood

Summary

Introduction

Especially those hospitalized in neonatal intensive care units (NICUs), underwent many painful procedures every day because of medical necessity (Chen et al, 2012; Cruz et al, 2016). The literature indicated that untreated pain during the critical development period might produce unfavorable neurodevelopmental outcomes, altering pain sensitivity and impairing cognitive, emotional, and psychosocial function later in life (Provenzi et al, 2015; Chen et al, 2016; Walker et al, 2018). Basal hyperalgesia has been observed to be caused by increased input in nociceptive primary afferent axons exposed to early pain (Ruda et al, 2000; Knaepen et al, 2013; Schwaller and Fitzgerald, 2014; Neonatal Pain Impairs Fear Memory van den Hoogen et al, 2018), while in extremely preterm children who underwent surgery in the neonatal period, thermal sensitivity was decreased in later life (Walker et al, 2009). It was confirmed that repetitive neonatal pain in rats led to impaired spatial learning (Chen et al, 2016)

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Conclusion