Neonatal repetitive pain in rats leads to impaired spatial learning and dysregulated hypothalamic-pituitary-adrenal axis function in later life.

Mengying Chen,Xiaoke Zhao,Yinhua Chen,Xiaonan Li,Li Liu,Dongqing Xia,Cuiting Min

doi:10.1038/srep39159

Mengying Chen, Xiaoke Zhao + Show 5 more

Open Access

https://doi.org/10.1038/srep39159

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Abstract

Preterm birth is a major health issue. As part of their life-saving care, most preterm infants require hospitalization and are inevitably exposed to repetitive skin-breaking procedures. The long-term effects of neonatal repetitive pain on cognitive and emotional behaviors involving hypothalamic-pituitary-adrenal (HPA) axis function in young and adult rats are unknown. From P8 to P85, mechanical hypersensitivity of the bilateral hindpaws was observed in the Needle group (P < 0.001). Compared with the Tactile group, the Needle group took longer to find the platform on P30 than on P29 (P = 0.03), with a decreased number of original platform site crossings during the probe trial of the Morris water maze test (P = 0.026). Moreover, the Needle group spent more time and took longer distances in the central area than the Tactile group in the Open-field test, both in prepubertal and adult rats (P < 0.05). The HPA axis function in the Needle group differed from the Tactile group (P < 0.05), with decreased stress responsiveness in prepuberty and puberty (P < 0.05) and increased stress responsiveness in adulthood (P < 0.05). This study indicates that repetitive pain that occurs during a critical period may cause severe consequences, with behavioral and neuroendocrine disturbances developing through prepuberty to adult life.

Highlights

A repeated needlestick protocol performed on rat pups was used to mimic the repeated heel/finger lances performed on preterm neonates during their stay in the neonatal intensive care unit (NICU) to investigate the effects of neonatal repetitive skin-breaking pain on later cognitive and emotional behaviors in both young and adult rats
These results indicate that stress responsiveness in rats subjected to repeated neonatal pain has age-specific patterns, which are associated with altered hippocampal glucocorticoid receptor (GR) expression and HPA axis function
Our results indicated that neonatal pain affected hippocampal neuronal plasticity, manifesting as increased GR expression, more efficiently transmitted negative glucocorticoid feedback to the HPA axis, down-regulated hypothalamic corticotropin-releasing hormone (CRH) and subsequent corticoid levels, and impaired learning and memory function in puberty

Summary

Introduction

SHRP can be considered a protective mechanism, because rats exposed to high levels of glucocorticoids during the first week of life showed altered social behavior and learning performance[31,32]. Based on these discoveries, we hypothesize that rats subjected to repetitive needlestick protocol during the SHRP could exhibit increased vulnerability to long-term cognitive and emotional impairment. Murphy’s group suggested that neonatal injury accelerated corticosterone negative feedback and resulted in compensatory changes of GR expression in adult rats[37] It is unknown whether the developmental GR expression in the hippocampus is changed with behavioral performance in rats that experienced neonatal repetitive pain. The second purpose was to examine the HPA axis function in the stress response after neonatal repetitive pain from prepuberty to adulthood

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