Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation.

Ning-Ning Ji,Gongliang Zhang,Yong-Mei Zhang,Lei Du,Rong Hua,Hui-Li Tang,Bin-Bin Chen

doi:10.3389/fphar.2017.00309

Abstract

Neonatal maternal separation (MS) is a major early life stress that increases the risk of emotional disorders, visceral pain perception and other brain dysfunction. Elevation of toll-like receptor 4 (TLR4) signaling in the paraventricular nucleus (PVN) precipitates early life colorectal distension (CRD)-induced visceral hypersensitivity and pain in adulthood. The present study aimed to investigate the role of TLR4 signaling in the pathogenesis of postnatal MS-induced visceral hypersensitivity and pain during adulthood. The TLR4 gene was selectively knocked out in C57BL/10ScSn mice (Tlr4-/-). MS was developed by housing the offspring alone for 6 h daily from postnatal day 2 to day 15. Visceral hypersensitivity and pain were assessed in adulthood. Tlr4+/+, but not Tlr4-/-, mice that had experienced neonatal MS showed chronic visceral hypersensitivity and pain. TLR4 immunoreactivity was observed predominately in microglia in the PVN, and MS was associated with an increase in the expression of protein and/or mRNA levels of TLR4, corticotropin-releasing factor (CRF), CRF receptor 1 (CRFR1), tumor necrosis factor-α, and interleukin-1β in Tlr4+/+ mice. These alterations were not observed in Tlr4-/- mice. Local administration of lipopolysaccharide, a TLR4 agonist, into the lateral cerebral ventricle elicited visceral hypersensitivity and TLR4 mRNA expression in the PVN, which could be prevented by NBI-35965, an antagonist to CRFR1. The present results indicate that neonatal MS induces a sensitization and upregulation of microglial TLR4 signaling activity, which facilitates the neighboring CRF neuronal activity and, eventually, precipitates visceral hypersensitivity in adulthood.Highlights (1)Neonatal MS does not induce chronic visceral hypersensitivity and pain in Tlr4-/- mice.(2)Neonatal MS increases the expression of TLR4 mRNA, CRF protein and mRNA, CRFR1 protein, TNF-α protein, and IL-1β protein in Tlr4+/+ mice.(3)TLR4 agonist LPS (i.c.v.) elicits visceral hypersensitivity and TLR4 mRNA expression in the PVN.

Highlights

Neonatal maternal separation (MS) and other adverse events in early life alter neural plasticity and the developmental trajectory across the nervous system (Hulshof et al, 2011; Ji et al, 2014; Wang et al, 2015)
We examined the influence of toll-like receptor 4 (TLR4) signaling on MS-induced visceral hypersensitivity and pain in mice
Our data indicated that MS was associated with an increase in visceral hypersensitivity, microglial TLR4, corticotropin-releasing factor (CRF), CRF receptor 1 (CRFR1), and inflammatory factors IL-1β and tumor necrosis factor-α (TNF-α) protein and/or mRNA expression in Tlr4+/+ mice

Summary

Introduction

Neonatal maternal separation (MS) and other adverse events in early life alter neural plasticity and the developmental trajectory across the nervous system (Hulshof et al, 2011; Ji et al, 2014; Wang et al, 2015). Neonatal MS increases the susceptibility of visceral hypersensitivity and pain in adulthood (Moloney et al, 2012). Recent studies have shown that toll-like receptor 4 (TLR4)-related neuroinflammation is a critical factor for early life stress-induced adult visceral hypersensitivity (Chen et al, 2015). We recently demonstrated that neonatal colorectal distension (CRD), a physical stress in early life, increases sensitization of the TLR4/MyD88 signaling pathway in the paraventricular nucleus (PVN) and in visceral pain precipitation in rats (Chen et al, 2015). The effect of TLR4 signaling in MS-induced visceral hypersensitivity has not been explored

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