序贯应激致焦虑样胃高敏的大鼠模型

Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress.

机构信息

Department of Gastroenterology, Second Hospital Affiliated to the Medical School of Xi'an Jiao Tong University, Xi'an 710004, Shaanxi Province, China.

Department of Pharmacology, Health Science Center, Xi'an Jiao Tong University, Xi'an 710061, Shaanxi Province, China.

出版信息

World J Gastroenterol. 2017 Nov 14;23(42):7594-7608. doi: 10.3748/wjg.v23.i42.7594.

DOI:10.3748/wjg.v23.i42.7594

PMID:29204059

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5698252/

Abstract

AIM

To establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress.

METHODS

Animal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined.

RESULTS

Sequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 104.21 ± 2.88, < 0.01), GABA (2.38 ± 0.16 5.01 ± 0.13, < 0.01) and BDNF (304.40 ± 10.16 698.17 ± 27.91, < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 1007.50 ± 33.05, < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 89.45 ± 2.61, < 0.01) and BDNF (257.05 ± 12.89 536.71 ± 20.73, < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 737.88 ± 33.15, < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 89.17 ± 2.31, < 0.01) and BDNF (226.49 ± 12.10 551.36 ± 16.47, < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 819.63 ± 38.04, < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 23865.75 ± 1868.60; < 0.05, respectively) and WB (0.38 ± 0.01 0.57 ± 0.03, < 0.01) ( = 8 in each group).

CONCLUSION

Sequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.

摘要

目的

建立一种新的序贯应激诱导的功能性消化不良（FD）焦虑样胃高敏（GHS）大鼠模型。

方法

动物幼仔从产后第 2 天分为两组：对照组和序贯应激处理组。序贯应激处理组在生命早期接受母婴分离和急性胃刺激，成年后接受束缚应激；对照组与母亲一起不受干扰地饲养。两组大鼠均饲养至成年（8 周），此时测试焦虑样行为和胃扩张（20-100mmHg）及胃排空的内脏运动反应。同时，检测大鼠海马中几种与焦虑相关的脑-胃调节剂的变化，包括 5-羟色胺（5-HT）、γ-氨基丁酸（GABA）、脑源性神经营养因子（BDNF）和 nesfatin-1，以及海马 CA1 亚区和胃底黏膜中的 5-羟色胺 1A 受体（5-HT1AR）。

结果

与对照组相比，序贯应激处理组大鼠同时表现出焦虑样行为和 GHS，呈剂量依赖性。尽管两组大鼠摄入的固体食物量相似，但序贯应激处理组大鼠的胃排空率低于对照组。序贯应激显著降低了海马中 5-HT（51.91 ± 1.88 104.21 ± 2.88， < 0.01）、GABA（2.38 ± 0.16 5.01 ± 0.13， < 0.01）和 BDNF（304.40 ± 10.16 698.17 ± 27.91， < 0.01）的水平，但增加了海马中 nesfatin-1 的含量（1961.38 ± 56.89 1007.50 ± 33.05， < 0.01）；显著降低了血浆中 5-HT（47.82 ± 2.29 89.45 ± 2.61， < 0.01）和 BDNF（257.05 ± 12.89 536.71 ± 20.73， < 0.01）的水平，但增加了血浆中 nesfatin-1 的含量（1391.75 ± 42.77 737.88 ± 33.15， < 0.01）；显著降低了胃底中 5-HT（41.15 ± 1.81 89.17 ± 2.31， < 0.01）和 BDNF（226.49 ± 12.10 551.36 ± 16.47， < 0.01）的水平，但增加了胃底中 nesfatin-1 的含量（1534.75 ± 38.52 819.63 ± 38.04， < 0.01）。免疫组织化学（光密度值：海马 15253.50 ± 760.35 21149.75 ± 834.13；胃底 15865.25 ± 521.24 23865.75 ± 1868.60； < 0.05，分别）和 WB（0.38 ± 0.01 0.57 ± 0.03， < 0.01）（每组 = 8）检测到海马 CA1 亚区和胃底黏膜中 5-HT1AR 的表达下调。