Stress-induced visceral pain in female rats is associated with epigenetic remodeling in the central nucleus of the amygdala.
Stress-induced visceral pain in female rats is associated with epigenetic remodeling in the central nucleus of the amygdala.
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DOI：
10.1016/j.ynstr.2021.100386
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发表时间：
2021-11
影响因子：
5
通讯作者：
Greenwood-Van Meerveld B
中科院分区：
文献类型：
--
作者：
Louwies T;Orock A;Greenwood-Van Meerveld B
应激和焦虑是肠易激综合征(IBS)的病理生理机制之一，IBS是一种以女性为主的肠道-脑轴疾病，其特征是由于内脏敏感性增强而导致腹痛。在目前的研究中，我们旨在评估雌性大鼠边缘脑，特别是杏仁中央核(CEA)的表观遗传重塑是否是应激诱导的内脏高敏感性的一个促成因素。我们的结果表明，连续7d的水回避胁迫1h降低了CEA中GR启动子的组蛋白乙酰化，增加了CRH启动子的组蛋白乙酰化。组蛋白乙酰化的改变分别由组蛋白去乙酰化酶(HDAC)SIRT-6和组蛋白乙酰化转移酶CBP介导。将HDAC抑制剂曲古抑素A(TSA)注入CEA可通过阻断SIRT-6介导的GR启动子上的组蛋白乙酰化来预防应激诱导的内脏高敏感性。此外，抑制CEA内的HDAC可阻止应激诱导的CRH启动子的组蛋白乙酰化。我们的结果表明，在女性中，边缘脑中调节GR和CRH表达的表观遗传修饰有助于应激诱导的内脏高敏感性，并为应激如何引发IBS患者的症状提供了潜在的解释。在雌性大鼠中，反复暴露在水回避应激下会导致内脏高敏感性，并扰乱CEA的表观基因组。在CEA中，重复的日常应激将组蛋白去乙酰化酶SIRT-6招募到GR启动子，将组蛋白乙酰转移酶CBP招募到CRH启动子。应激诱导的GR和CRH启动子上组蛋白乙酰化的改变与CEA中GR和CRH mRNA表达的变化有关。抑制CEA中的组蛋白脱乙酰酶通过抑制SIRT-6介导组蛋白在GR启动子上的脱乙酰化来预防慢性应激诱导的内脏高敏感性。
Stress and anxiety contribute to the pathophysiology of irritable bowel syndrome (IBS), a female-predominant disorder of the gut-brain axis, characterized by abdominal pain due to heightened visceral sensitivity. In the current study, we aimed to evaluate in female rats whether epigenetic remodeling in the limbic brain, specifically in the central nucleus of the amygdala (CeA), is a contributing factor in stress-induced visceral hypersensitivity. Our results showed that 1 h exposure to water avoidance stress (WAS) for 7 consecutive days decreased histone acetylation at the GR promoter and increased histone acetylation at the CRH promoter in the CeA. Changes in histone acetylation were mediated by the histone deacetylase (HDAC) SIRT-6 and the histone acetyltransferase CBP, respectively. Administration of the HDAC inhibitor trichostatin A (TSA) into the CeA prevented stress-induced visceral hypersensitivity through blockade of SIRT-6 mediated histone acetylation at the GR promoter. In addition, HDAC inhibition within the CeA prevented stress-induced histone acetylation of the CRH promoter. Our results suggest that, in females, epigenetic modifications in the limbic brain regulating GR and CRH expression contribute to stress-induced visceral hypersensitivity and offer a potential explanation of how stress can trigger symptoms in IBS patients. In female rats, repeated exposure to water avoidance stress causes visceral hypersensitivity and dysregulates the epigenome of the CeA. Repetitive daily stress recruits the histone deacetylase SIRT-6 to the GR promoter and the histone acetyltransferase CBP to the CRH promoter in the CeA. Stress-induced alterations in histone acetylation at the GR and CRH promoters are associated with changes in GR and CRH mRNA expression in the CeA. Inhibition of histone deacetylases into the CeA prevents chronic stress-induced visceral hypersensitivity by inhibiting the SIRT-6 mediated histone deacetylation at the GR promoter.
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影响因子：
2.9
作者：
Greenwood-Van Meerveld, B;Gibson, M;Myers, D
通讯作者：
Myers, D
影响因子：
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影响因子：
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影响因子：
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