Environmental enrichment prevents stress-induced epigenetic changes in the expression of glucocorticoid receptor and corticotrophin releasing hormone in the central nucleus of the amygdala to inhibit visceral hypersensitivity.
Environmental enrichment prevents stress-induced epigenetic changes in the expression of glucocorticoid receptor and corticotrophin releasing hormone in the central nucleus of the amygdala to inhibit visceral hypersensitivity.
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DOI：
10.1016/j.expneurol.2021.113841
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发表时间：
2021-11
影响因子：
5.3
通讯作者：
Greenwood-Van Meerveld B
中科院分区：
文献类型：
--
作者：
Orock A;Louwies T;Ligon CO;Mohammadi E;Greenwood-Van Meerveld B
应激是肠易激综合征（IBS）症状的已知触发因素，肠易激综合征是一种胃肠道（GI）疾病，表现为肠道习惯异常和内脏高敏感性引起的腹痛。虽然行为疗法已被用于减轻IBS症状，但这些疗法与应激诱导的病理学相互作用的潜在机制仍有待阐明。在这里，我们使用大鼠模型来测试的假设，暴露于环境富集（EE）抑制脑肠轴内的应激诱导的变化，以防止内脏和躯体的高敏感性和结肠通透性过高。雌性大鼠（n = 8/组）在暴露于避水应激（WAS）前一周和暴露期间一周饲养在EE中，而对照组饲养在标准笼中（SH）。在末次WAS暴露后1天，分别通过大鼠对结肠直肠扩张（CRD）的内脏反应（VMR）和由电子von Frey在大鼠后爪上引起的退缩阈值来评估结肠和躯体敏感性。所有大鼠返回SH 3周，然后在第28天重新评估结肠和躯体敏感性。然后立即对大鼠实施安乐死，并收集脊髓以评估响应于有害CRD的神经元活化的变化（通过ERK磷酸化评估）。在最后一次WAS暴露后第二天，对未进行行为评估的单独动物队列（n = 8/组）实施安乐死，并收集杏仁核中央核（CeA），以研究WAS和EE诱导的糖皮质激素受体（GR）和促肾上腺皮质激素释放激素（CRH）启动子的表观遗传变化。还收集来自这些大鼠的结肠以通过体外跨上皮电阻（TEER）的变化来评估结肠渗透性。应激可使雌性大鼠的VMR增加（P < 0.01），缩足阈降低（P < 0.001）。WAS还降低了雌性大鼠结肠组织中的TEER（p = 0.05）。在CeA中，WAS诱导GR启动子处的组蛋白乙酰化减少，但增加CRH启动子处的组蛋白乙酰化，并降低CeA中的GR-CRH相互作用。对脊髓的分析表明，WAS增加了背角中CRD诱发的ERK磷酸化。暴露于EE防止WAS诱导的变化，分别在CeA，背角和结肠，以防止内脏和躯体的超敏反应。我们的数据表明，行为疗法可以产生持久的分子和表观遗传变化，即使在治疗完成后也可以预防压力诱导的病理。这些结果突出了行为疗法可能改善内脏疼痛相关的应激相关病理学（如肠易激综合征）的潜在机制。
Stress is a known trigger for the symptoms of irritable bowel syndrome (IBS), a gastrointestinal (GI) disorder that presents with abnormal bowel habits and abdominal pain due to visceral hypersensitivity. While behavioral therapies have been used to attenuate IBS symptoms, the underlying mechanisms by which these therapies interact with stress-induced pathology remains to be delineated. Here we use a rat model to test the hypothesis that exposure to environmental enrichment (EE) inhibits stress-induced changes within the brain-gut axis to prevent visceral and somatic hypersensitivity and colonic hyperpermeability. Female rats (n = 8/group) were housed in EE one week before and one week during exposure to water avoidance stress (WAS) while controls were housed in standard cages (SH). One day after the final WAS exposure, colonic and somatic sensitivity were assessed by the visceromotor response (VMR) to colorectal distension (CRD) and withdrawal threshold elicited by an electronic von Frey on the hind paw of the rats respectively. All rats were returned to SH for 3 weeks before colonic and somatic sensitivity were reassessed on day 28. The rats were then immediately euthanized and the spinal cord was collected to assess changes in neuronal activation (assessed via ERK phosphorylation) in response to noxious CRD. A separate cohort of animals (n = 8/group) that did not undergo behavioral assessments was euthanized the day after the final WAS exposure and the central nucleus of the amygdala (CeA) was collected to investigate WAS and EE induced epigenetic changes at the glucocorticoid receptor (GR) and corticotrophin releasing hormone (CRH) promoter. The colon from these rats was also collected to assess colonic permeability via changes in transepithelial electrical resistance (TEER) in vitro. Exposure to stress persistently increased VMR to CRD (P < 0.01) and decreased the hind paw withdrawal threshold (P < 0.001) in female rats. WAS also decreased TEER in the colon tissue of female rats (p = 0.05). In the CeA, WAS induced a decrease in histone acetylation at the GR promoter but increased histone acetylation at the CRH promoter and reduced GR-CRH interactions in the CeA. Analysis of the spinal cord showed that WAS increased CRD-evoked ERK phosphorylation in the dorsal horn. Exposure to EE prevented WAS-induced changes in the CeA, dorsal horn and colon respectively to prevent visceral and somatic hypersensitivity. Our data reveals that behavioral therapies can produce long lasting molecular and epigenetic changes that can prevent stress-induced pathologies even after completion of the therapy. These results highlight the potential mechanisms by which behavioral therapies may ameliorate visceral pain associated stress-related pathologies such as the irritable bowel syndrome.
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影响因子：
3.6
作者：
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通讯作者：
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