Environmental enrichment reverses stress-induced changes in the brain-gut axis to ameliorate chronic visceral and somatic hypersensitivity.
Environmental enrichment reverses stress-induced changes in the brain-gut axis to ameliorate chronic visceral and somatic hypersensitivity.
复制标题
DOI：
10.1016/j.ynstr.2023.100590
复制
发表时间：
2024-01
影响因子：
5
通讯作者：
Meerveld, B. Greenwood-Van
中科院分区：
文献类型：
--
作者：
Orock, A.;Johnson, A. C.;Mohammadi, E.;Meerveld, B. Greenwood-Van
关键词：
行为疗法，包括认知行为疗法、催眠疗法和压力管理活动，已成为治疗肠易激综合征（IBS）的有效方法，肠易激综合征是一种女性主导的脑-肠轴疾病。IBS影响超过10%的全球人口，通常表现为由于内脏高敏感性导致的排便习惯异常和腹痛。虽然行为疗法如何治疗IBS的潜在机制仍然难以捉摸，但我们之前已经表明，慢性应激改变了对应激处理和伤害感受至关重要的大脑区域的基因表达。我们发现，暴露于丰富的环境（EE），啮齿类动物的行为疗法，之前和期间的压力是足以防止应激诱导的糖皮质激素受体（GR）在中央核杏仁核（CeA）和海马体的表达变化。预先暴露于EE也抑制应激诱导的结肠通透性增加，并能够阻断应激诱导的内脏和躯体高敏感性的诱导。然而，它仍然是未知的，如果EE可以逆转慢性内脏过敏，持续暴露于压力。我们假设慢性应激后EE足以逆转应激诱导的变化：i）CeA和海马GR表达，ii）改善应激诱导的结肠通透性增高，iii）恢复雄性和雌性大鼠正常的内脏和躯体敏感性。雄性和雌性大鼠每日暴露于避水应激（WAS）。在确认大鼠出现内脏高敏感性后，将50%的动物饲养在EE中2周，而另外50%的动物仍留在标准饲养（SH）中。在这一阶段结束时，我们评估了内脏和躯体的敏感性。我们还收集结肠组织以测量结肠渗透性。分离来自CeA和海马的组织的微穿孔以测量GR表达。在研究期间，未暴露于WAS的对照动物饲养在SH中（每组n = 8）。在雄性和雌性大鼠中，与SH中饲养的WAS动物相比，EE逆转了应激诱导的内脏（p < 0.001）和躯体（p < 0.01）超敏反应，达到与对照动物相当的水平。EE暴露还逆转了海马（p < 0.01）和CeA（p < 0.01）中GR表达的变化，使GR表达正常化至对照水平。与SH中的WAS大鼠相比，EE暴露改善了雄性（p < 0.01）和雌性（p < 0.01）大鼠中应激诱导的结肠通透性过高。我们的研究结果表明，行为疗法是IBS的可行治疗选择，因为它们可以对抗IBS症状的应激诱导的病理生理学，包括内脏高敏感性，结肠通透性增加和基因表达改变。应激是肠易激综合征（IBS）症状的主要诱因。应激干扰海马和杏仁核糖皮质激素受体（GR）的表达。环境富集（EE）可以逆转应激诱导的结肠通透性增高。EE逆转应激诱导的GR表达变化至对照水平。暴露于EE逆转了雄性和雌性动物的内脏和躯体超敏反应。
Behavioral therapies, including cognitive behavioral therapy, hypnotherapy and stress management activities, have emerged as effective treatments for irritable bowel syndrome (IBS), a female predominant disorder of the brain-gut axis. IBS, affecting over 10% of the global population, typically presents with abnormal bowel habits and abdominal pain due to visceral hypersensitivity. While the mechanisms underlying how behavioral therapies treat IBS are still elusive, we had previously shown that chronic stress alters gene expression in brain regions critical for stress processing and nociception. We found that exposure to an enriched environment (EE), the rodent analogue of behavioral therapies, prior to and during the stressor was sufficient to prevent stress-induced changes in glucocorticoid receptor (GR) expression in the central nucleus of the amygdala (CeA) and hippocampus. Pre-exposure to EE also inhibited stress-induced increased colonic permeability and was able to block the induction of stress-induced visceral and somatic hypersensitivity. However, it remains unknown if EE can reverse chronic viscerosomatic hypersensitivity that persists following exposure to stress. We hypothesized that EE after chronic stress would be sufficient to reverse stress-induced changes in i) GR expression in the CeA and hippocampus, ii) ameliorate stress-induced colonic hyperpermeability and iii) restore normal visceral and somatic sensitivity in male and female rats. Male and female rats were exposed to daily water avoidance stress (WAS). After confirming the rats had developed visceral hypersensitivity, 50% of the animals were housed in EE for 2 weeks while the other 50% remained in standard housing (SH). At the end of this period, we assessed visceral and somatic sensitivity. We also collected colon tissue to measure colonic permeability. Micro-punches of tissue from the CeA and hippocampus were isolated to measure GR expression. Control animals not exposed to WAS were kept in SH for the duration of the study (n = 8 per group). In both male and female rats, EE reversed stress-induced visceral (p < 0.001) and somatic (p < 0.01) hypersensitivity when compared to WAS animals housed in SH to levels comparable to control animals. EE exposure also reversed changes in GR expression in both the hippocampus (p < 0.01) and CeA (p < 0.01), normalizing GR expression to control levels. EE exposure ameliorated stress-induced colonic hyperpermeability in both male (p < 0.01) and female (p < 0.01) rats compared to WAS rats in SH. Our findings suggest that behavioral therapies are viable therapeutic options for IBS as they can counter the stress-induced pathophysiology underlying IBS symptoms including visceral hypersensitivity, increased colonic permeability and altered gene expression. Stress is a major trigger for the symptoms of irritable bowel syndrome (IBS). Stress disrupts glucocorticoid receptor (GR) expression in hippocampus and amygdala. Environmental enrichment (EE) can reverse stress-induced colonic hyperpermeability. EE reverses stress induced changes in GR expression to control levels. Exposure to EE reversed visceral and somatic hypersensitivity in males and females.
登录
查看更多内容
影响因子：
2.7
作者：
Skwara, Amanda J.;Karwoski, Tracy E.;Czambel, R. Kenneth;Rubin, Robert T.;Rhodes, Michael E.
通讯作者：
Rhodes, Michael E.
影响因子：
29.4
作者：
Lackner JM;Jaccard J;Keefer L;Brenner DM;Firth RS;Gudleski GD;Hamilton FA;Katz LA;Krasner SS;Ma CX;Radziwon CD;Sitrin MD
通讯作者：
Sitrin MD
影响因子：
5.3
作者：
Orock A;Louwies T;Ligon CO;Mohammadi E;Greenwood-Van Meerveld B
通讯作者：
Greenwood-Van Meerveld B
影响因子：
5.2
作者：
Jankord R;Herman JP
通讯作者：
Herman JP
DOI：
10.3389/fpain.2020.609292
发表时间：
2020
期刊：
Frontiers in pain research (Lausanne, Switzerland)
影响因子：
--
作者：
Orock A;Yuan T;Greenwood-Van Meerveld B
通讯作者：
Greenwood-Van Meerveld B