Environmental enrichment reverses stress-induced changes in the brain-gut axis to ameliorate chronic visceral and somatic hypersensitivity

IF 4.3 2区 医学 Q1 NEUROSCIENCES Neurobiology of Stress Pub Date : 2023-11-24 DOI:10.1016/j.ynstr.2023.100590
A. Orock , A.C. Johnson , E. Mohammadi , B. Greenwood-Van Meerveld
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Abstract

Introduction

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.

Methods

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).

Results

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.

Conclusion

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.

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环境富集逆转应激诱导的脑肠轴变化,改善慢性内脏和躯体超敏反应
行为疗法,包括认知行为疗法、催眠疗法和压力管理活动,已经成为肠易激综合征(IBS)的有效治疗方法,IBS是一种女性主要的脑-肠轴疾病。IBS影响全球10%以上的人口,通常表现为肠道习惯异常和内脏过敏引起的腹痛。虽然行为疗法治疗肠易激综合征的机制仍然难以捉摸,但我们之前已经表明,慢性压力会改变大脑中对压力处理和伤害感觉至关重要的区域的基因表达。我们发现,在应激源之前和期间暴露于富集环境(EE),即行为治疗的啮齿动物模拟物,足以防止应激引起的杏仁核中央核(CeA)和海马糖皮质激素受体(GR)表达的变化。预暴露于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超敏反应的诱导。然而,EE是否可以逆转暴露于压力后持续存在的慢性脏器体超敏反应仍不清楚。我们假设慢性应激后的EE足以逆转应激诱导的变化:1)CeA和海马GR表达,2)改善应激诱导的结肠高通透性,3)恢复雄性和雌性大鼠正常的内脏和身体敏感性。方法将雄性和雌性大鼠置于每日避水应激(WAS)下。在确认大鼠出现内脏过敏后,50%的动物被安置在EE中2周,而另外50%的动物仍被安置在标准住房(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测量结肠通透性。从CeA和海马组织中分离微孔,测定GR表达。未暴露于WAS的对照动物在研究期间保持在SH中(每组n = 8)。结果在雄性和雌性大鼠中,EE均能逆转应激诱导的内脏(p <0.001)和躯体(p <0.01),与被置于SH环境中的WAS动物相比,过敏程度与对照动物相当。EE暴露也逆转了海马中GR表达的变化(p <0.01)和CeA (p <0.01),使GR表达正常化至控制水平。EE暴露可改善应激性结肠高通透性(p <0.01)和女性(p <结论我们的研究结果表明,行为疗法是治疗IBS的可行选择,因为它们可以对抗应激诱导的IBS症状的病理生理,包括内脏过敏、结肠通透性增加和基因表达改变。
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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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