Hassan Ahmed M, Jain Piyush, Reichmann Florian, Mayerhofer Raphaela, Farzi Aitak, Schuligoi Rufina, Holzer Peter
Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz Graz, Austria.
Front Behav Neurosci. 2014 Nov 6;8:386. doi: 10.3389/fnbeh.2014.00386. eCollection 2014.
Inflammatory bowel disease is associated with an increased risk of mental disorders and can be exacerbated by stress. In this study which was performed with male 10-week old C57Bl/6N mice, we used dextran sulfate sodium (DSS)-induced colitis to evaluate behavioral changes caused by intestinal inflammation, to assess the interaction between repeated psychological stress (water avoidance stress, WAS) and colitis in modifying behavior, and to analyze neurochemical correlates of this interaction. A 7-day treatment with DSS (2% in drinking water) decreased locomotion and enhanced anxiety-like behavior in the open field test and reduced social interaction. Repeated exposure to WAS for 7 days had little influence on behavior but prevented the DSS-induced behavioral disturbances in the open field and SI tests. In contrast, repeated WAS did not modify colon length, colonic myeloperoxidase content and circulating proinflammatory cytokines, parameters used to assess colitis severity. DSS-induced colitis was associated with an increase in circulating neuropeptide Y (NPY), a rise in the hypothalamic expression of cyclooxygenase-2 mRNA and a decrease in the hippocampal expression of NPY mRNA, brain-derived neurotrophic factor mRNA and mineralocorticoid receptor mRNA. Repeated WAS significantly decreased the relative expression of corticotropin-releasing factor mRNA in the hippocampus. The effect of repeated WAS to blunt the DSS-evoked behavioral disturbances was associated with a rise of circulating corticosterone and an increase in the expression of hypothalamic NPY mRNA. These results show that experimental colitis leads to a particular range of behavioral alterations which can be prevented by repeated WAS, a model of predictable chronic stress, while the severity of colitis remains unabated. We conclude that the mechanisms underlying the resilience effect of repeated WAS involves hypothalamic NPY and the hypothalamic-pituitary-adrenal axis.
炎症性肠病与精神障碍风险增加相关，且可因压力而加重。在这项以10周龄雄性C57Bl/6N小鼠进行的研究中，我们使用葡聚糖硫酸钠（DSS）诱导的结肠炎来评估肠道炎症引起的行为变化，评估反复心理应激（水回避应激，WAS）与结肠炎在改变行为方面的相互作用，并分析这种相互作用的神经化学相关性。用DSS（饮用水中含2%）进行7天的治疗可降低旷场试验中的运动能力，增强焦虑样行为，并减少社交互动。反复暴露于WAS 7天对行为影响不大，但可预防DSS诱导的旷场试验和社交互动试验中的行为障碍。相比之下，反复的WAS并未改变用于评估结肠炎严重程度的结肠长度、结肠髓过氧化物酶含量和循环促炎细胞因子。DSS诱导的结肠炎与循环神经肽Y（NPY）增加、下丘脑环氧化酶-2 mRNA表达升高以及海马体NPY mRNA、脑源性神经营养因子mRNA和盐皮质激素受体mRNA表达降低有关。反复的WAS显著降低了海马体中促肾上腺皮质激素释放因子mRNA的相对表达。反复的WAS减轻DSS诱发的行为障碍的作用与循环皮质酮升高和下丘脑NPY mRNA表达增加有关。这些结果表明，实验性结肠炎会导致特定范围的行为改变，而反复的WAS（一种可预测的慢性应激模型）可预防这些改变，同时结肠炎的严重程度并未减轻。我们得出结论，反复的WAS产生恢复力作用的潜在机制涉及下丘脑NPY和下丘脑-垂体-肾上腺轴。
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