Menneson Sophie, Ménicot Samuel, Ferret-Bernard Stéphanie, Guérin Sylvie, Romé Véronique, Le Normand Laurence, Randuineau Gwénaëlle, Gambarota Giulio, Noirot Virginie, Etienne Pierre, Coquery Nicolas, Val-Laillet David
INRA, INSERM, Univ Rennes, Nutrition Metabolisms and Cancer, NuMeCan, Rennes, France.
Phodé, Terssac, France.
Front Behav Neurosci. 2019 Jul 16;13:161. doi: 10.3389/fnbeh.2019.00161. eCollection 2019.
Psychological chronic stress is an important risk factor for major depressive disorder, of which consequences have been widely studied in rodent models. This work aimed at describing a pig model of chronic stress based on social isolation, environmental impoverishment and unpredictability. Three groups of animals of both sexes were constituted. Two were exposed to the psychosocial stressors while receiving (SF, = 12) or not (SC, = 22) the antidepressant fluoxetine, and a third group (NSC, = 22) remained unstressed. Animals were observed in home pens and during dedicated tests to assess resignation and anxiety-like behaviors. Brain structure and function were evaluated proton MRS and fMRI. Hippocampal molecular biology and immunodetection of cellular proliferation (Ki67) and neuron maturation (DCX) in the dentate gyrus were also performed. Salivary cortisol, fecal short-chain fatty acids (SCFAs), and various plasmatic and intestinal biomarkers were analyzed. Compared to NSC, SC animals showed more resignation ( = 0.019) and had a higher level of salivary cortisol ( = 0.020). SC brain responses to stimulation by a novel odor were lower, similarly to their hippocampal neuronal density ( = 0.015), cellular proliferation ( = 0.030), and hippocampal levels of BDNF and 5-HTR ( = 0.056 and = 0.007, respectively). However, the number of DCX cells was higher in the ventral dentate gyrus in this group ( = 0.025). In addition, HOMA-IR was also higher ( < 0.001) and microbiota fermentation activity was lower (SCFAs, SC/NSC: < 0.01) in SC animals. Fluoxetine partially or totally reversed several of these effects. Exposure to psychosocial stressors in the pig model induced effects consistent with the human and rodent literature, including resignation behavior and alterations of the HPA axis and hippocampus. This model opens the way to innovative translational research exploring the mechanisms of chronic stress and testing intervention strategies with good face validity related to human.
心理慢性应激是重度抑郁症的一个重要风险因素，其后果已在啮齿动物模型中得到广泛研究。这项工作旨在描述一种基于社会隔离、环境匮乏和不可预测性的慢性应激猪模型。构建了三组雌雄动物。两组暴露于心理社会应激源，同时接受（SF，n = 12）或不接受（SC，n = 22）抗抑郁药氟西汀，第三组（NSC，n = 22）保持无应激状态。在圈舍和专门测试期间观察动物，以评估听任和焦虑样行为。通过质子磁共振波谱和功能磁共振成像评估脑结构和功能。还进行了海马分子生物学以及齿状回细胞增殖（Ki67）和神经元成熟（DCX）的免疫检测。分析了唾液皮质醇、粪便短链脂肪酸（SCFAs）以及各种血浆和肠道生物标志物。与NSC相比，SC动物表现出更多听任行为（P = 0.019），唾液皮质醇水平更高（P = 0.020）。SC组大脑对新气味刺激的反应较低，类似于其海马神经元密度（P = 0.015）、细胞增殖（P = 0.030）以及海马脑源性神经营养因子（BDNF）和5-羟色胺受体（5-HTR）水平（分别为P = 0.056和P = 0.007）。然而，该组腹侧齿状回中DCX细胞数量较多（P = 0.025）。此外，SC动物的胰岛素抵抗指数（HOMA-IR）也较高（P < 0.001），微生物群发酵活性较低（SCFAs，SC/NSC：P < 0.01）。氟西汀部分或完全逆转了其中一些效应。在猪模型中暴露于心理社会应激源会产生与人类和啮齿动物文献一致的效应，包括听任行为以及下丘脑-垂体-肾上腺（HPA）轴和海马的改变。该模型为探索慢性应激机制和测试与人类相关且具有良好表面效度的干预策略的创新性转化研究开辟了道路。
