Treatments are only partially effective in major depressive disorders (MDD) but no biomarker exists to predict symptom improvement in patients. Animal models are essential tools in the development of antidepressant medications, but while recent genetic studies have demonstrated the polygenic contribution to MDD, current models are limited to either mimic the effect of a single gene or environmental factor. We developed in the past a model of depressive-like behaviors in mice (H/Rouen), using selective breeding based on behavioral reaction after an acute mild stress in the tail suspension test. Here, we propose a new mouse model of depression (H-TST) generated from a more complex genetic background and based on the same selection process. We first demonstrated that H/Rouen and H-TST mice had similar phenotypes and were more sensitive to glutamate-related antidepressant medications than selective serotonin reuptake inhibitors. We then conducted an exome sequencing on the two mouse models and showed that they had damaging variants in 174 identical genes, which have also been associated with MDD in humans. Among these genes, we showed a higher expression level of Tmem161b in brain and blood of our two mouse models. Changes in TMEM161B expression level was also observed in blood of MDD patients when compared with controls, and after 8-week treatment with duloxetine, mainly in good responders to treatment. Altogether, our results introduce H/Rouen and H-TST as the two first polygenic animal models of MDD and demonstrate their ability to identify biomarkers of the disease and to develop rapid and effective antidepressant medications.

治疗对重度抑郁症（MDD）仅部分有效，但不存在预测患者症状改善的生物标志物。动物模型是开发抗抑郁药物的重要工具，但尽管最近的遗传学研究已经证明了多基因对重度抑郁症的影响，但目前的模型仅限于模拟单个基因或环境因素的影响。我们过去开发了一种小鼠抑郁样行为模型（H/Rouen），采用基于尾悬试验中急性轻度应激后行为反应的选择性育种。在这里，我们提出了一种新的抑郁症小鼠模型（H-TST），该模型是根据更复杂的遗传背景并基于相同的选择过程而生成的。我们首先证明 H/Rouen 和 H-TST 小鼠具有相似的表型，并且对谷氨酸相关的抗抑郁药物比选择性血清素再摄取抑制剂更敏感。然后，我们对这两个小鼠模型进行了外显子组测序，结果显示它们的 174 个相同基因具有破坏性变异，这些变异也与人类 MDD 相关。在这些基因中，我们在两个小鼠模型的大脑和血液中显示出较高的Tmem161b表达水平。与对照组相比，以及在度洛西汀治疗 8 周后，MDD 患者血液中也观察到TMEM161B表达水平的变化，主要是在治疗反应良好的患者中。总而言之，我们的结果将 H/Rouen 和 H-TST 作为 MDD 的两个第一个多基因动物模型，并证明了它们识别疾病生物标志物和开发快速有效的抗抑郁药物的能力。