Translational animal models for studying post-traumatic stress disorder (PTSD) are valuable for elucidating the poorly understood neurobiology of this neuropsychiatric disorder. These models should encompass crucial features, including persistence of PTSD-like phenotypes triggered after exposure to a single traumatic event, trauma susceptibility/resilience and predictive validity. Here we propose a novel arousal-based individual screening (AIS) model that recapitulates all these features. The AIS model was designed by coupling the traumatization (24 h restraint) of C57BL/6 J mice with a novel individual screening. This screening consists of z-normalization of post-trauma changes in startle reactivity, which is a measure of arousal depending on neural circuits conserved across mammals. Through the AIS model, we identified susceptible mice showing long-lasting hyperarousal (up to 56 days post-trauma), and resilient mice showing normal arousal. Susceptible mice further showed persistent PTSD-like phenotypes including exaggerated fear reactivity and avoidance of trauma-related cue (up to 75 days post-trauma), increased avoidance-like behavior and social/cognitive impairment. Conversely, resilient mice adopted active coping strategies, behaving like control mice. We further uncovered novel transcriptional signatures driven by PTSD-related genes as well as dysfunction of hypothalamic–pituitary–adrenal axis, which corroborated the segregation in susceptible/resilient subpopulations obtained through the AIS model and correlated with trauma susceptibility/resilience. Impaired hippocampal synaptic plasticity was also observed in susceptible mice. Finally, chronic treatment with paroxetine ameliorated the PTSD-like phenotypes of susceptible mice. These findings indicate that the AIS model might be a new translational animal model for the study of crucial features of PTSD. It might shed light on the unclear PTSD neurobiology and identify new pharmacological targets for this difficult-to-treat disorder.

用于研究创伤后应激障碍（PTSD）的转化动物模型对于阐明这种神经精神疾病的神经生物学了解甚少。这些模型应包含关键特征，包括暴露于单个创伤事件后触发的PTSD样表型的持久性，创伤易感性/韧性和预测有效性。在这里，我们提出了一个新颖的基于唤醒的个体筛选（AIS）模型，概括了所有这些功能。通过将C57BL / 6 J小鼠的创伤（约束24小时）与新颖的个体筛查偶联来设计AIS模型。这种筛选包括惊吓反应性的创伤后变化的z归一化，这是唤醒的一种手段，取决于跨哺乳动物保守的神经回路。通过AIS模型，我们确定了易感小鼠表现出持久的高唤醒（创伤后长达56天），而有弹性的小鼠表现出正常的唤醒。易感小鼠进一步表现出持续的PTSD样表型，包括夸张的恐惧反应性和避免创伤相关提示（创伤后长达75天），回避样行为增加和社会/认知障碍。相反，有弹性的小鼠采取主动应对策略，表现得像对照小鼠。我们进一步发现了由PTSD相关基因驱动的新的转录特征以及下丘脑-垂体-肾上腺轴功能障碍，这证实了通过AIS模型获得的易感/弹性亚群中的隔离，并与创伤易感性/韧性相关。在易感小鼠中还观察到海马突触可塑性受损。最后，帕罗西汀的长期治疗改善了易感小鼠的PTSD样表型。这些发现表明，AIS模型可能是用于研究PTSD关键特征的新的转化动物模型。它可能揭示了尚不清楚的PTSD神经生物学，并为这种难以治疗的疾病确定了新的药理学靶标。