Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging, as it is a heterogeneous disorder with ≥20 symptoms. Clinical research increasingly utilizes objective biological measures (e.g., imaging, peripheral biomarkers) or nonverbal behaviors and/or physiological responses to complement verbally reported symptoms. This shift toward more-objectively measurable phenotypes enables refinement of current animal models of PTSD, and it supports the incorporation of homologous measures across species. We reviewed >600 articles to examine the ability of current rodent models to probe biological phenotypes of PTSD (e.g., sleep disturbances, hippocampal and fear-circuit dysfunction, inflammation, glucocorticoid receptor hypersensitivity) in addition to behavioral phenotypes. Most models reliably produced enduring generalized anxiety-like or depression-like behaviors, as well as hyperactive fear circuits, glucocorticoid receptor hypersensitivity, and response to long-term selective serotonin reuptake inhibitors. Although a few paradigms probed fear conditioning/extinction or utilized peripheral immune, sleep, and noninvasive imaging measures, we argue that these should be incorporated more to enhance translation. Data on female subjects, on subjects at different ages across the life span, or on temporal trajectories of phenotypes after stress that can inform model validity and treatment study design are needed. Overall, preclinical (and clinical) PTSD researchers are increasingly incorporating homologous biological measures to assess markers of risk, response, and treatment outcome. This shift is exciting, as we and many others hope it not only will support translation of drug efficacy from animal models to clinical trials but also will potentially improve predictability of stage II for stage III clinical trials.

中文翻译：

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PTSD 动物模型的现状：行为和生物学表型，以及改进翻译的未来挑战

提高创伤后应激障碍 (PTSD) 动物模型的可预测性需要临床和临床前科学家之间的积极合作。对 PTSD 进行建模具有挑战性，因为它是一种具有 20 种以上症状的异质性疾病。临床研究越来越多地利用客观生物学测量（例如，成像、外周生物标志物）或非语言行为和/或生理反应来补充口头报告的症状。这种向更客观可测量的表型的转变能够改进当前的 PTSD 动物模型，并支持跨物种的同源测量的结合。我们回顾了 600 多篇文章，以检查当前啮齿动物模型探测 PTSD 生物表型的能力（例如，睡眠障碍、海马和恐惧回路功能障碍、炎症、糖皮质激素受体超敏反应）以及行为表型。大多数模型可靠地产生持久的广泛性焦虑样或抑郁样行为，以及过度活跃的恐惧回路、糖皮质激素受体超敏反应和对长期选择性血清素再摄取抑制剂的反应。尽管一些范式探讨了恐惧条件反射/灭绝或利用外周免疫、睡眠和非侵入性成像措施，但我们认为应该更多地纳入这些以增强翻译。需要关于女性受试者、整个生命周期中不同年龄的受试者或压力后表型的时间轨迹的数据，这些数据可以为模型有效性和治疗研究设计提供信息。全面的，临床前（和临床）PTSD 研究人员越来越多地结合同源生物学测量来评估风险、反应和治疗结果的标志物。这种转变令人兴奋，因为我们和许多其他人希望它不仅能支持将药物功效从动物模型转化为临床试验，而且有可能提高 III 期临床试验 II 期的可预测性。