The limited neurobiological understanding of posttraumatic stress disorder (PTSD) has been partially attributed to the need for improved animal models. Stress-enhanced fear learning (SEFL) in rodents recapitulates many PTSD-associated behaviors, including stress-susceptible and stress-resilient subgroups in outbred rats. Identification of subgroups requires additional behavioral phenotyping, a confound to mechanistic studies. We employed a SEFL paradigm in inbred male and female C57BL/6 mice that combines acute stress with fear conditioning to precipitate traumatic-like memories. Extinction and long-term retention of extinction were examined after SEFL. Further characterization of SEFL effects on male mice was performed with additional behavioral tests, determination of regional activation by Fos immunofluorescence, and RNA sequencing of the basolateral amygdala. Stressed animals displayed persistently elevated freezing during extinction. While more uniform in females, SEFL produced male subgroups with differential susceptibility that were identified without posttraining phenotyping. Additional phenotyping of male mice revealed PTSD-associated behaviors, including extinction-resistant fear memory, hyperarousal, generalization, and dysregulated corticosterone in stress-susceptible male mice. Altered Fos activation was also seen in the infralimbic cortex and basolateral amygdala of stress-susceptible male mice after remote memory retrieval. Key behavioral outcomes, including susceptibility, were replicated by two independent laboratories. RNA sequencing of the basolateral amygdala revealed transcriptional divergence between the male subgroups, including genes with reported polymorphic association to patients with PTSD. This SEFL model provides a tool for development of PTSD therapeutics that is compatible with the growing number of mouse-specific resources. Furthermore, use of an inbred strain allows for investigation into epigenetic mechanisms that are expected to critically regulate susceptibility and resilience.

中文翻译：

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近交小鼠对创伤后应激障碍样行为的敏感性和恢复力


对创伤后应激障碍（PTSD）的神经生物学理解有限，部分原因是需要改进动物模型。啮齿类动物的压力增强恐惧学习（SEFL）重现了许多与创伤后应激障碍（PTSD）相关的行为，包括近交系大鼠中的压力敏感亚群和压力恢复亚群。亚组的识别需要额外的行为表型分析，这与机制研究相混淆。我们在近交系雄性和雌性 C57BL/6 小鼠中采用了 SEFL 范例，将急性应激与恐惧条件反射相结合，以促进类似创伤的记忆。 SEFL 后检查消光和消光的长期保留。通过额外的行为测试、通过 Fos 免疫荧光确定区域激活以及基底外侧杏仁核的 RNA 测序，进一步表征了 SEFL 对雄性小鼠的影响。受到压力的动物在灭绝过程中表现出持续升高的冰冻状态。虽然女性的情况更为一致，但 SEFL 产生了具有不同易感性的男性亚组，这些亚组无需训练后表型分析即可识别。雄性小鼠的其他表型分析揭示了与 PTSD 相关的行为，包括应激敏感雄性小鼠的抗灭绝恐惧记忆、过度觉醒、泛化和皮质酮失调。在远程记忆恢复后，应激敏感雄性小鼠的边缘下皮层和基底外侧杏仁核中也发现了 Fos 激活的改变。包括易感性在内的关键行为结果由两个独立实验室复制。基底外侧杏仁核的 RNA 测序揭示了男性亚群之间的转录差异，包括据报道与 PTSD 患者存在多态性关联的基因。 该 SEFL 模型为开发 PTSD 疗法提供了一种工具，该工具与越来越多的小鼠特异性资源兼容。此外，使用近交系可以研究表观遗传机制，这些机制有望严格调节易感性和恢复力。