Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here, we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrated that mice directly subjected to a threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5α-reductase type 2, is decreased in the basolateral amygdala, which is a major emotional processing hub implicated in PTSD. We demonstrated that genetic knockdown or pharmacological inhibition of 5α-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas oral treatment with an exogenous, synthetic neuroactive steroid gamma-aminobutyric acid-A receptor positive allosteric modulator with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreased the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.

中文翻译：

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目睹的创伤暴露通过减少内源性神经类固醇合成而引起小鼠的恐惧

神经类固醇与创伤后应激障碍（PTSD）的病理生理学有关。在患有 PTSD 的个体亚群中，四氢孕酮的含量减少，并已被探索作为一种新的治疗策略。直接创伤暴露和目击创伤都是 PTSD 的危险因素；然而，神经类固醇在这些独特经历的行为结果中的作用尚未被探索。在这里，我们研究观察性恐惧是否与内源性神经类固醇生成能力降低以及与行为结果的关系有关。我们证明，直接受到威胁（足部电击）的小鼠和目睹威胁的小鼠血浆中四氢孕酮水平降低。基底外侧杏仁核中参与内源性神经类固醇合成的关键酶（2 型 5α-还原酶）的表达减少，基底外侧杏仁核是与 PTSD 相关的主要情绪处理中心。我们证明，基因敲低或药物抑制 2 型 5α-还原酶会夸大对目击创伤的恐惧行为表达，而口服外源性合成神经活性类固醇 γ-氨基丁酸-A 受体正变构调节剂的分子药理学相似四氢孕酮（SGE-516 [工具化合物]）降低了对观察恐惧的行为反应。这些数据表明，直接和目睹的威胁暴露的病理生理学中内源性神经类固醇生成受损。此外，这些数据表明，用外源性 5α 减少的神经类固醇治疗或靶向内源性神经类固醇生成可能有益于治疗 PTSD 个体，无论是由直接创伤还是目击创伤所致。