Monash Institute of Cognitive and Clinical Neuroscience, Monash University, Notting Hill, VIC, Australia.
Department of Pharmacology and Therapeutics, School of Biomedical Sciences, University of Melbourne, Parkville, VIC, Australia.
Br J Pharmacol. 2019 Nov;176(21):4149-4158. doi: 10.1111/bph.14600. Epub 2019 Apr 15.
Women are overrepresented in post-traumatic stress disorder (PTSD), a mental disorder characterised by ineffective inhibition of fear. The use of male animals dominates preclinical studies, which may contribute to a lack of understanding as to why this disparity exists. Thus, the current study explores sex differences in three mouse models of fear inhibition.
All experiments tested male and female C57Bl/6J mice. Experiment 1 employed two fear conditioning protocols, in which tones were paired with footshocks of differing intensity (moderate or intense). Fear recall and extinction were tested subsequently. In Experiment 2, safety learning was investigated. Tones were explicitly unpaired with footshocks during safety conditioning. Recall of safety learning was tested 24 hr later. Experiment 3 assessed a model of fear-safety discrimination. Cued stimuli were paired or never paired with footshocks during fear and safety conditioning, respectively. Discrimination between stimuli was assessed 24 hr later.
In fear extinction, males, compared to females, responded with greater fear in sessions most proximal to conditioning but subsequently showed a more rapid fear extinction over time. Sex differences were not observed during safety learning. During fear-safety discrimination, both males and females discriminated between stimuli; however, males revealed a greater level of freezing to stimuli.
The current study provides evidence that sex differences influence fear but not safety-based behaviour in C57Bl/6J mice. These findings indicate that processing of fear, but not safety, may play a greater role in sex differences observed for PTSD.
This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
创伤后应激障碍（PTSD）是一种以恐惧抑制无效为特征的精神障碍，女性在其中的发病率过高。临床前研究主要使用雄性动物，这可能导致人们对这种差异存在的原因缺乏了解。因此，本研究探讨了三种恐惧抑制小鼠模型中的性别差异。
所有实验均测试了雄性和雌性 C57Bl/6J 小鼠。实验 1 采用了两种恐惧条件反射协议，其中音调与不同强度（中度或高强度）的足底电击配对。随后测试了恐惧回忆和消退。在实验 2 中，研究了安全性学习。在安全条件反射期间，音调与足底电击明确不配对。24 小时后测试了对安全学习的回忆。实验 3 评估了恐惧-安全辨别模型。在恐惧和安全条件反射期间，分别用线索刺激与足底电击配对或从不配对。24 小时后评估了对刺激的辨别。
在恐惧消退中，与雌性相比，雄性在与条件反射最接近的阶段表现出更大的恐惧反应，但随后随着时间的推移表现出更快的恐惧消退。在安全性学习中未观察到性别差异。在恐惧-安全辨别中，雄性和雌性均能辨别刺激；然而，雄性对刺激的冻结程度更高。
本研究提供了证据表明，性别差异影响 C57Bl/6J 小鼠的恐惧，但不影响基于安全性的行为。这些发现表明，在 PTSD 中观察到的性别差异可能与恐惧的处理而非安全性的处理有关。
本文是关于“药理学研究中性别差异的重要性”专题的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
