Sex differences in mouse models of fear inhibition: Fear extinction, safety learning, and fear–safety discrimination

Jacob W. Clark, Sean P.A. Drummond, Daniel Hoyer, Laura H. Jacobson

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)


Background and Purpose: 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. Experimental Approach: 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. Key Results: 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. Conclusion and Implications: 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.

Original languageEnglish
Pages (from-to)4149-4158
Number of pages10
JournalBritish Journal of Pharmacology
Issue number21
Publication statusPublished - Nov 2019

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