On the basis of sex: Differences in safety discrimination vs. conditioned inhibition

Behav Brain Res. 2021 Feb 26:400:113024. doi: 10.1016/j.bbr.2020.113024. Epub 2020 Dec 5.


Inaccurate discrimination between threat and safety cues is a common symptom of anxiety disorders such as Post-Traumatic Stress Disorder (PTSD). Although females experience higher rates of these disorders than males, the body of literature examining sex differences in safety learning is still growing. Learning to discriminate safety cues from threat cues requires downregulating fear to the safety cue while continuing to express fear to the threat cue. However, successful discrimination between safety and threat cues does not necessarily guarantee that the safety cue can effectively reduce fear to the threat cue when they are presented together. The conditioned inhibitory ability of a safety cue to reduce fear in the presence of both safety and threat is most likely dependent on the ability to discriminate between the two. There are relatively few studies exploring conditioned inhibition as a method of safety learning. Adding to this knowledge gap is the general lack of inclusion of female subjects within these studies. In this review, we provide a qualitative review of our current knowledge of sex differences in safety discrimination versus conditioned inhibition in both humans and rodents. Overall, the literature suggests that while females and males perform similarly in discrimination learning, females show deficits in conditioned inhibition compared to males. Furthermore, while estrogen appears to have a protective effect on safety learning in humans, increased estrogen in female rodents appears to be correlated with impaired safety learning performance.

Keywords: conditioned inhibition; humans; rodents; safety discrimination; sex differences.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Conditioning, Classical / physiology*
  • Discrimination Learning / physiology*
  • Estrogens / physiology*
  • Fear / physiology*
  • Female
  • Humans
  • Inhibition, Psychological*
  • Male
  • Safety*
  • Sex Characteristics*


  • Estrogens