Sex differences in discriminating between cues predicting threat and safety

Abstract

Post-traumatic stress disorder (PTSD) is more prevalent in women than men. PTSD is characterized by overgeneralization of fear to innocuous stimuli and involves impaired inhibition of learned fear by cues that predict safety. While evidence indicates that learned fear inhibition through extinction differs in males and females, less is known about sex differences in fear discrimination and safety learning. Here we examined auditory fear discrimination in male and female rats. In Experiment 1A, rats underwent 1-3days of discrimination training consisting of one tone predicting threat (CS+; presented with footshock) and another tone predicting safety (CS-; presented alone). Females, but not males, discriminated between the CS+ and CS- after one day of training. After 2-3days of training, however, males discriminated whereas females generalized between the CS+ and CS-. In Experiment 1B, females showed enhanced anxiety-like behaviour and locomotor activity in the open field, although these results were unlikely to explain the sex differences in fear discrimination. In Experiment 2, we found no differences in shock sensitivity between males and females. In Experiment 3, males and females again discriminated and generalized, respectively, after three days of training. Moreover, fear generalization in females resulted from impaired safety learning, as shown by a retardation test. Whereas subsequent fear conditioning to the previous CS- retarded learning in males, females showed no such retardation. These results suggest that, while females show fear discrimination with limited training, they show fear generalization with extended training due to impaired safety learning.

Keywords: Discrimination; Fear; Generalization; Post-traumatic stress disorder; Safety; Threat.

Fig. 1

Sex differences in auditory fear discrimination depend on the extent of training received. (A) Schematic representation of the fear discrimination paradigm used. (B) Freezing in response to CS+ and CS− presentation during discrimination retrieval testing after one day of training. Males showed no significant difference in freezing between the CS+ and CS−, whereas freezing was increased during CS+ compared to CS− presentation in females (^*P < 0.05). (C and D) Freezing to the CS+ and CS− during retrieval testing after two (C) or three (D) days of training. Freezing was increased to the CS+ compared to the CS− in males (^*P < 0.05, ^**P < 0.01), while freezing during CS+ and CS− presentation did not differ in females. (E–G) Freezing before CS+ and CS− presentations during retrieval testing after one (E), two (F), or three (G) days of training. There were no significant differences in freezing between any of the males and females.

Fig. 2

Females show enhanced anxiety-like behaviour and locomotor activity during open field testing. (A) There was no difference between males and females in the duration of time spent in the center of the open field. (B) Females showed an increased latency to first enter the center of the open field (^*P < 0.05). (C) The frequency of entries into the center of the open field did not differ significantly between males and females. (D) The horizontal distance moved in the open field was increased in females (^*P < 0.05).

Fig. 3

The threshold current eliciting flinch or vocalization responses does not differ between males and females, indicating a lack of sex differences in shock sensitivity.

Fig. 4

Sex differences in auditory fear discrimination with extended training involve altered safety signaling by the CS−. (A) Schematic representation of the discrimination and retardation testing paradigm used. (B) Freezing in response to the CS+ and CS− during discrimination retrieval testing after three days of training. Freezing was increased during CS+ compared to CS− presentation in males (^***P < 0.001) but not females. (C) Males subjected to discrimination training (Discrim Train) followed by fear conditioning using the previous CS− as the cue showed decreased freezing to the cue during fear retrieval testing, compared to controls pre-exposed (Pre-Exp) to the cue before conditioning (^*P < 0.05). There was no difference in freezing to the cue between females that underwent discrimination training and pre-exposed controls (note that the discrimination retrieval data in (B) is from the Discrim Train groups in (C).