Fear-Conditioning to Unpredictable Threats Reveals Sex and Strain Differences in Rat Fear-Potentiated Startle (FPS)

Fear startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies showed higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock un-paired). Although there are no sex differences in the startle ampli-tudes when corrected for body weight, females consistently demonstrate higher shock reactivity during fear -conditioning. Both sexes and strains demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS and FPS following fear-conditioning with 70% contingency or backward order (cue co-starts with shock). However, in the classic FPS, Sprague-Dawley females show reduced proportion between cued fear and cue-elicited vigilant state than males. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning (cue and shock un-paired), with Wistar, but not Sprague-Dawley, females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mecha-nisms underlying higher incidence of PTSD in women.(c) 2023 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

This study investigates the effects of signal-threat contingency, signal-threat order, and threat predictability on fear-potentiated startle (FPS) in both sexes. Results show higher shock reactivity in females during fear-conditioning and a lower proportion between cue-elicited vigilant state and cued fear in Sprague-Dawley females in the classic FPS. Following unpredictable fear-conditioning, Wistar females exhibit significantly higher startle and contextual fear than males. These findings contribute to understanding the mechanisms underlying the higher incidence of PTSD in women.