Fear-conditioning to unpredictable threats reveals sex differences in rat fear-potentiated startle (FPS)

Abstract

Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies have shown 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 often 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 unpaired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females demonstrate higher shock reactivity during fear-conditioning. Both sexes demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS but females show reduced fear discrimination vs. males. Fear-conditioning with 70% contingency or backward order (cue co-starts with shock) induces similar levels of cued, non-cued, and contextual fear in both sexes but they differ in contextual fear extinction. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning protocol (cue and shock un-paired), with 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 mechanisms underlying higher incidence of PTSD in women.

Sex and the facilitation of cued fear by prior contextual fear conditioning in rats

“…In our prior work (Cole and Parsons, 2023) we found lower levels of fear to the light in females when visual fear conditioning was preceded by auditory fear conditioning, although this effect was specific to rats that had been trained with a 24-hour interval. Results from prior studies using more traditional designs in which rats of both sexes are trained with a single conditioning experience are mixed, with some work showing lower fear-potentiated startle in females, and others showing higher fear-potentiated startle in females or no differences (de Jongh et al, 2005; Voulo and Parsons, 2017; Zhao et al, 2018; Olivera-Pasilio and Dabrowska, 2023). Our results also indicate that males showed higher levels of contextual fear than females, which is consistent with a number of prior studies (Maren et al, 1994; Wiltgen et al, 2001; Chang et al, 2009; Gresack et al, 2009; Barker & Galea, 2010; Colon et al, 2018).…”