Stress-enhanced fear learning can be reduced with unconditional stimulus deflation with constraints

Abstract

Exposure to extreme stress can negatively impact behavior and lead to prolonged fear sensitization. These processes can be studied in the lab using stress-enhanced fear learning (SEFL), where prior exposure to inescapable stress exacerbates later contextual fear conditioning. A common method to reduce conditional fear is through extinction, where a conditional stimulus once paired with an unconditional (US; e.g., a footshock) is presented alone. Previous research shows that extinction learning may not be as effective at reducing fear behavior in rodents previously exposed to stress, mirroring similar extinction impairments observed in aged rodents. Weak-shock exposure (termed US deflation) following conditioning with a strong shock has been proposed to be an alternative to extinction where presentations of weaker versions of the US would work to modify the original fear memory rather than create a new memory as in extinction and thus more precisely target the original context fear memory. While effective under normal conditions, it has yet to be studied how effective US deflation is at reducing stress-enhanced context fear. Here we aimed to test if US deflation could reduce fear in a SEFL paradigm and identify any constraints of this effect. Following 15 inescapable footshocks or matched chamber exposure, male and female Long Evans rats received 1 context-shock pairing or 5 context-shock pairings in a novel context. The next day, they were given either 10 weak footshocks (US deflation) or extinction before behavioral testing. Following training with 1 context-shock pairing, both US deflation and extinction functioned similarly in reducing freezing behavior of stressed rodents. However, following 5 context-shock pairings, only the unstressed rodents displayed a significant decrease in fear behavior, suggesting that prior stress coupled with more robust conditioning can limit the efficacy of US deflation in reducing fear behavior. Finally, we replicated the SEFL effect in aged rodents and found that they showed a significant decrease in stress-enhanced fear learning following US deflation, whereas our previous research showed impairments of traditional extinction in aged rodents. Together, these results suggest that US deflation can reduce SEFL in both adult and aged rodents following a single context-shock pairing, with additional pairings rendering this procedure ineffective at mitigating the effects of prior stress.

Keywords: Extinction; Fear; Learning; Memory; SEFL; Stress.