Circadian disruption impairs fear extinction and memory of conditioned safety in mice

Abstract

Animal models of fear conditioning and fear inhibition are frequently employed in the study of associative learning and commonly derive important human implications. Animal and human studies have demonstrated fear processing abilities are moderated by circadian rhythms, however, the influence of circadian disruption on fear inhibition is not well understood. Here, we examined the effects of circadian disruption on fear inhibition processes (i.e., fear extinction and safety learning) in a pre-clinical model. Adult male C57Bl/6 J mice completed cued fear and safety conditioning in the active phase before undergoing acute shifts in the Light-Dark (LD) cycle. Specifically, the light-phase was advanced by eight-hours across a one-day period (Experiment 1) or a two-day period (Experiment 2), before returning to original timing. Fear and safety recall were assessed over two days following LD shifts. Control groups maintained one LD cycle throughout both experiments. In both experiments, mice allocated to LD shifted groups revealed misaligned patterns of previously circadian locomotor activity. In the second recall session of Experiment 1, LD shifted mice demonstrated reduced retention of conditioned safety memory. However, in Experiment 2, LD shifted mice displayed heightened fear across conditioned fear cues in both recall sessions, therefore demonstrating consistent fear extinction impairment. Moreover, in recall session two, these mice revealed impaired ability to suppress fear during initial presentations of fear and safety cues. Overall, our data suggest maintaining a consistent LD cycle may be crucially important to individuals at high-risk of trauma-exposure and subsequent development of posttraumatic stress disorder.

Keywords: Circadian disruption; Fear extinction; Memory; Mice; Posttraumatic stress disorder; Safety learning.