Female Wistar Kyoto More Immobile rats with genetic stress hyper‐reactivity show enhanced contextual fear memory without deficit in extinction of fear

The prevalence of post‐traumatic stress disorder (PTSD) is higher in females than males, but pre‐clinical models are established almost exclusively in males. This study is aimed to investigate the stress‐enhanced fear learning model of PTSD in females. The model mirrors PTSD symptomology in males, whereby prior stress leads to extinction resistant exaggerated contextual fear memory. As stress reactivity is highly relevant to the study and risk for PTSD, females of the stress hyper‐reactive Wistar Kyoto More Immobile (WMI) and its nearly isogenic control the Wistar Kyoto Less Immobile (WLI) strains were employed. Prior studies have shown WMI females presenting unchanged or enhanced fear memory in the stress‐enhanced fear learning paradigm compared WLIs. The present study confirmed the enhanced fear memory following contextual fear conditioning in WMIs compared to WLI females, but this increased fear memory was neither exaggerated by prior stress nor showed extinction deficit. The novel stressor of a glucose challenge test resulted in subtle strain‐ and prior stress‐induced differences in plasma glucose responses. However, fasting plasma corticosterone levels were lower, and rose slower in response to glucose challenge in WMI females, suggesting a PTSD‐like dysfunctional stress response. Hippocampal expressions of genes relevant to both learning and memory and the stress response were decreased in stressed WMIs compared to WLI females, further suggesting a marked dysregulation in stress‐related functions like in PTSD. Thus, although WMI females do not show extinction‐resistant enhanced fear memory, they do present other characteristics that are relevant to PTSD in women.