Sex-Specific Development in the Persistence of Stress-Induced Enhancement of Fear Learning in Juvenile and Adult Rats

Abstract

It is estimated that approximately fifty percent of the population will encounter at least one traumatic event during their lifetime; however, only six percent develop Posttraumatic Stress Disorder (PTSD), a trauma-related disorder characterized by persistent alterations in affect and cognition, including an exaggerated fear response. It is well established that females (9.7%) are more than twice as likely as males (3.6%) to be diagnosed with PTSD. Nevertheless, a significant challenge remains in understanding how the severity of traumas experienced in childhood versus adulthood influences PTSD development across sexes. To address this challenge effectively, the adoption of preclinical animal models that accurately reflect these key characteristics is crucial. The Stress Enhanced Fear Learning (SEFL) paradigm in rodents encapsulates some of these complexities associated with PTSD, such as persistent fear sensitization following exposure to acute trauma. This study investigates how stress severity and developmental timing affect the long-term maintenance of SEFL in male and female rats. Juvenile and adult rats were initially subjected to no stress (control, context only), low stress (1 footshock), moderate stress (3 footshocks), or high stress (15 footshocks), followed by an extinction session either one day (recent) or sixty days (remote) later. Subsequently, to evaluate SEFL in a new context, all subjects received a single footshock and were tested the following day. Shortly after stress induction, all groups displayed SEFL. Although the effects persisted for sixty days in adult males and juvenile females, even at the lowest stress level, they were significantly reduced in juvenile males and adult females. These findings offer novel insights into sex-related differences in the persistence of SEFL and introduce new considerations regarding how the timing of developmental stressors influences future threat encoding and fear responses.