Abstract
Sex differences have been documented in threat conditioning, but research into potential sex differences in avoidance paradigms, particularly active avoidance, remains limited. This research gap is particularly concerning given that women are disproportionately affected by stress- and anxiety-related disorders, characterized by maladaptive avoidance. Yet, preclinical research has historically focused on male subjects, limiting our understanding of the neurobiological mechanisms underlying sex differences in threat responses. To address this, we investigated sex-specific strategies in adult Long Evans rats (10 female, 9 male) using a modified platform-mediated avoidance (PMA) task that created a high-conflict choice between reward-seeking and safety. Behavior was tracked over 25 days, with analyses focusing on a stable performance phase (days 20-25) objectively defined using change point analysis. The study design included an initial cohort and a replication cohort to ensure the findings' robustness. Females consistently prioritized safety, spending significantly more time foregoing reward to avoid foot shock, while males engaged in more persistent reward-seeking despite the risk of shock. This difference was not driven by differential reward motivation. Furthermore, female strategies were not significantly modulated by the estrous cycle. Thus, male and female rats employ fundamentally different strategies to resolve approach-avoidance conflict: females adopt a robust, safety-first strategy, while males demonstrate a risk-prone, reward-oriented approach. These findings highlight the importance of considering biological factors underlying threat responses, suggesting that characterizing these neural mechanisms may guide more targeted interventions for anxiety and trauma-related disorders.