Female rats adopt a safety-first strategy in a high-conflict platform mediated avoidance task

Abstract

Maladaptive avoidance is a central feature of many mental disorders, particularly stress- and anxiety-related disorders. Those disorders are more prevalent in women, suggesting that there may be sex differences in avoidance propensity. Sex differences have been documented in threat conditioning, but not in active avoidance paradigms, despite their potential clinical relevance. Preclinical research has historically focused on males, limiting our understanding of the neurobiological mechanisms underlying sex differences in threat responses. To address this gap, we investigated sex-specific strategies in adult Long Evans rats (10 female, 9 male) using a 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. Females consistently prioritized safety, spending significantly more time foregoing reward to avoid foot shock and retreating earlier to the safe zone. 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. These results were consistent in a pre-registered replication study. 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. Identifying the neural mechanisms underlying these differences may guide more targeted interventions for anxiety and trauma-related disorders.

Keywords: active avoidance; anxiety disorders; approach-avoidance conflict; estrous cycle; platform mediated avoidance; sex differences.