Passive Behavioral Patterns in Symptomatic WAG/Rij Rats: Dissociation From Absence Epilepsy and Sex-Dependent Link Between Early Fear Coping and Post-Stress Freezing

Background: Acute stress exposure can lead to delayed behavioral changes, which are widely regarded as core endophenotypes of post-traumatic stress disorder (PTSD). Identifying pre-existing behavioral traits that predict later maladaptive responses is crucial. We investigated whether early fear-related passive coping behavior during an active avoidance task predicts subsequent freezing reactions in a safe, stimulus-free environment. This context-inappropriate fear pattern may model individual vulnerability to PTSD-like symptoms. We used Wistar Albino rats from Rijswijk (WAG/Rij rats), which are genetically predisposed to develop absence epilepsy. This condition is non-convulsive and characterized by sudden, brief periods of behavioral arrest known as absences. Absence-like seizures in WAG/Rij rats are accompanied by spike-and-wave discharge (SWDs) on electroencephalogram (EEG) and behavioral arrest. We also examined the relationship between the severity of absence epilepsy and passive behavioral patterns in WAG/Rij rats at symptomatic ages (10–12 months), as well as sex-related differences. Methods: We used an automated fear-conditioning paradigm to identify individual differences in baseline stress vulnerability that predict delayed, context-independent freezing behavior. Rats were tested in an active avoidance paradigm to assess fear-induced passive behavior under threat at the age of 9 months, and the percentage of passive behavioral responses was scored. Rats were then tested in a safe environment using the StartFear system, and the percentage of freezing was measured monthly at the ages of 10, 11, and 12 months. Finally, the rats underwent EEG examination, and SWDs were scored during 12-hour dark-phase recordings. Results: In the safe environment, 10- to 12-month-old WAG/Rij rats exhibited low levels of freezing (9.5%–13.9% of the total time). No significant sex differences were observed in freezing behavior within the safe environment. However, in the unsafe, fear-inducing active avoidance task, males displayed significantly higher levels of passive behavior than females. Female rats showed strong correlations between passive responses in the fear-inducing situation and freezing in the safe environment, whereas males did not. Results from EEG examinations indicated that males exhibited a higher number of SWDs than females. Neither the percentage of freezing in the safe environment nor the percentage of passive responses in the active avoidance task correlated with the severity of absence epilepsy, as assessed by the number and duration of SWDs. WAG/Rij rats tested after avoidance training exhibited low freezing in the StartFear paradigm and a sex-dependent increase in passive responses following conditioning; these findings are consistent with altered tonic inhibitory regulation but require naïve controls and EEG-behavior coupling to establish causality. Conclusions: Four primary conclusions emerge from this study: (1) symptomatic WAG/Rij rats exhibit low levels of freezing in a safe environment; (2) sex differences exist in unsafe contexts, but not safe ones; (3) there is a sex-dependent association between early passive behavior and later freezing; (4) there is no relationship between the severity of absence epilepsy and passive behavioral patterns. Therefore, thalamocortical disturbances associated with SWDs do not correlate with fear-related freezing or passive coping behaviors, suggesting a distinction between seizure-related immobility and non-seizure passive behaviors. There is also a sex-specific link between early passive coping and later context-inappropriate freezing, warranting further study in models of anxiety and PTSD.