Longitudinal shifts in avoidance-based phenotypes in a predator odor conditioned place aversion model of posttraumatic stress disorder.

Introduction: Posttraumatic stress disorder (PTSD) develops in a subset of trauma-exposed individuals and is characterized by persistent intrusion, avoidance, negative mood and cognition, and arousal symptoms, with heterogeneous symptom trajectories. There is a need for longitudinal rodent models of PTSD that incorporate individual differences in post-stress outcomes to probe mechanisms of susceptibility and resilience. Method: We used a predator odor (bobcat urine) conditioned place aversion (CPA) paradigm in male Wistar rats to examine the emergence and persistence of anxiety-like avoidance behavior over 6 weeks. Automated tracking during CPA testing quantified time in the predator odor (PO)-paired chamber and chamber-specific locomotor metrics; animals were further assessed with an acoustic startle response (ASR) test (Day 2), open field (OF, Day 5), and elevated plus maze (EPM, Day 16). At 6 weeks post-stress, rats were re-exposed to the CPA apparatus, modeling contextual reminder-induced trauma recall. Longitudinal body weight and endocrine endpoints (adrenal gland weight and circulating corticosterone) were collected. Results: At 24 h post-stress, Avoider rats, approximately 40% of exposed animals, showed avoidance of the PO-paired chamber, whereas Non-Avoider rats made more entries into and moved more slowly within the PO-paired chamber. By 6 weeks, initial classifications no longer predicted avoidance behavior; CPA-based diagnosis revealed substantial phenotypic shifts, with 24% of rats remaining Avoiders, 28% remaining Non-Avoiders, and the remainder switching phenotypes (16% Avoiders to Non-Avoiders; 32% Non-Avoiders to Avoiders). Re-analysis of the ASR test showed similar startle responses across phenotypes at lower and intermediate intensities; however, rats that shifted from Non-Avoiders to Avoiders displayed greater startle responses than rats that remained Non-Avoiders at the highest sound level. In contrast, OF and EPM measures showed no phenotypic differences. Sustained Avoider rats exhibited modestly greater weight gain, whereas corticosterone and adrenal gland mass did not differ among groups. Discussion: These findings indicate that PO models identify early Avoider and Non-Avoider phenotypes with distinct behavioral profiles but also reveal dynamic shifts in avoidance-based classifications over time. This work highlights the need for longitudinal studies to better characterize evolving behavioral phenotypes, endocrine, and physiological changes in rodent PTSD models and understand neural mechanisms underlying interindividual variability in PTSD symptom trajectories.