INVESTIGATING NETWORK-LEVEL ALTERATIONS UNDERLYING THE TEMPORAL DYNAMICS OF GENERALIZED FEAR

Fear learning is key process shaping adaptive, and also maladaptive behavioral responses. Its dysregulation can lead to excessive, persistent fear responses that generalizes to safe conditions, representing core features of post-traumatic stress disorder (PTSD). As these maladaptive changes evolve over time, understanding the temporal dynamics of fear generalization is essential for identifying mechanisms underlying PTSD development. Here, we assessed whole brain neuronal activity changes across early and late timepoints following trauma, i.e. under low and high fear generalization conditions. Namely, we exposed TRAP2 mice to a single series of footshocks and subsequently tested their fear recall in a safe/novel context 2 and 14 days after trauma. Early-timepoint neuronal activity was captured via tamoxifen-induced labeling, while late-timepoint activity was assessed by means of c-Fos labeling. We observed a marked increase of fear generalization from day 2 to 14. Comparative network and statistical analyses revealed significant temporal shifts in neuronal activation across established fear-processing areas (prelimbic and insular cortices) and less traditionally implicated areas (e.g. ectorhinal and perirhinal cortices) with distinct correlation hubs emerging during increased fear generalization. Regional activity-freezing correlations varied by timepoint, indicating dynamic functional reorganization. Together, these results reveal dynamic network-level changes in fear learning circuits and further elucidate neural mechanisms underlying maladaptive fear learning in PTSD.