Progress in spatiotemporal regulation of fear memory: neural circuit mechanisms and implications for PTSD

Post-traumatic stress disorder (PTSD) is a severe neuropsychiatric disorder characterised by re-experiencing, avoidance and hyperarousal. Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence. Over the past decades, convergent results from human and animal studies have systematically investigated contributions of the amygdala, hippocampus and medial prefrontal cortex (mPFC) in fear memory processes, including fear acquisition, storage, reconsolidation and extinction. These findings provide mechanistic insights for cognitive–behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD. Taking advantage of advances in cell-type selective labelling and manipulation technologies, recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes. These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network. Moreover, the functional role of distinct neuronal ensembles within the amygdala–hippocampus–mPFC pathway, identified by genetic markers and projection profiles, has been assigned to temporally separate features of fear processing, demonstrating the sophistication of the fear encoding circuit. These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD. Therefore, the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory, with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.