Making extinction last: mechanistically understanding and causally probing the role of the ventromedial prefrontal cortex in extinction memory consolidation

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Fear extinction consists in learning that a previously threatening stimulus is now safe. Fear extinction establishes a fear-inhibitory safety memory (‘extinction memory’) that needs to be retrieved and expressed when encountering the once-threatening stimulus in order to prevent the recovery of the extinguished fear response. Fear extinction is supposed to underlie the immediate fear/anxiety-reducing effects of exposure-based therapy, and the consolidation of the extinction memories generated during exposure into strong long-term memories is supposed to underlie its long-term beneficial effects. This makes the investigation of the neurophysiological mechanisms underlying extinction memory consolidation a key topic for both the basic neuroscience of learning and memory and for clinical research into fear/anxiety disorders. Based on own previous work, we here focus on the contribution of spontaneous reactivations of neural activity related to extinction learning in the ventromedial prefrontal cortex (vmPFC) during the post-extinction consolidation phase. We aim to determine the electrophysiological correlates of these reactivations, observed in functional magnetic resonance imaging (fMRI), using electroencephalography (EEG) in humans and optical as well as electrophysiological recordings in rats. On this basis, we manipulate reactivations using anatomically precisely targeted tonic and activity-triggered transcranial magnetic stimulation (TMS) in humans and activity-triggered optogenetics in rats, to thus causally probe their effects on extinction consolidation. Experiments will benefit from latest methodological developments in our laboratories and a strictly comparative-translational approach. The project will yield entirely new insights into the mechanisms of extinction memory consolidation and open up new avenues for the neurobiological augmentation of this key resilience and therapy process.