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

恐惧消退是指学习到以前威胁性的刺激现在是安全的。恐惧消退建立了一种恐惧抑制性安全记忆（“消退记忆”），当遇到曾经威胁过的刺激时，这种记忆需要被检索和表达，以防止被熄灭的恐惧反应的恢复。恐惧消退被认为是基于恐惧的治疗的直接恐惧/焦虑减少效果的基础，而在暴露期间产生的消退记忆巩固为强大的长期记忆被认为是其长期有益效果的基础。这使得对消退记忆巩固的神经生理机制的研究成为学习和记忆基础神经科学以及恐惧/焦虑障碍临床研究的关键主题。基于自己以前的工作，我们在这里专注于在后灭绝巩固阶段的腹内侧前额叶皮层（vmPFC）与灭绝学习相关的神经活动的自发再激活的贡献。我们的目的是确定这些重新激活的电生理相关性，观察功能性磁共振成像（fMRI），使用脑电图（EEG）在人类和光学以及大鼠的电生理记录。在此基础上，我们使用解剖学上精确靶向的强直和活动触发的经颅磁刺激（TMS）在人类和大鼠中的活动触发的光遗传学来操纵再激活，从而因果地探索它们对灭绝巩固的影响。实验将受益于我们实验室的最新方法发展和严格的比较翻译方法。该项目将对灭绝记忆巩固的机制产生全新的见解，并为这一关键恢复力和治疗过程的神经生物学增强开辟新的途径。

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.