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

恐惧消除包括了解到以前具有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的安全记忆（“消退记忆”），需要在遇到曾经具有威胁性的刺激时进行检索和表达，以防止已消失的恐惧反应的恢复。恐惧消退被认为是暴露疗法直接减少恐惧/焦虑效果的基础，而在暴露过程中产生的消退记忆被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背后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课题。在此基础上，我们重点研究了消失后巩固阶段腹内侧前额叶皮层（vmPFC）中与消失学习相关的神经活动自发再激活的作用。我们的目标是确定在功能磁共振成像（fMRI）中观察到的这些再激活的电生理相关性，使用人类脑电图（EEG）和大鼠的光学和电生理记录。在此基础上，我们利用解剖学上精确定位的强直性和活动触发的经颅磁刺激（TMS）在人类和活动触发的光遗传学在大鼠中操纵再激活，从而探索它们对消退巩固的因果关系。实验将受益于我们实验室最新的方法发展和严格的比较-转化方法。该项目将对灭绝记忆巩固的机制产生全新的见解，并为这一关键的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.