Institute for Systems Neuroscience, University Medical Center Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany.
Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):E2428-36. doi: 10.1073/pnas.1303061110. Epub 2013 Jun 10.
Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory "extinction memories" that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression--and, thus, return of fear--is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor L-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy.
创伤事件会导致对创伤提示的持续过度恐惧反应，即使在成功治疗后也可能会出现。在实验室中，消退是行为治疗的模拟，它不会抹去条件性恐惧记忆，而是产生竞争的、抑制恐惧的“消退记忆”，然而，这些记忆与消退发生的情境有关。因此，如果在消退（治疗）情境之外遇到已消退的恐惧刺激，通常会观察到恐惧对消退记忆表达的主导作用，从而导致恐惧的回归。我们发现，在消退后给予多巴胺前体左旋多巴可使消退记忆不受情境影响，从而大大减少了老鼠和人类的恐惧回归。在两种物种中，恐惧的减少伴随着杏仁核的减少和腹内侧前额叶皮层的增强。在人类中，腹内侧前额叶皮层的活动可以通过增强该区域在消退后巩固阶段与多巴胺能中脑之间的静息状态功能耦合来预测。我们的数据表明，多巴胺依赖性增强消退记忆巩固是改善焦虑治疗的一个有前途的途径。
