Dopamine-dependent prefrontal reactivations explain long-term benefit of fear extinction

• Published in: Nature communications Vol. 9; no. 1; pp. 4294 - 9
• Main Authors: Gerlicher, A. M. V., Tüscher, O., Kalisch, R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.10.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 59/57; 631/378/1595/2167; 631/378/1595/2618; 631/378/1595/2636; 631/378/1595/2637; 631/378/1595/2638; Activation; Administration, Oral; Adult; Consolidation; Domains; Dopamine; Dopamine - administration & dosage; Dopamine - metabolism; Dopamine - pharmacology; Dopamine receptors; Extinction, Psychological - physiology; Fear; Fear - physiology; Fear conditioning; Humanities and Social Sciences; Humans; Learning; Magnetic Resonance Imaging; Male; Memory; Memory Consolidation; multidisciplinary; Nontherapeutic Human Experimentation; Pharmacology; Post traumatic stress disorder; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiology; Retrieval; Rodents; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06785-y

Fear extinction does not prevent post-traumatic stress or have long-term therapeutic benefits in fear-related disorders unless extinction memories are easily retrieved at later encounters with the once-threatening stimulus. Previous research in rodents has pointed towards a role for spontaneous prefrontal activity occurring after extinction learning in stabilizing and consolidating extinction memories. In other memory domains spontaneous post-learning activity has been linked to dopamine. Here, we show that a neural activation pattern — evoked in the ventromedial prefrontal cortex (vmPFC) by the unexpected omission of the feared outcome during extinction learning — spontaneously reappears during postextinction rest. The number of spontaneous vmPFC pattern reactivations predicts extinction memory retrieval and vmPFC activation at test 24 h later. Critically, pharmacologically enhancing dopaminergic activity during extinction consolidation amplifies spontaneous vmPFC reactivations and correspondingly improves extinction memory retrieval at test. Hence, a spontaneous dopamine-dependent memory consolidation-based mechanism may underlie the long-term behavioral effects of fear extinction. The success of extinction learning is not predictive of long-term retrieval of an extinction memory. Using fMRI to study consolidation of fear extinction in human subjects, the authors show that reactivation in the ventromedial prefrontal cortex during memory retrieval predicts extinction memory retrieval, and that increasing dopaminergic signaling increases the number of these activations.