Abstract
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.
Highlights
There is increasing evidence that neural consolidation processes may not be a deterministic prolongation of encoding processes but may, instead, make an independent contribution to memory formation[7]
Our study shows that spontaneous postextinction reactivations of an activity pattern evoked in the ventromedial prefrontal cortex (vmPFC) by the unexpected omission of the US during extinction learning predict long-term extinction memory retrieval, as assessed by differential skin conductance responses (SCRs)
The relationship between spontaneous CS+ offset-related postextinction reactivations and extinction memory retrieval at test was specific to the vmPFC and could not be detected in any other region of interest (ROI)
Summary
There is increasing evidence that neural consolidation processes may not be a deterministic prolongation of encoding processes but may, instead, make an independent contribution to memory formation[7]. Dopamine was shown to increase the reactivation of learning-related neural activity during consolidation in the domain of spatial memory[21] Based on these findings, the second aim of the study was to test whether a postextinction enhancement of dopaminergic activity increases vmPFC reactivations of extinction-related activity patterns after learning and thereby improves extinction memory retrieval. The second aim of the study was to test whether a postextinction enhancement of dopaminergic activity increases vmPFC reactivations of extinction-related activity patterns after learning and thereby improves extinction memory retrieval We tested these hypotheses in n = 40 male human participants (Supplementary Table 1) in a functional magnetic resonance imaging (fMRI) experiment, with fear conditioning on day 1, extinction training immediately followed by the oral administration of either placebo or 150/37, 5 mg levodopa/benserazide (L-DOPA) on day 2, and retrieval test on day 3 (Fig. 1). We show that spontaneous vmPFC pattern reactivations can explain long-term extinction memory retrieval above and beyond a marker of extinction learning success
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