disrupting-reconsolidation-fear-memory-humans-noradrenergic

Disrupting Reconsolidation of Fear Memory in Humans by a Noradrenergic &#946;-Blocker

The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive ...

University of Amsterdam

Ample evidence suggests that consolidated memories, upon their retrieval, enter a labile state, in which they might be susceptible to change. It has been proposed that memory labilization allows for the integration of relevant information in the established memory trace (memory updating). Memory labilization and reconsolidation do not necessarily occur when a memory is being reactivated, but only when there is something to be learned during memory retrieval (prediction error). Thus, updating of a fear memory trace should not occur under retrieval conditions in which the outcome is fully predictable (no prediction error). Here, we addressed this issue, using a human differential fear conditioning procedure, by eliminating the very possibility of reinforcement of the reminder cue. A previously established fear memory (picture-shock pairings) was reactivated with shock-electrodes attached (Propranolol group, n=18) or unattached (Propranolol No-Shock Expectation group, n=19). We additionally tested a placebo-control group with the shock-electrodes attached (Placebo group, n=18). Reconsolidation was not triggered when nothing could be learned during the reminder trial, as noradrenergic blockade did not affect expression of the fear memory 24h later in the Propranolol No-Shock Expectation group. Only when the outcome of the retrieval cue was not fully predictable, propranolol, contrary to placebo, reduced the startle fear response and prevented the return of fear (reinstatement) the following day. In line with previous studies, skin conductance response and shock expectancies were not affected by propranolol. Remarkably, a double dissociation emerged between the emotional (startle response) and more cognitive expression (expectancies, SCR) of the fear memory. Our findings have important implications for reconsolidation blockade as treatment strategy for emotional disorders. First, fear reducing procedures that target the emotional component of fear memory do not necessarily affect the cognitive component and vice versa. Second, mere retrieval of the fear memory is not sufficient to induce its labilization and reconsolidation.

Retrieval per se is not sufficient to trigger reconsolidation of human fear memory.

Instructed extinction after fear conditioning is relatively effective in attenuating electrodermal responding. Testing the single-process account of fear learning, we examined whether this manipulation similarly affects the startle response. Skin conductance responses (SCRs), startle responses, and online unconditioned stimulus (US) expectancy ratings were measured during fear acquisition (Day 1), extinction, and reinstatement (Day 2). Before extinction onset, half of the subjects were instructed that the conditioned stimulus would not be followed by the US (Instructed Extinction) whereas the other subjects were not instructed (Normal Extinction). This simple instruction completely abolished both differential SCR and US expectancy ratings, but not the startle fear response. Although the manipulation facilitated extinction learning, it did not prevent the recovery of the startle response. The present findings are better explained by a dual- rather than a single-process account of fear learning.

Instructed extinction differentially affects the emotional and cognitive expression of associative fear memory.

Although reconsolidation opens up new avenues to erase excessive fear memory, subtle boundary conditions put constraints on retrieval-induced plasticity. Reconsolidation may only take place when memory reactivation involves an experience that engages new learning (prediction error). Thus far, it has not been possible to determine the optimal degree of novelty required for destabilizing the memory. The occurrence of prediction error could only be inferred from the observation of a reconsolidation process itself. Here, we provide a noninvasive index of memory destabilization that is independent from the occurrence of reconsolidation. Using this index, we show in humans that prediction error is (i) a necessary condition for reconsolidation of associative fear memory and (ii) determined by the interaction between original learning and retrieval. Insight into the process of memory updating is crucial for understanding the optimal and boundary conditions on reconsolidation and provides a clear guide for the development of reconsolidation-based treatments.

Prediction error governs pharmacologically induced amnesia for learned fear.

There is conflicting evidence as to whether awareness is required for conditioning of the skin conductance response (SCR). Recently, Schultz and Helmstetter (2010) reported SCR conditioning in contingency unaware participants by using difficult to discriminate stimuli. These findings are in stark contrast with other observations in human fear conditioning research, showing that SCR predominantly reflects contingency learning. Therefore, we repeated the study by Schultz and Helmstetter and additionally measured conditioning of the startle response, which seems to be less sensitive to declarative knowledge than SCR. While we solely observed SCR conditioning in participants who reported awareness of the contingencies (n = 16) and not in the unaware participants (n = 18), we observed startle conditioning irrespective of awareness. We conclude that SCR but not startle conditioning depends on conscious discriminative fear learning.

Fear conditioning of SCR but not the startle reflex requires conscious discrimination of threat and safety.

Although disrupting reconsolidation is promising in targeting emotional memories, the conditions under which memory becomes labile are still unclear. The current study showed that post-retrieval changes in expectancy as an index for prediction error may serve as a read-out for the underlying processes engaged by memory reactivation. Minor environmental changes define whether retrieval induces memory reconsolidation or the initiation of a new memory trace even before fear extinction can be observed.

Article	Year
Retrieval per se is not sufficient to trigger reconsolidation of human fear memory. Neurobiology of learning and memory\| PubMed ID: 22406658	2012
Instructed extinction differentially affects the emotional and cognitive expression of associative fear memory. Psychophysiology\| PubMed ID: 22958209	2012
Prediction error governs pharmacologically induced amnesia for learned fear. Science (New York, N.Y.)\| PubMed ID: 23413355	2013
Fear conditioning of SCR but not the startle reflex requires conscious discrimination of threat and safety. Frontiers in behavioral neuroscience\| PubMed ID: 24616672	2014
Prediction error demarcates the transition from retrieval, to reconsolidation, to new learning. Learning & memory (Cold Spring Harbor, N.Y.)\| PubMed ID: 25320349	2014

Dieuwke Sevenster

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