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memories up to date with new learning. Indeed, reconsolidation is triggered only when there is opportunity for new learning to take place during reactivation (3–5). Because associative learning requires prediction error (PE) (a discrepancy between actual and expected events) (6), reconsolidation might also be a PE-driven process. Even though it has frequently been suggested, there is no experimental evidence that PE is a necessary condition for reconsolidation. So far, PE could only be inferred from effective reconsolidation without an independent assessment of PE-driven relearning (3–5). Unveiling a crucial role for PE in reconsolidation of fear memory—which may serve as an index for memory destabilization independent from the process of reconsolidation itself—will provide a clear guide for developing treatments to permanently reduce unwanted and excessive fears (such as posttraumatic stress disorder). General associative learning models (6) argue that PE is not determined by the mere co-occurrence of the conditioned stimulus (CS) and unconditioned stimulus (US), but by the discrepancy between what has already been learned (learning history) and what can be learned on a given trial. If memory retrieval follows a fully reinforced asymptotic learning episode, omission of a predicted reinforcement during reactivation (negative PE) (7) may destabilize a consolidated memory during its reactivation, whereas a reinforced reactivation trial would leave the memory intact given that PE would then be absent. In contrast, if memory retrieval follows a partially reinforced, non-asymptotic learning episode, a similar reinforced reminder trial (positive PE) (7) should generate additional learning and consequently be capable of inducing postretrieval plasticity because memory-strengthening through further learning also requires reconsolidation mechanisms (8). The noradrenergic b-blocker propranolol administered either before or after memory retrieval eliminates affective responding (fear-potentiated startle) in human participants but leaves the predominantly cognitive component of fear (USexpectancy ratings or skin conductance response) intact (5, 9, 10). Given that propranolol does not affect declarative memory when reactivated with a single trial, online US-expectancy ratings during acquisition, retrieval, and test could serve as an independent measure to test whether PE-driven relearning during reactivation is essential for reconsolidation of affective fear memory. The current study had a threefold aim: (i) to examine the role of PE in reconsolidation of fear memory, (ii) to examine whether PE depends on the interaction between the available information during re- 1 Department of Clinical Psychology, University of Amsterdam, Weesperplein 4, 1018 XA, Amsterdam, Netherlands. 2 Cognitive Science Center Amsterdam, 1018 WS, Amsterdam, Netherlands. 3 Department of Psychology, University of Leuven, KU Leuven, Tiensestraat 102, 3712 B-3000, Leuven, Belgium. *To whom correspondence should be addressed. E-mail: m.kindt@uva.nl activation and the learning history, and (iii) to provide a measure for memory destabilization that is independent from the occurrence of reconsolidation itself. In a human differential fear conditioning paradigm, we tested two groups in which fear acquisition was fully reinforced (100% of the trials) (Fig. 1, A and B). To ensure that asymptotic learning was indeed realized, the participants received explicit instructions regarding the contingencies between the CS and the US. On day 2, the memory was reactivated through either an unreinforced (negative PE group; n = 15 participants) or a reinforced (no PE group; n = 15 participants) reactivation trial, followed by administration of propranolol (40 mg) (Fig. 1, A and B). PE-driven cognitive relearning and corresponding reconsolidation should occur in the negative PE group but not in the no PE group. We tested a third group to examine whether PE depends on the interaction between the information presented during reactivation and the learning history. In this group, acquisition was partially reinforced (33% of the trials), and the memory was reactivated with a reinforced reminder trial (positive PE group; n =15 participants), followed by administration of propranolol (40 mg) (Fig. 1, A and B). In contrast to the full-reinforcement condition, here the reinforced reminder trial should induce PE-driven additional learning given that a partial reinforcement schedule will not induce asymptotic learning. As such, a reinforced reactivation trial might also induce reconsolidation. Noradrenergic blockade after memory retrieval should disrupt reconsolidation—operationalized as a reduction in conditioned startle fear responding—in both the negative PE and positive PE group but not in the no PE group. On day 3, all groups underwent an extinction session followed by a reinstatement REPORTS procedure to test to what extent the original fear memory trace was weakened (Fig. 1, A and B). All three groups showed fear learning and memory reactivation on days 1 and 2, respectively, for the startle fear response and online US-expectancy ratings (data available in the supplementary materials). Analyses of differential US-expectancy ratings (CS1 versus CS2) from the last trial of acquisition (day 1) to the first trial of extinction (day 3) revealed differences between the three groups [stimulus × trial × group, analysis of variance (ANOVA) F 2,42 = 25.44, P < 0.001, h 2 p = 0.55]. Follow-up analyses of the differential US-expectancy ratings from the last trial of acquisition (day 1) to the first trial of extinction (day 3) revealed a decrease in the negative PE group (stimulus × trial × group, F1,28 = 8.18, P < 0.008, h 2 p = 0.23) and an increase in the positive PE group (stimulus × trial × group, F1,28 = 42.98, P
REPORTS 832 trial in both the negative PE (stimulus × group, F 1,28 = 10.76, P < 0.003, h 2 p = 0.28) and positive PE group (stimulus × group, F1,28 = 7.89, P < 0.009, h 2 p = 0.22) as compared with the no PE group. Indeed, propranolol completely erased differential responding on the first extinction trial in the negative PE (main effect stimulus, F1,14
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