Disrupting reconsolidation: Pharmacological and behavioral manipulations

Abstract

We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited modifications. At the same time, the fear-erasing effects should not be restricted to the feared cue itself considering that fear generalization is a main characteristic of anxiety disorders. In Experiment I and Experiment I b , we addressed these issues using a within-subject differential startle fear conditioning paradigm and a test of fear generalization. In Experiment II, we tested whether a behavioral approach targeting the reconsolidation through extinction learning was also effective in weakening the original fear memory. A behavioral procedure is evidently preferred over drug manipulations provided that similar effects can be obtained. Here, the extinction procedure subsequent to retrieval did not "erase" the emotional expression of the fear memory as the retrieval techniques (i.e., reminder shocks and reacquisition) unveiled a return of the startle fear response to the fear-relevant stimuli. In contrast, b-adrenergic receptor blockade during reconsolidation selectively deleted the fear-arousing aspects of the memory (i.e., startle fear response) along with its category-related information. The pharmacological manipulation rendered the core memory trace too weak to observe fear generalization after successful reacquisition. Hence, relearning following the disruption of reconsolidation seems to be qualitatively different from initial learning. Our findings demonstrate that disrupting reconsolidation by pharmacological manipulations, although selective, undermines the generalization of fear, a key feature of anxiety disorders.[Supplemental material is available for this article.]The phenomenon of reconsolidation, the stabilization of a memory after retrieval, enables the modification of memory representation (Nader et al. 2000). Considerable evidence in animals now indicates that blockade of the process of reconsolidation by pharmacological manipulations produces amnesia for the original fear learning (Nader et al. 2000;Dudai 2006;Tronson and Taylor 2007;Nader and Hardt 2009). We previously demonstrated that disrupting reconsolidation by administering propranolol prior to memory reactivation resulted in erasure of the fear response in humans (Kindt et al. 2009), an effect that persisted over time (Soeter and Kindt 2010). However, the typical differential fear conditioning paradigm (i.e., CS1-US vs. CS2) did not allow any inference about the nature of the fear memory erasure. Even though animal studies showed selective amnesia for the specific fear association (i.e., CS1-US) (Doyère et al. 2007), studying humans necessitates systemic (as opposed to intra-amygdala) drug administration. Accordingly, the erasure of the fear response could also have resulted from a more diffuse effect of the propranolol manipulation by reduc...

Prediction error demarcates the transition from retrieval, to reconsolidation, to new learning

“…Thus, noradrenergic blockade neither eliminated fear directly nor prevented the return of fear after successful extinction when there was no PE at all or when multiple PEs reduced US-expectancy during memory retrieval. In line with our previous studies, propranolol did not affect the skin conductance response (see Supplemental Material; Soeter and Kindt 2010, 2011a,b, 2012Sevenster et al 2012).…”

Modification of episodic memories by novel learning: a failed replication study

“…However, our study joins a growing number of other studies showing failures to replicate the reconsolidation effect using behavioural manipulations (e.g. Golkar, Bellander, Olsson, & Öhman, 2012; Hardwicke, Taqi, & Shanks, 2016; Kindt & Soeter, 2013; Soeter & Kindt, 2011; Wichert et al, 2011) or pharmacological manipulations (e.g. Bos, Beckers, & Kindt, 2014; Wood et al, 2015).…”

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

“…However, the extension of our findings and findings like these to the clinic is premature. Although some studies in humans suggest that immediate behavioral intervention (e.g., extinction) may dampen fear and drug-seeking behavior (Schiller et al 2008;Xue et al 2012), there are human studies that indicate that this approach may have little effect or even enhance memory expression (Karpicke and Roediger 2008;Soeter and Kindt 2011;Wichert et al 2011;Potts and Shanks 2012;Kindt and Soeter 2013). Particularly problematic for clinical applications are rodent and preclinical studies like ours suggesting that across a variety of conditions an immediate extinction experience may actually prevent the elimination or weakening of the fear response and promote its persistent expression (Morris et al 2005;Chan et al 2010;Kim et al 2010).…”