Dissociable memory modulation mechanisms facilitate fear amnesia at different timescales

Memory retrieval provides a unique window through which consolidated memories can be modified or even neutralized. Studies of memory reconsolidation suggest that memories are rendered fragile each time they are retrieved (Alberini, 2005; Dudai, 2006; Nader et al., 2000), possibly due to the disruption of the old memory trace. The reconsolidation of the new memory trace also requires de novo protein synthesis, which usually takes hours to complete. Pharmacological blockade of protein synthesis and behavioral interventions diminish the original fear memory expression in the long-term (24 hr later) memory test (Lee, 2008; Lee et al., 2017; Schiller et al., 2013; Schiller et al., 2010), resulting in the cue-specific fear memory deficit (Debiec et al., 2002; Lee, 2008; Nader et al., 2000). For example, during the reconsolidation window, retrieving a fear memory allows it to be updated through extinction training (i.e. the retrieval-extinction paradigm; Agren, 2014; Agren et al., 2012; Lee, 2008; Lee et al., 2017; Schiller et al., 2013; Schiller et al., 2010, but also see Chalkia et al., 2020a; Chalkia et al., 2020b; Schiller et al., 2020).

However, the exact functional role of memory retrieval remains unclear. For example, while previous fear memory studies typically reported the reconsolidation effects that emerged several hours later (the long-term effect) (Kindt and Soeter, 2018; Lee, 2008; Speer et al., 2021), the temporal dynamics of the amnesia effect through behavioral manipulation such as retrieval-extinction was often overlooked in the fear memory literature (Lee et al., 2017; Schiller et al., 2013; Schiller et al., 2010). It is possible that memory retrieval might facilitate memory modification at different temporal scales. The long-term effect is in stark contrast to semantic and episodic memory studies where the behavioral manipulations such as the retrieval-induced forgetting (RIF) protocol or direct suppression result in short-term memory deficit within 30 min (Anderson et al., 2000; Anderson et al., 1994). More recently, behavioral strategies originally developed in the declarative memory studies such as direct suppression had also been successfully applied to the fear memory paradigms in humans and prevented the return of fear shortly afterward (30 min), suggesting that the fear memory might be amenable to modulation at a more immediate timescale, to which the memory reconsolidation theory remains agnostic (Wang et al., 2021).

Corresponding to the long-term behavioral manifestation, concurrent neural evidence supporting memory reconsolidation hypothesis emphasizes that synapse degradation and de novo protein synthesis are required for fear memory reconsolidation. These processes typically take several hours, if not longer, and are often aided by overnight sleep (Kindt and Soeter, 2018). On the contrary, previous behavioral manipulations engendering the short-term amnesia on declarative memory, such as the think/no-think (TNT) paradigm, hinge on the intact activities in brain areas such as dorsolateral prefrontal cortex (cognitive control) and its functional coupling with specific brain regions such as hippocampus (memory retrieval) (Anderson and Green, 2001; Wimber et al., 2015). The declarative amnesia effect arises much earlier due to the more instant modulation of functional connectivity, rather than the slower processes of new protein synthesis in these brain regions (Wang et al., 2021). However, it remains unclear whether experimental paradigms such as memory retrieval-extinction, a method developed to induce long-term prevention of fear expression based on the memory reconsolidation hypothesis, might also trigger short-term amnesia for the fear memory.

To fully comprehend the temporal dynamics of the memory retrieval-extinction training effect, we first carried out a simple fear memory study by pairing a neutral cue (conditioned stimulus [CS]) with the electric shock (unconditioned stimulus [US]) to directly test whether the fear retrieval-extinction paradigm would yield a short-term effect on fear expression. We then performed another double cue CS-US fear memory experiment to study the temporal characteristics of fear memory malleability to behavioral extinction at the short- (30 min), medium- (6 hr), and long-term (24 hr) timescales.

We hypothesize that the labile state triggered by the memory retrieval may facilitate different memory deficits following extinction training, and these deficits can be further disentangled through the lens of temporal dynamics and cue specificities. In theory, different cognitive mechanisms underlying specific fear memory deficits, therefore, can be inferred based on the difference between memory deficits. Specifically, memory reconsolidation effect, if it exists, should only be evident in the long-term (24 hr) memory test due to the requirement of new protein synthesis and should be cue-dependent (Monfils et al., 2009). In contrast, if more immediate memory update mechanisms are involved, then the fear memory deficit should be observed relatively early (30 min) after extinction training (Anderson and Floresco, 2022; Anderson and Green, 2001). There may even exist a ‘limbo’ state: when the immediate memory update effects dissipate and the reconsolidation updating is yet to take effect (6 hr), the CSs should still elicit fear responses, regardless of the reminder (cue). Previous research in the short-term declarative and fear memory deficits highlighted the role of cognitive control. Subjects with stronger control over intrusive thoughts or stronger functional connectivity between brain regions such as the dorsolateral prefrontal cortex (dlPFC) and hippocampus exhibited more pronounced amnesia in the memory suppression tasks (Anderson et al., 1994; Wells and Davies, 1994; Wimber et al., 2015). We reason that if the retrieval-related short-term fear amnesia is also related to cognitive control and the dlPFC activities, then the individual difference of such immediate fear memory deficits should be associated with individual subject’s control abilities over intrusive thoughts (Küpper et al., 2014), which can be measured via the Thought-Control Ability Questionnaire (TCAQ) scale.

Indeed, through a series of experiments, we identified a short-term fear amnesia effect following memory retrieval-extinction training, in addition to the long-term amnesia effect that appeared much later. Finally, by applying the continuous theta-burst stimulation (cTBS) protocol over the dlPFC, the brain region critical for cognitive control and goal maintenance, we showed that both memory reactivation and intact dlPFC activity were necessary for the more immediate fear amnesia effect.

Our results provide direct evidence to support the hypothesis that memory reactivation might engage distinct cognitive mechanisms for fear memory modulation, which can be separated by their temporal dynamics, cue specificity, and the dependence of thought-control ability. In line with previous research on fear memory reconsolidation (Liu et al., 2014), our research replicated the reported results that the retrieval-extinction paradigm blocked fear responses to the reminded CS+ while leaving non-reminded CS+ response intact (cue-specificity) in the long-term test (Figure 6a and b). However, thought-control ability was not related to the long-term fear amnesia (Figure 6c). Therefore, findings of the short-term fear amnesia suggest that the reconsolidation framework falls short to accommodate this more immediate effect (Figure 6a and b).

Figure 6

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Research in both declarative and associative emotional memories suggests that memory retrieval is not a simple act of obtaining a copy of stored information, but provides a critical time window where the old memory is eligible to be integrated with new information (Gershman et al., 2013b; Hupbach et al., 2007; Monfils et al., 2009). Research in the field of declarative memory has shown that the motivated forgetting effect can appear early (10–30 min) after the memory suppression practices such as the influential TNT protocol (Anderson and Green, 2001), suggesting that memory retrieval may also facilitate short-term memory update (Benoit and Anderson, 2012; Engen and Anderson, 2018). Unlike the slow protein synthesis process involved in memory reconsolidation, the motivated forgetting effect was accompanied by heightened dlPFC activity, diminished hippocampal activation, and altered functional connectivity between these brain regions and hence more context adaptive (Anderson et al., 2004; Wimber et al., 2015).

Previous studies indicate that a memory suppression mechanism can be characterized by three distinct features: first, the memory suppression effect tends to emerge early, usually 10–30 min after memory suppression practice and can be transient (MacLeod and Macrae, 2001; Saunders and MacLeod, 2002); second, the memory suppression practice seems to directly act upon the unwanted memory itself (Levy and Anderson, 2002), such that the presentation of other cues originally associated with the unwanted memory also fails in memory recall (cue independence); third, the magnitude of memory suppression effects is associated with individual differences in control abilities over intrusive thoughts (Küpper et al., 2014). The short-term fear amnesia effects we identified are fundamentally different from memory reconsolidation effects and fit closely with the characteristics of the memory suppression effect. Inspired by the similarities between our results and suppression-induced declarative memory amnesia (Gagnepain et al., 2017), we speculate that the retrieval-extinction procedure might facilitate a spontaneous memory suppression process and thus yield a short-term amnesia effect. Accordingly, the activated fear memory induced by the retrieval cue would be subjected to an automatic fear memory suppression through the extinction training (Anderson and Floresco, 2022).

In our experiments, subjects were not explicitly instructed to suppress their fear expression, yet the retrieval-extinction training significantly decreased short-term fear expression. These results are consistent with the short-term amnesia induced with the more explicit suppression intervention (Anderson et al., 1994; Kindt and Soeter, 2018; Speer et al., 2021; Wang et al., 2021; Wells and Davies, 1994). It is worth noting that although consciously repelling unwanted memory is a standard approach in memory suppression paradigm, it is possible that the engagement of the suppression mechanism can be unconscious. For example, in the RIF paradigm, recall of a stored memory impairs the retention of related target memory, and this forgetting effect emerges as early as 20 min after the retrieval procedure, suggesting memory suppression or inhibition can occur in a more spontaneous and automatic manner (Imai et al., 2014). Moreover, subjects with trauma histories exhibited more suppression-induced forgetting for both negative and neutral memories than those with little or no trauma (Hulbert and Anderson, 2018). Similarly, people with higher self-reported thought-control capabilities showed more severe cue-independent memory recall deficit, suggesting that suppression mechanism is associated with individual differences in spontaneous control abilities over intrusive thoughts (Küpper et al., 2014). It has also been suggested that similar automatic mechanisms might be involved in organic retrograde amnesia of traumatic childhood memories (Schacter et al., 2012; Schacter et al., 1996).

Therefore, it is theoretically possible that similar brain mechanisms, such as the dynamic brain activity and connectivity modulation, involved in memory suppression may be deployed spontaneously and act as a general cognitive mechanism to cope with intrusive memories in daily life. Indeed, recently researchers have proposed that the standard retrieval-extinction paradigm to study fear memory might also involve automatic memory suppression (Anderson and Floresco, 2022). Consistent with this hypothesis, we showed that the retrieval cue was necessary to produce the short-term amnesia effect (Figure 1) and critically, our results fitted well with the three key characteristics of the active suppression mechanism: temporal dynamics, cue specificity, and the dependence of thought-control ability (Figures 2 and 3).

To calibrate the temporal boundaries of the short- and long-term effects, we also included a separate group (medium-term group) where fear expression was tested 6 hr after the retrieval-extinction training. Interestingly, fear returned at this time point (Figure 6a and b), confirming the 6 hr lower time boundary for the hypothesized memory reconsolidation in previous animal and human studies (Agren, 2014; Agren et al., 2012; Debiec et al., 2002; Kindt and Soeter, 2018; Lee, 2008; Nader et al., 2000; Speer et al., 2021). However, the return of fear expression in the medium-term group also indicates that the short-term fear amnesia is transient, laying out the upper time boundary for the hypothesized fear memory suppression effect. Although mixed results have been reported regarding the durability of suppression effects in the declarative memory studies (Meier et al., 2011; Storm et al., 2012), future research will be needed to investigate whether the short-term effect we observed is specifically related to associative memory or the spontaneous nature of suppression as in RIF (Figure 6c). Previous research also showed that separate mnemonic processes can be involved after emotional memory retrieval. For example, by varying the duration length and repetition number of memory cue re-exposure, different levels of memory persistence (reconsolidation, extinction, or a ‘limbo’ state in between) can be induced, suggesting a neural titration mechanism for memory de-stabilization and re-stabilization (Faliagkas et al., 2018; Merlo et al., 2014). These works identified important ‘boundary conditions’ of memory retrieval in affecting the retention of the maladaptive emotional memories. In our study, however, we showed that even within a boundary condition previously thought to elicit memory reconsolidation, mnemonic processes other than reconsolidation could also be at work, and these processes jointly shape the persistence of fear memory.

Our results also corroborate with a recent study showing that blocking fear reconsolidation using post-retrieval repetitive transcranial magnetic stimulation (rTMS) did not influence the short-term fear memory expression (Borgomaneri et al., 2020). However, as we demonstrated in Studies 2 and 3, memory retrieval and intact rdlPFC function were both necessary for the short-term fear amnesia after the extinction training. Therefore, instead of ‘intact short-term fear expression by the rTMS over the dlPFC’, their results could also be interpreted such that the rTMS on the dlPFC demolished the otherwise short-term fear amnesia induced by the memory retrieval cue. Indeed, a series of neuroimaging studies have revealed that the prefrontal neural network including anterior cingulate cortex, anterior ventrolateral prefrontal cortex, and the dlPFC is directly engaged in purging the unwanted declarative memory from consciousness (Anderson et al., 2004; Benoit and Anderson, 2012; Levy and Anderson, 2002). Moreover, previous research has established a causal relationship between dlPFC activity and the memory suppression mechanism underlying RIF using transcranial direct current stimulation (Penolazzi et al., 2014; Stramaccia et al., 2017; Valle et al., 2020). In our experiment (Studies 2 and 3), when the dlPFC function was intact, subjects’ thought-control abilities were positively correlated with fear amnesia in the test phase. Such correlations disappeared in the no-reminder groups (NR-VER and NR-PFC) and the R-PFC group (Figures 3 and 5), establishing a causal link between the dlPFC activity and short-term fear amnesia.

It should be noted that while our long-term amnesia results were consistent with the fear memory reconsolidation literatures, there were also studies that failed to observe fear prevention (Chalkia et al., 2020a; Chalkia et al., 2020b; Schroyens et al., 2023). Although the memory reconsolidation framework provides a viable explanation for the long-term amnesia, more evidence is required to validate the presence of reconsolidation, especially at the neurobiological level (Elsey et al., 2018). While it is beyond the scope of the current study to discuss the discrepancies between these studies, one possibility to reconcile these results concerns the procedure for the retrieval-extinction training. It has been shown that the eligibility for old memory to be updated is contingent on whether the old memory and new observations can be inferred to have been generated by the same latent cause (Gershman et al., 2017; Gershman and Niv, 2012). For example, prevention of the return of fear memory can be achieved through a gradual extinction paradigm, which is thought to reduce the size of prediction errors to inhibit the formation of new latent causes (Gershman et al., 2013a). Therefore, the effectiveness of the retrieval-extinction paradigm might depend on the reliability of such a paradigm in inferring the same underlying latent cause. Furthermore, other studies highlighted the importance of memory storage per se and suggested that memory retention was encoded in the memory engram cell ensemble connectivity, whereas the engram cell synaptic plasticity is crucial for memory retrieval (Ryan et al., 2015; Tonegawa et al., 2015a; Tonegawa et al., 2015b). It remains to be tested how the cue-independent short-term and cue-dependent long-term amnesia effects we observed could correspond to the engram cell synaptic plasticity and functional connectivity among engram cell ensembles (Figure 6). This is particularly important, since the cue-independent characteristic of the short-term amnesia suggests that either different memory cues fail to evoke engram cell activities, or the retrieval-extinction training transiently inhibits connectivity among engram cell ensembles. Finally, SCR is only one aspect of the fear expression, how the retrieval-extinction paradigm might affect subjects’ other emotional (such as the startle response) and cognitive fear expressions such as reported fear expectancy needs to be tested in future studies since they do not always align with each other (Kindt et al., 2009; Sevenster et al., 2012; Sevenster et al., 2013).

These results help shed light on the dynamics of memory modulation after memory activation and designing novel treatment of psychiatric disorders caused by excessive fear or anxiety (Chen et al., 2021). Memory reconsolidation and suppression both have been studied thoroughly in separate fields. Specifically, aversive memories are usually associated with different retrieval cues, and interfering memory reconsolidation only blocks fear memory recall from the retrieval memory probe but not the others (Debiec et al., 2002; Kindt and Soeter, 2018; Lee, 2008; Nader et al., 2000; Speer et al., 2021). On the other hand, memory suppression is cue-independent and directly suppresses the fear memory trace yet only effective with limited durability (MacLeod and Macrae, 2001). Although future research is clearly needed to understand the brain mechanisms for the short-term amnesia and its potential connection to the memory suppression effect, especially in relevance to clinical populations such as posttraumatic stress disorder and phobia patients (Homan et al., 2019; Stramaccia et al., 2021), our results provide a general framework to highlight the potential of memory retrieval to triggering different memory updating mechanisms with unique temporal dynamics.

The data and analysis codes for all studies are publicly accessible at https://osf.io/9agvk/.

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Author details

1. Yinmei Ni

   School of Psychological and Cognitive Sciences and Beijing Key Laboratory of Behavior and Mental Health, Peking University, Beijing, China

   Contribution

   Data curation, Formal analysis, Visualization, Methodology, Writing – review and editing

   Contributed equally with

   Ye Wang

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3614-1828

2. Ye Wang

   School of Psychological and Cognitive Sciences and Beijing Key Laboratory of Behavior and Mental Health, Peking University, Beijing, China

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft

   Contributed equally with

   Yinmei Ni

   Competing interests

   No competing interests declared

3. Zijian Zhu

   School of Psychology, Shaanxi Normal University, Xi'an, China

   Contribution

   Conceptualization

   Competing interests

   No competing interests declared

4. Jingchu Hu

   Department of Anxiety Disorders, Shenzhen Kangning Hospital, Shenzhen Mental Health Institute, Shenzhen, China

   Contribution

   Formal analysis, Methodology

   Competing interests

   No competing interests declared

5. Daniela Schiller

   Departments of Psychiatry and Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, United States

   Contribution

   Conceptualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0357-7724

6. Jian Li

   1. School of Psychological and Cognitive Sciences and Beijing Key Laboratory of Behavior and Mental Health, Peking University, Beijing, China
   2. IDG/McGovern Institute for Brain Research, Peking University, Beijing, China

   Contribution

   Conceptualization, Resources, Supervision, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   leekin@gmail.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3941-2622

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