On the transition from reconsolidation to extinction of contextual fear memories

Abstract

Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate "null point" period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3-and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine "null point" between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions.[Supplemental material is available for this article.]The retrieval of an associative memory can result in different outcomes. Retrieval in the absence of further reinforcement can destabilize a memory, requiring a process of reconsolidation (Nader and Hardt 2009), or can cause memory extinction through new inhibitory learning (Giustino and Maren 2015). The balance between destabilization and extinction appears to be influenced by the relative strength of learning and extent of nonreinforced retrieval (Eisenberg et al. 2003;Suzuki et al. 2004;Lee et al. 2006;de la Fuente et al. 2011;Flavell and Lee 2013). More extensive stimulus reexposure (i.e., extinction training), or weaker initial conditioning is more likely to result in extinction, whereas more restricted stimulus reexposure preferentially engages memory destabilization. This apparent competition between destabilization and extinction manifests as a bidirectional effect of amnestic treatment, depending of the parameters of conditioning and retrieval. Either reconsolidation is impaired to reduce subsequent memory expression, or extinction is disrupted to maintain expression of the original memory (Eisenberg et al. 2003;Suzuki et al. 2004;Lee et al. 2006;de la Fuente et al. 2011;Flavell and Lee 2013).In both appetitive Pavlovian and conditioned fear memories, recent evidence has indicated that extinction per se does not prevent memory destabilization and reconsolidation. In cue-sucrose, cue-fear, and context-fear settings, there appears to be a reexposure period between the parameters that engage destabilization and extinction, in which there is no behavioral effect of amnestic treatment (Flavell and Lee 2013;Merlo et al. 2014;Alfei et al. 2015). This "limbo" or "null poin...

Dopaminergic signalling is necessary, but not sufficient for cued fear memory destabilisation

“…Therefore, if the combination of pre-reactivation nefiracetam and post-reactivation mifepristone is to have genuine therapeutic promise, it is important to rule out potential counterproductive effects. This is especially the case, due to the observation that the parametric determinants of destabilisation and extinction are still not well understood (Merlo et al, 2014;Cassini et al, 2017;Merlo et al, 2018). Our results suggest that dual treatment with nefiracetam and mifepristone does not disrupt or facilitate cued fear memory extinction.…”

“…Moreover, mifepristone has previously been shown to impair the reconsolidation of cued fear memories (Jin et al, 2007;Pitman et al, 2011), as well as a number of different memory types (Taubenfeld et al, 2009;Nikzad et al, 2011;Achterberg et al, 2014), although it has yet to be successfully translated to a human clinical setting (Wood et al, 2015). While we did not include a formal non-reactivation control condition (Dudai, 2004), the fact that mifepristone only disrupted freezing to the conditioned tone under certain parametric conditions rules out non-specific interpretations of the amnestic effect (see also Cassini et al, 2017).…”

“…Given the complex mechanistic relationship between destabilisation, reconsolidation and extinction (Almeida-Correa and Amaral, 2014;Merlo et al, 2014;Cassini et al, 2017), any potential therapeutic strategy that targets one of these processes has the potential to result in "off-target" effects on another process, leading to the possibility of maintaining or even enhancing the problematic memory (Lee et al, 2006;Tronson et al, 2006). Therefore, if the combination of pre-reactivation nefiracetam and post-reactivation mifepristone is to have genuine therapeutic promise, it is important to rule out potential counterproductive effects.…”

“…It is increasingly evident that successful reconsolidation impairment is far from guaranteed (Kindt and van Emmerik, 2016), especially as there are unpredictable boundary conditions that govern memory destabilisation (Wideman et al, 2018). For example, we recently demonstrated that there appears to be no reliable basis upon which to predict the behavioural parameters that will trigger memory destabilisation/reconsolidation (Cassini et al, 2017). In fact, lack of replicability of reconsolidation impairments may well be due to poorly-understood boundary conditions on memory destabilisation (Bos et al, 2014).…”

On the Boundary Conditions of Avoidance Memory Reconsolidation: An Attractor Network Perspective

“…The model thus tries to explain memory reconsolidation and extinction in a simple structural perspective. It should be noted, however, that the model does not address the theory that there is a null point between the phenomena (Cassini et al, 2017;Merlo et al, 2014), i.e., the transition between reconsolidation and extinction is abrupt in terms of network structure and its dynamics.…”