Reconsolidation or Extinction: Transcription Factor Switch in the Determination of Memory Course after Retrieval

Abstract

In fear conditioning, aversive stimuli are readily associated with contextual features. A brief reexposure to the training context causes fear memory reconsolidation, whereas a prolonged reexposure induces memory extinction. The regulation of hippocampal gene expression plays a key role in contextual memory consolidation and reconsolidation. However, the mechanisms that determine whether memory will reconsolidate or extinguish are not known. Here, we demonstrate opposing roles for two evolutionarily related transcription factors in the mouse hippocampus. We found that nuclear factor-B (NF-B) is required for fear memory reconsolidation. Conversely, calcineurin phosphatase inhibited NF-B and induced nuclear factor of activated T-cells (NFAT) nuclear translocation in the transition between reconsolidation and extinction. Accordingly, the hippocampal inhibition of both calcineurin and NFAT independently impaired memory extinction, whereas inhibition of NF-B enhanced memory extinction. These findings represent the first insight into the molecular mechanisms that determine memory reprocessing after retrieval, supporting a transcriptional switch that directs memory toward reconsolidation or extinction. The precise molecular characterization of postretrieval processes has potential importance to the development of therapeutic strategies for fear memory disorders.

Calcineurin inhibition blocks within-, but not between-session fear extinction in mice

“…On this matter, conflicting results have been reported using different paradigms, with some studies showing facilitation of conditioning by FK-506 (de la Fuente et al 2014), antisense DNA against genes coding for the catalytic subunits of CaN (Ikegami and Inokuchi 2000), and transgenic inhibition of CaN (Malleret et al 2001;Baumgärtel et al 2008;Havekes et al 2008) and others finding no effect of the latter intervention (Zeng et al 2001). Still, in accordance with our results, most of these studies have found that the transgenic (Baumgärtel et al 2008; Havekes It should be noted that, unlike what occurred in our study, some of these previous investigations (de la Fuente et al 2011;Merlo et al 2014) did find an effect of calcineurin inhibition on long-term extinction. This disparity could be due to methodological differences such as different animal species or strains, different behavioral protocols, or different sites of CaN inhibition.…”

“…This disparity could be due to methodological differences such as different animal species or strains, different behavioral protocols, or different sites of CaN inhibition. In these previous studies, which used inbred C57BL/6 mice (de la Fuente et al 2011) and rats (Merlo et al 2014), animals were trained in an auditory fear conditioning paradigm, even though they were tested for contextual fear conditioning in de la Fuente et al (2011). Furthermore, in these studies CaN was inhibited locally in the hippocampus by FK-506 (de la Fuente et al 2011) or in the amygdala by an antisense oligodeoxynucleotide (Merlo et al 2014), a fact that might also account for the observed disparities.…”

“…Mice with genetic inhibition of calcineurin activity also present enhanced initial learning of some tasks (Malleret et al 2001;Baumgärtel et al 2008;Havekes et al 2008;de la Fuente et al 2014) but impaired extinction of taste and contextual fear conditioning (Baumgärtel et al 2008;Havekes et al 2008). Moreover, CaN activity in the amygdala seems to be unaltered (Lin et al 2003a) or repressed during initial learning (Baumgärtel et al 2008), but both its activity (Lin et al 2003a) and protein content (Merlo et al 2014) in the amygdala and its nuclear content in the hippocampus (de la Fuente et al 2011) are increased after extinction. Finally, blockade of calcineurin activity in the hippocampus (de la Fuente et al 2011) or of its expression in the amygdala (Merlo et al 2014) can disrupt extinction of fear conditioning, and its inhibition in the amygdala interferes with memory destabilization during reconsolidation of an inhibitory avoidance memory (Fukushima et al 2014).…”

“…Moreover, CaN activity in the amygdala seems to be unaltered (Lin et al 2003a) or repressed during initial learning (Baumgärtel et al 2008), but both its activity (Lin et al 2003a) and protein content (Merlo et al 2014) in the amygdala and its nuclear content in the hippocampus (de la Fuente et al 2011) are increased after extinction. Finally, blockade of calcineurin activity in the hippocampus (de la Fuente et al 2011) or of its expression in the amygdala (Merlo et al 2014) can disrupt extinction of fear conditioning, and its inhibition in the amygdala interferes with memory destabilization during reconsolidation of an inhibitory avoidance memory (Fukushima et al 2014). Taken together, these results suggest that CaN seems to be more involved in labilization of an existing memory trace than in formation of a fear memory.…”

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

“…Second, some opposing molecular mechanisms in the hippocampus underlie these two processes. For example, hippocampal CREB and NF-kB are activated by reconsolidation but not by extinction (de la Fuente et al, 2011;Mamiya et al, 2009), suggesting that some specific mechanism determines the memory process after retrieval.…”