Several studies support that stored memories undergo a new period of consolidation after retrieval. It is not known whether this process, termed reconsolidation, requires the same transcriptional mechanisms involved in consolidation. Increasing evidence supports the participation of the transcription factor NF-B in memory. This was initially demonstrated in the crab Chasmagnathus model of associative contextual memory, in which re-exposure to the training context induces a well characterized reconsolidation process. Here we studied the role of NF-B in reconsolidation. NF-B was specifically activated in trained animals re-exposed to the training context but not to a different context. NF-B was not activated when animals were re-exposed to the context after a weak training protocol insufficient to induce long-term memory. A specific inhibitor of the NF-B pathway, sulfasalazine, impaired reconsolidation when administered 20 min before re-exposure to the training context but was not effective when a different context was used. These findings indicate for the first time that NF-B is activated specifically by retrieval and that this activation is required for memory reconsolidation, supporting the view that this molecular mechanism is required in both consolidation and reconsolidation.

Initially, memory is labile and requires consolidation to become stable. However, several studies support that consolidated memories can undergo a new period of lability after retrieval. The mechanistic differences of this process, termed reconsolidation, with the consolidation process are under debate, including the participation of hippocampus. Up to this point, few reports describe molecular changes and, in particular, transcription factor (TF) involvement in memory restabilization. Increasing evidence supports the participation of the TF nuclear factor-B (NF-B) in memory consolidation. Here, we demonstrate that the inhibition of NF-B after memory reactivation impairs retention of a hippocampal-dependent inhibitory avoidance task in mice. We used two independent disruptive strategies to reach this conclusion. First, we administered intracerebroventricular or intrahippocampal sulfasalazine, an inhibitor of IKK (IB kinase), the kinase that activates NF-B. Second, we infused intracerebroventricular or intrahippocampal B decoy, a direct inhibitor of NF-B consisting of a double-stranded DNA oligonucleotide that contains the B consensus sequence. When injected immediately after memory retrieval, sulfasalazine or B decoy (Decoy) impaired long-term retention. In contrast, a one base mutated B decoy (mDecoy) had no effect. Furthermore, we also found NF-B activation in the hippocampus, with a peak 15 min after memory retrieval. This activation was earlier than that found during consolidation. Together, these results indicate that NF-B is an important transcriptional regulator in memory consolidation and reconsolidation in hippocampus, although the temporal kinetics of activation differs between the two processes.

Although it is generally accepted that memory consolidation requires regulation of gene expression, only a few transcription factors (TFs) have been clearly demonstrated to be specifically involved in this process. Increasing research data point to the participation of the Rel/nuclear factor-kappaB (NF-kappaB) family of TFs in memory and neural plasticity. Here we found that two independent inhibitors of NF-kappaB induced memory impairment in the one-trial step-through inhibitory avoidance paradigm in mice: post-training administration of the drug sulfasalazine and 2 h pretraining administration of a double-stranded DNA oligonucleotide containing the NF-kappaB consensus sequence (kappaB decoy). Conversely, one base mutation of the kappaB decoy (mut-kappaB decoy) injection did not affect long-term memory. Accordingly, the kappaB decoy inhibited NF-kappaB in hippocampus 2 h after injection but no inhibition was found with mut-kappaB decoy administration. A temporal course of hippocampal NF-kappaB activity after training was determined. Unexpectedly, an inhibition of NF-kappaB was found 15 min after training in shocked and unshocked groups when compared with the naïve group. Hippocampal NF-kappaB was activated 45 min after training in both shocked and unshocked groups, decreasing 1 h after training and returning to basal levels 2 and 4 h after training. On the basis of the latter results, we propose that activation of NF-kappaB in hippocampus is part of the molecular mechanism involved in the storage of contextual features that constitute the conditioned stimulus representation. The results presented here provide the first evidence to support NF-kappaB activity being regulated in hippocampus during consolidation, stressing the role of this TF as a conserved molecular mechanism for memory storage.

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.

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There is increasing evidence that transcription factors (TFs) play a critical role in maintaining later phases of hippocampal long-term potentiation (LTP). We have been led to study the role in synaptic plasticity of the powerful, yet generally unheralded, NF-kappaB TF because it may serve as both a signaling molecule after its activation at the synapse and then a transcription initiator upon reaching the nucleus. In the present study, we show that LTP activates NF-kappaB in the intact mouse hippocampus. Mice were sacrificed 15 min after one of three treatments: tetanization (high-frequency stimulation [HFS]), low-frequency stimulation (LFS), or no stimulated control animals (CT). In a first study, nuclear NF-kappaB activity from hippocampus was estimated by electrophoretic mobility shift assays (EMSAs). A higher level of hippocampal TF binding to the NF-kappaB recognition element was found in the HFS group compared with LFS or CT. In a second study, NF-kappaB activity was evaluated by immunohistochemistry with a specific antibody that recognizes the activated form of NF-kappaB. This antibody binds to the exposed nuclear location sequence on the p65 subunit of NF-kappaB consequent to its dissociation from the inhibitory IkappaB molecule. In the four subfields of hippocampus examined--granule cell layer, hilus of the dentate gyrus, CA3 and CA1 pyramidal fields of the hippocampal gyrus--the highest levels of activated NF-kappaB, statistically significant in all cases were found after HFS. In certain comparisons, LFS animals also showed significant elevation with respect to CT. These results support the role of NF-kappaB as part of the synaptic signaling and transcriptional regulation mechanism required in long-term plasticity, emphasizing the combinatorial nature of TF function.

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