NF‐κB transcription factor is required for inhibitory avoidance long‐term memory in mice

Abstract

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.

Pharmacological effects and behavioral interventions on memory consolidation and reconsolidation

“…Intracerebroventricular injection of sulfasalazine immediately after training (memory consolidation) impaired retention test performance in a dose-and time-dependent manner (12). These results agree with those of Merlo et al (40).…”

“…The time course of hippocampal NF-κB activation during memory consolidation showed an inhibition of NF-κB 15 min after training followed by an activation peak at 45 min, returning to basal levels 2 and 4 h after training, in shocked and unshocked groups when compared with the naive group (12). NF-κB is also activated in the hippocampus by memory retrieval, and is probably involved in restabilization of the original memory, but its activation occurs earlier in memory reconsolidation than in memory consolidation: the peak of NF-κB activation takes place 15 min after memory reactivation (13).…”

“…Direct inhibition of NF-κB using icv injection of κBdecoy 2 h before training, both to shocked and unshocked mice during the learning trial, revealed a specific NF-κB inhibition in the hippocampus, well correlated with an impairment of long-term memory (LTM) consolidation (12). Conversely, injection of κBdecoy with one base mutation (mκBdecoy) did not affect LTM, and no inhibition of NF-κB was found in the hippocampus.…”

“…The role of NF-κB in memory consolidation and reconsolidation was further assessed by NF-κB inhibition using two independent strategies: the administration of the NF-κB pathway inhibitor sulfasalazine, which acts as a direct IκB kinase inhibitor (40), and the use of a double-stranded DNA oligonucleotide containing the NF-κB consensus sequence (κBdecoy) for direct inhibition (12).…”

“…We shall consider in this article the effects of intracerebroventricular (icv ) infusions of hemicholinium (HC-3), a central inhibitor of acetylcholine (Ach) synthesis (7), of intraperitoneal administration of N ω -nitro-L-arginine methyl ester (L-NAME), a non-specific inhibitor of nitric oxide synthase (NOS; 8), on post-training (memory consolidation) and post-reactivation (memory reconsolidation), and Memory consolidation and reconsolidation www.bjournal.com.br of intrahippocampal injections of an inhibitor of the transcription factor (nuclear factor κB, NF-κB; 9) on retention performance of an inhibitory avoidance response in mice (10)(11)(12)(13). We also will briefly discuss both the posttraining and the post-retrieval effects of the exposure of mice to a new learning experience (14).…”