Role Of IKK/NF-κB Signaling Pathway In Reconsolidation And Extinction In Auditory Fear Conditioning

Objective:For the delayed emergence and long-term persistent mental disorders, following with the threat of extraordinary or catastrophic trauma, PTSD (post traumatic stress disorder) has become a global public health problem. There has been no particularly effective way in treatment, The main reason is that there is no specific mechanism. By using the fear conditioning model of PTSD, we try to explore its consolidate and subside in the molecular pathway. NF-kappa B, as a number of transcription regulation, being part in a number of physiological responses, has been always a hot part. Recently, the new finding of regulation mechanism about IKKa, makes the IKK/NF-κB signaling pathway the focus in the field of Molecular Neuroscience. By using behavioral and pharmacological interventions, the subject mainly discuss the role of the IKK/NF-kappa B signaling pathways in the auditory fear memory consolidation and extinction. Through that we expect to find the effective target which can specifically block the IKK/NF-kappa B signaling pathway, and then it may block reconsolidation if fear conditioning and promote its extinction. We also hope that our research may provide a theoretical basis for looking for the elimination of PTSD drug treatment targets.Methods:The first part of the study has demonstrated that the IKK/NF-kappa B signaling pathways involves in reconsolidation of auditory fear conditioning. Adult SD rats were treated with nuclei buried surgery. After a week recovery of nuclei buried surgery, adult SD rats accept auditory fear conditioning training. Here, we demonstrate that inhibition of NF-κB in the basolateral amygdala (BLA), but not central nucleus of the amygdala, after memory reactivation impairs the retention of amygdala-dependent auditory fear conditioning (AFC). We used two independent pharmacological strategies to disrupt the reconsolidation of AFC. Bilateral intra-BLA infusion of sulfasalazine, an inhibitor of IκB kinase that activates NF-κB, and bilateral intra-BLA infusion of SN50, a direct inhibitor of the NF-κB DNA-binding complex, immediately after retrieval disrupted the reconsolidation of AFC. The second part of the study was to explore the role of IKK/NF-kappa B signaling pathway in the extinction of auditory fear conditioning. In the part, we use auditory fear conditioning model. After injected with the SSZ, we detect the behavior changes in rats in the different process of extinction.Results:The first part shows that the IKK complex antagonist, sulfasalazine (SSZ) and direct antagonist of NF-κB DNA complexes SN50,4h animal behavior TEST SSZ group and SN50groups show no significant difference (P>0.1) compared with the control group. The24h TEST detection SSZ and SN50groups animals show significantly less than the control group (P<0.01). All above results suggest that interference of IKK/NF-κB signaling pathway destruction of the auditory fear memory long-term memory in the reconsolidation phase, while no effect of short-term memory. While the groups injected with the histone deacetylase inhibitor NaB and SSZ, show24h after the significantly higher than the SSZ group (P<0.01) or NaB group after24h TEST. SSZ group shows no significant difference (P>0.1) compared with NaB. The results suggest that histone acetylation regulation may play an important role in the IKK/NF-κB signaling pathways involved in auditory fear memory reconsolidation. These results suggest that IKK/NF-kappa B signaling pathways involves in reconsolidation of auditory conditioning, and histone deacetylation may be an intra-nuclear molecular switch that culminates in the termination of the NF-κB transcriptional response in long-term memory.The second shows that SSZ group freezing behavior date has no significant difference (P>0.1) at each time point compared with Vehicle group in the acquirement of AFC. After24h, SSZ group freezing time show significantly higher than Vehicle group, suggesting that blocking the IKK/NF-κB signaling pathway had no effect on the acquirement of the auditory fear memory, but destruct consolidation of the extinction memory. In all, IKK/NF-κB signaling pathways involves in the consolidation of extinction memory, while there no effect on the process of extinction memory.Conclusions:Through a series of experiments, the study has demonstrated that the IKK/NF-κB signaling pathways take part in the in the reconsolidation and extinction of auditory fear memory. The main conclusions are as follows:(1) IKK/NF-kappa B signaling pathways in the BLA involves in reconsolidation of auditory conditioning and histone deacetylation may be an intra-nuclear molecular switch that culminates in the termination of the NF-κB transcriptional response in long-term memory.(2) IKK/NF-kappa B signaling pathways in the BLA involves in the consolidation of extinction memory, while there no effect on the process of extinction memory.In all, this study firstly confirmed that the IKK/NF-κB signaling pathways in the BLA involve in reconsolidation and extinction of auditory fear memory, and preliminary molecular interventions could disrupt the performance of the animal’s fear. Therefore, this study makes further research about the biological mechanisms of fear conditioning and provide a theoretical basis for looking for the elimination of PTSD drug treatment targets.