【文章內(nèi)容簡(jiǎn)介】 dayold, memories—leaving it unclear whether they would also be effective for remote, ., monthold, memories. As traumatic memories are oftentimes not readily amenable to immediate treatments and because remote memories are more stable than recent ones , there is a clear need to investigate options to overe remote fear memories.RESULTSDespite Using ReconsolidationUpdating Paradigms, Remote Memories Cannot Be Persistently Attenuated To test whether exposuretherapybased approaches can be used to attenuate remote traumatic memories, we used Pavlovian fear conditioning in mice, a monly employed method to study fear responses underlying traumatic memories such as posttraumatic stress disorder (PTSD). In fear conditioning, an unconditioned stimulus (US)—an electrical footshock—is paired with a conditioned stimulus (CS)—either a specific tone or context for cued and contextual fear conditioning, respectively. When the animals are later tested for their fear memory by exposing them to the CS, the CS alone will elicit the conditioned response (CR), freezing. Specifically, we trained mice for either cued or contextual fear conditioning, 1 day and 30 days after which we attempted to attenuate their CR by different fear extinction paradigms . All of these paradigms take advantage of a transient period of memory lability, the reconsolidation window, that occurs between 1 and 6 hr following the memory recall.The first protocol aimed at extinguishing the CR to a tone (the CS) by employing a massed extinction paradigm for cued fear conditioning . We found that, for recent memories, this paradigm persistently attenuated the CR immediately and 1 day after extinction。Importantly, there were no signs of spontaneous recovery (SR) or reinstatement (RI) of the fear, the presence of which is indicative of inplete fear extinction .For remote memories, in contrast, we found that, although this paradigm was effective in decreasing the freezing response after the extinction session, there were significant RI and SR , indicating persistence of the original memory. This finding is consistent with the occurrence of both RI and SR upon remote memory extinction without memory recall .The second protocol aimed at attenuating the CR to a context (the CS) by a massed extinction paradigm adopted for contextual fear conditioning . By using this paradigm, recent fear memories could be successfully and permanently attenuated, but remote fear memories showed significant SR. Similar results were obtained when no recall was presented. Furthermore, because increasing the intertrial interval during fear extinction training has been shown to facilitate fear extinction of recent memories, we reasoned that such spacing would also help in attenuating remote memories. This paradigm significantly attenuated recent fear memories, and there were no signs of , when applied to remote memories, the same paradigm failed to even temporarily reduce fear, and when tested for SR, freezing levels were parable to those during memory recall . Similar results were obtained in the absence of memory recall. Together, these results indicate that three different behavioral paradigms that successfully extinguish recent fear memories were not capable of doing so for remote fear memories, despite taking advantage of the transient period of memory lability induced by memory recall. The question arises as to why remote fear memories are more difficult to extinguish.Recalling Remote Memories Is Not Salient Enough to Induce Histone AcetylationMediated Neuronal Plasticity in the Hippocampus By definition, the reconsolidation window opened by memory recall allows previously acquired memories to be updated with new information and is thereby thought to initiate a new period of neuronal plasticity. We hypothesized that the same memory recall might not induce the same extent of neuronal plasticity for remote as for recent the subsequent analyses, we focused on contextual fear memories, the formation of which depends on the hippocampus, a brain area crucial for memoryrelated neuronal plasticity that is activated upon remote memory fundamental mechanism that governs neuronal plasticity is the epigenetic modification of gene expression by acetylation of histone proteins. Histone acetylation promotes a chromatin structure that is more permissive for gene transcription and thereby positively regulates transcriptiondependent longlasting forms of neuronal plasticity. To test whether the same memory recall leads to differences in histone acetylation between remote and recent memories, we first used immunohistochemical analyses to assess the acetylation of histone 3 on lysine residues 9 and 14 (H3K9/14), a modi fication associated with facilitated neuronal plasticity. We found that, 1 hr post memory recall, hippocampal H3K9/14 acetylation of remote memories was indistinguishable from behaviorally naive animals but was significantly smaller than that of recent , we carried out chromatin immunoprecipitation (ChIP) to determine the abundance of H3K9/14 acetylation at the promoter region of cFos, an immediate early gene regulated by neuronal activity and critical for neuronal plasticity. Consistent with the overall histone acetylation pattern, we found the cFos promoter to be hypoacetylated after remote memory recall pared to after recent memory recall. Accordingly, the expression of cFos was significantly reduced after remote memory recall , an effect that was also observed at the protein level evidenced by the number cFospositive cells, as reported previously. Increments in histone acetylation are dependent on neuronal activity , and one pathway shown to mediate these changes in cultured neurons involves the dissociation of histone deacetylase 2 (HDAC2) from the chromatin following its nitrosylation on Cys262 and Cys274. We therefore investigated whether the lack of increased histone acetylation following remote memory recall might