Abstract
Renewal of extinguished fear memory in an altered context is widely believed to be a major limiting issue for exposure therapy in treating various psychiatric diseases. Effective prevention of fear renewal will significantly improve the efficacy of exposure therapy. DNA methyltransferase (DNMTs) mediated epigenetic processes play critical roles in long term memory, but little is known about their functions in fear memory extinction or renewal. Here we investigated whether DNMTs regulate fear renewal after extinction. We found that elevated Dnmt3a level in the dorsal dentate gyrus (dDG) of hippocampus was associated with the absence of fear renewal in an altered context after extinction training. Overexpression and knockdown of Dnmt3a in the dDG regulated the occurrence of fear renewal in a bi-directional manner. In addition, Dnmt3a overexpression was associated with elevated expression of c-Fos in the dDG during extinction training. Furthermore, we found that renewal of remote fear memory can be prevented, and the absence of renewal was concurrent with an elevated Dnmt3a level. Our results indicate that Dnmt3a in the dDG is a key regulator of fear renewal after extinction, and Dnmt3a may play a critical role in controlling fear memory return and thus has therapeutic values.
Highlights
Exposure therapy has widely been used and is effective in treating various psychiatric disorders, especially phobia and PTSD
By using fear renewal in an altered context as readout, we found that Dnmt3a expression was elevated in the dorsal dentate gyrus after extinction training followed by a brief memory retrieval (Rec+extinction in context B (Ext)), which was associated with the absence of fear renewal when tested in an altered context
We found that renewal of remote fear memory can be prevented using the Rec+Ext protocol, and the absence of renewal was concurrent with an elevated Dnmt3a level
Summary
Elevated Dnmt3a expression associated with the absence of fear renewal after extinction. We examined the density of c-Fos-positive cells in mice received Rec+Ext protocol (which showed high Dnmt3a level in Fig. 1e left), and found higher density in the dDG compared to mice received the Ext protocol (Fig. S5) Put together, these results suggest that Dnmt3a overexpression in the dDG is associated with elevated neural activity in the dDG during extinction training which may serve to prevent fear renewal. Since Dnmt3a level was elevated for a sustained period of time in AAV-Dnmt3a over-expression (Fig. 3), this high level of Dnmt3a in the dDG might in some way “keep” the remote memory in a “recent” state (i.e., allowing this remote memory to be updated or modified as recent memory)[33] To distinguish between these two possibilities, we fear conditioned mice on day 1, divided them into two groups based on their freezing levels, and subjected them to either Ext protocol or Rec+Ext protocol for 2 days on day 19 and 20 (Fig. 6a). Our results suggest that an increase in Dnmt3a level might be effective in preventing fear renewal after extinction for both recent and remote memory
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