Dnmt3a in the dorsal dentate gyrus is a key regulator of fear renewal

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.

Elevated activity in the dorsal dentate gyrus reduces expression of fear memory after fear extinction training

“…This finding was consistent with those of our previous work: that Dnmt3a overexpression in the dDG prevents fear renewal and elevates the activity of dDG, and that knockdown of Dnmt3a in the dDG promotes fear renewal. 14 Overexpression of Dnmt3a in the dDG resulted in higher density of c-Fos neurons in the dDG. 14 This result means that the activity of the dDG is associated with expression levels of Dnmt3a in the dDG.…”

“…14 Overexpression of Dnmt3a in the dDG resulted in higher density of c-Fos neurons in the dDG. 14 This result means that the activity of the dDG is associated with expression levels of Dnmt3a in the dDG. Mice with Dnmt3a overexpression in the dDG showed no significant fear renewal, supporting our finding in the present study about a correlation between fear expression and the activity of the dDG.…”

“…Immunostaining protocols were taken from previous studies. 14 Briefly, sections were treated with 3% H 2 O 2 in phosphatebuffered saline (PBS) for 30 minutes at room temperature, blocked with mouse immunoglobulin G blocking reagent from a Mouse on Mouse Basic Kit (BMK-2202; Vector Laboratories) for 1.5 hours at room temperature and then incubated with mouse anti-c-Fos primary antibody (ab208942; 1:1000; Abcam) overnight at 4°C. Sections were incubated with biotin ylated goat anti-mouse secondary antibody (Vectastain ABC Kit; Vector Laboratories) for 1.5 hours at room temperature.…”

“…Conclusion: Activation of the dorsal dentate gyrus may play an important role in modulating the expression of fear memory; its potential use in fear memory extinction is worthy of further exploration.Elevated activity in the dorsal dentate gyrus reduces fear memory expression Neurosci 2021;46(3) E391 extinction, regulating fear renewal. 14 After fear extinction training, the return of fear responses to a cue in a context that is different from the context used in extinction (i.e., fear renewal) is widely believed to represent limited efficacy of exposure therapy. We found that mice without significant fear renewal showed elevated levels of Dnmt3a in the dDG, and that overexpression of Dnmt3a resulted in a higher density of c-Fos neurons in the dDG.…”

AAV Ablates Neurogenesis in the Adult Murine Hippocampus

“…1). The doses demonstrated to ablate neurogenesis are within or below the range of experimentally relevant titers commonly injected into the mouse DG, 1.5 E12 to 3.6 E13 gc/mL (Anacker et al, 2018;Castle et al, 2018;Danielson et al, 2016Danielson et al, , 2017Gong and Zhou, 2018;Hashimotodani et al, 2017;Hayashi et al, 2017;Kaspar et al, 2002;Kirschen et al, 2017;Liu et al, 2012;McAvoy et al, 2016;Ni et al, 2019;Pilz et al, 2016;Ramirez et al, 2013;Raza et al, 2017;Redondo et al, 2014;Senzai and Buzsáki, 2017;Swiech et al, 2015;Zetsche et al, 2017). This rAAV-induced cell death is rapid and persistent; BrdU-labeled cells and Tbr2+ intermediate progenitors begin to die within 12 to 18 hours post-injection and are eliminated by 48 hours (Fig.…”