Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories.
Traumatic events generate some of the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that, in mice, successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes, which is accompanied by higher metabolic, synaptic, and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata.
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Johannes
J
Gräff
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Nadine F
NF
Joseph
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Meryl E
ME
Horn
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Alireza
A
Samiei
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Jia
J
Meng
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Jinsoo
J
Seo
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Damien
D
Rei
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Adam W
AW
Bero
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Trongha X
TX
Phan
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Florence
F
Wagner
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Edward
E
Holson
Mallinckrodt Institute of Radiology, Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jinbin
J
Xu
Mallinckrodt Institute of Radiology, Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jianjun
J
Sun
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Rachael L
RL
Neve
Mallinckrodt Institute of Radiology, Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Robert H
RH
Mach
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Center for Human Genetic Research, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Stephen J
SJ
Haggarty
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: lhtsai@mit.edu.
Li-Huei
LH
Tsai
D000818:Animals; D044127:Epigenesis, Genetic; D005239:Fear; D006624:Hippocampus / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D059467:Transcriptome
D056572:Histone Deacetylase Inhibitors; D056464:Histone Deacetylase 2