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Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories
Open accessAbstract
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.
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“CI-994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment.”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [17]
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“CI-994 can cross the blood–brain barrier and is a cognitive enhancer.”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [17]
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“CI-994 is a molecular memory aid and promotes memory formation and cognitive function in vivo [9, 17, 21–24].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [17]
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“CI-994 is an orally bioavailable specific class I HDAC inhibitor which can across the blood–brain barrier [16, 17].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [17]
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“CI-994 acts as a memory enhancer and alleviates cognitive deficits in mouse models of neurodegenerative disorders [9, 17, 21–24].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [17]
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“CI-994 can cross the blood–brain barrier and is a cognitive enhancer.”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [17]
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“CI-994 acts as a memory enhancer and alleviates cognitive deficits in mouse models of neurodegenerative disorders [9, 17, 21–24].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [17]
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Citations
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Cited by
Sorted by citations
An Update on Memory Reconsolidation Updating
Lee, J. L. C., Nader, K., & Schiller, D. (2017) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2017.04.006 · Cited by 557
Singewald, N., Schmuckermair, C., Whittle, N., Holmes, A., & Ressler, K. J. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.12.004 · Cited by 390
“Extinction of recent fear memories (1 day after conditioning), using a memory update-consolidation paradigm, increases HDAC2 nitrosylation (Graff et al., 2014), which facilitates the dissociation of HDAC2 from chromatin (Nott et al.”
BackgroundInfluentialMaren, S., & Holmes, A. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.180 · Cited by 412
The Regulation of Transcription in Memory Consolidation
Alberini, C. M., & Kandel, E. R. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021741 · Cited by 362
Sartori, S. B., & Singewald, N. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107402 · Cited by 236
Metadata
- Authors
- Gräff, J., Joseph, N. F., Horn, M. E., Samiei, A., Meng, J., Seo, J., Rei, D., Bero, A. W., Phan, T. X., Wagner, F., Holson, E., Xu, J., Sun, J., Neve, R. L., Mach, R. H., Haggarty, S. J., & Tsai, L.-H.
- Affiliations
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Massachusetts Institute of Technology (US)
- Washington University in St. Louis (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 156
- Issue
- 1-2
- Pages
- 261-276
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3986862
- OpenAlex
- W2021415039
- Cited by
- 357
- References
- 75
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 21 · 2023: 20 · 2022: 28 · 2021: 27 · 2020: 25 · 2019: 22 · 2018: 45 · 2017: 32 · 2016: 34 · 2015: 32 · 2014: 36
- FWCI
- 22.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute on Aging
- National Institute on Drug Abuse (R01DA028301)
- National Institute of Neurological Disorders and Stroke (NS078839, R03NS090214, R01NS078839)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Keywords
- memory reconsolidation, HDAC2, S-nitrosylation, histone acetylation, hippocampal plasticity, histone deacetylase inhibitors, anxiety disorders, memory retrieval, synaptic plasticity
- MeSH terms
- Animals, Fear, Hippocampus, Male, Mice, Inbred C57BL, Neuronal Plasticity, Epigenesis, Genetic, Mice, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Memory, Long-Term, Transcriptome
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