Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom

Hemstedt, Thekla J.; Lattal, K. Matthew; Wood, Marcelo A.

doi:10.1016/j.nlm.2017.01.007

Cited by 30 publications

(15 citation statements)

References 130 publications

(143 reference statements)

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“…Knockdown of the histone methyltransferase MLL1 in CA1 abolished retrieval-induced increases in DNA 5hmC levels at the Npas4 gene and prevented both fear memory and retrieval-induced increases in CA1 Npas4 mRNA 108 . The field of DNA methylation is still in its nascent stages, and future research will focus on understanding how gene-specific and locus-specific DNA methylation affects memory processes 104,105,109,110 .…”

Section: Dna Modificationmentioning

confidence: 99%

“…Studies involving systemic or region-specific infusions of HDAC inhibitors revealed that histone acetylation can enhance the extinction of recent long-term memories, including fearassociated or drug-associated memories [129][130][131][132][133][134] . Similar studies have examined the role of histone acetylation in reconsolidation; however, the findings are conflicting, suggesting that the effects of manipulating reconsolidation by altering histone acetylation may be specific to the type of memory or learning process 109 . For example, the retrieval or reactivation of contextual memory is reported to induce acetylation of H3 and H4 in the hippocampus and lateral amygdala.…”

Section: Targeting Histone Modificationsmentioning

confidence: 99%

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How the epigenome integrates information and reshapes the synapse

2019

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In the past few decades, the field of neuroepigenetics has investigated how the brain encodes information to form long-lasting memories that lead to stable changes in behaviour. Activitydependent molecular mechanisms, including, but not limited to, histone modification, DNA methylation and nucleosome remodelling, dynamically regulate the gene expression required for memory formation. Recently, the field has begun to examine how a learning experience is integrated at the level of both chromatin structure and synaptic physiology. Here, we provide an overview of key established epigenetic mechanisms that are important for memory formation. We explore how epigenetic mechanisms give rise to stable alterations in neuronal function by modifying synaptic structure and function, and highlight studies that demonstrate how manipulating epigenetic mechanisms may push the boundaries of memory.

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Section: Dna Modificationmentioning

confidence: 99%

Section: Targeting Histone Modificationsmentioning

confidence: 99%

How the epigenome integrates information and reshapes the synapse

2019

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“…Extinction, reconsolidation, and generalization can also be considered processes that comprise the brain’s memory management system (Seger and Miller, 2010; Censor, 2013; Giustino and Maren, 2015; Dunsmoor et al, 2015; Helmstedt et al, 2017). Much has been learned about several of these processes.…”

Section: Introductionmentioning

confidence: 99%

The Biology of Forgetting—A Perspective

Davis

Zhong

2017

Neuron

249

268

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Pioneering research studies, beginning with those using Drosophila, have identified several molecular and cellular mechanisms for active forgetting. The currently known mechanisms for active forgetting include neurogenesis-based forgetting, interference-based forgetting, and intrinsic forgetting, the latter term describing the brain’s chronic signaling systems that function to slowly degrade molecular and cellular memory traces. The best-characterized pathway for intrinsic forgetting includes “forgetting cells” that release dopamine onto engram cells, mobilizing a signaling pathway that terminates in the activation of Rac1/cofilin to effect changes in the actin cytoskeleton and neuron/synapse structure. Intrinsic forgetting may be the default state of the brain, constantly promoting memory erasure and competing with processes that promote memory stability like consolidation. A better understanding of active forgetting will provide insights into the brain’s memory management system and human brain disorders that alter active forgetting mechanisms.

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“…9 Given that 5-mC is often associated with transcriptional silencing of genes, a decrease in 5-mC as a consequence of DNMT inhibition hypothetically leads to an upregulation of gene expression, which then may interfere with fear memory (re)consolidation. 14 There is also a relationship between demethylation and fear extinction. The overexpression of TET1 or a catalytically inactive mutant (TET1 m) resulted in impaired expression of contextual fear.…”

Section: Introductionmentioning

confidence: 99%

Impaired fear extinction in serotonin transporter knockout rats is associated with increased 5‐hydroxymethylcytosine in the amygdala

Shan¹,

Guo

Heuvel³

et al. 2018

CNS Neurosci Ther

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SummaryAimsOne potential risk factor for posttraumatic stress disorder (PTSD) involves the low activity (short; s) allelic variant of the serotonin transporter‐linked polymorphic region (5‐HTTLPR), possibly due to reduced prefrontal control over the amygdala. Evidence shows that DNA methylation/demethylation is crucial for fear extinction in these brain areas and is associated with neuronal activation marker c‐Fos expression. We hypothesized that impaired fear extinction in serotonin transporter knockout (5‐HTT −/−) rats is related to changes in DNA (de) methylation and c‐Fos expression in the prefrontal cortex (PFC) and/or amygdala.Methods5‐HTT −/− and 5‐HTT +/+ rats were subjected to fear extinction. 2 hours after the extinction session, the overall levels of DNA methylation (5‐mC), demethylation (5‐hmC), and c‐Fos in fear extinction and nonfear extinction rats were measured by immunohistochemistry.Results5‐HTT −/− rats displayed decreased fear extinction. This was associated with reduced c‐Fos activity in the infralimbic PFC. In the central nucleus of the amygdala, c‐Fos immunoreactivity was increased in the fear extinction group compared to the no‐fear extinction group, regardless of genotype. 5‐hmC levels were unaltered in the PFC, but reduced in the amygdala of nonextinction 5‐HTT −/− rats compared to nonextinction wild‐type rats, which caught up to wild‐type levels during fear extinction. 5‐mC levels were stable in central amygdala in both wild‐type and 5‐HTT −/− extinction rats. Finally, c‐Fos and 5‐mC levels were correlated with the prelimbic PFC, but not amygdala.ConclusionsIn the amygdala, DNA demethylation, independent from c‐Fos activation, may contribute to individual differences in risk for PTSD, as conferred by the 5‐HTTLPR s‐allele.

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Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom

Cited by 30 publications

References 130 publications

How the epigenome integrates information and reshapes the synapse

How the epigenome integrates information and reshapes the synapse

The Biology of Forgetting—A Perspective

Impaired fear extinction in serotonin transporter knockout rats is associated with increased 5‐hydroxymethylcytosine in the amygdala

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