Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear
Open accessAbstract
Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore, in these studies, we have investigated whether epigenetic regulation of gene expression contributes to fear extinction. Since brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity and for the maintenance of long-term memory, we examined histone modifications around two BDNF gene promoters after extinction of cued fear, as potential targets of learning-induced epigenetic regulation of gene expression. Valproic acid (VPA), used for some time as an anticonvulsant and a mood stabilizer, modulates the expression of BDNF, and is a histone deacetylase (HDAC) inhibitor. Here, we report that extinction of conditioned fear is accompanied by a significant increase in histone H4 acetylation around the BDNF P4 gene promoter and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that VPA enhances long-term memory for extinction because of its HDAC inhibitor effects, and that VPA potentiates the effect of weak extinction training on histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF exon IV mRNA expression. These results suggest a relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. In addition, they suggest that HDAC inhibitors may become a useful pharmacological adjunct to psychotherapy for human anxiety disorders.
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Threat extinction is associated with acetylation of histones near the Bdnf locus, changes to the p300/CBP complex (PCAF), and deposition of DNA-modification marks such as 5-hydroxymethylcytosine and N6-methyl-2'deoxyadenosine (m6dA) near loci of activity-dependent genes such as Bdnf.
“In the IL, threat extinction is associated with acetylation of histones near the Bdnf locus [61], changes to the p300/CBP complex (PCAF) [62], as well as deposition of DNA-modification marks such as 5-hydroxymethylcytosine and N6-methyl-2’deoxyadenosine (m6dA) near loci of activity-dependent genes such as Bdnf.”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [61]
This hyperacetylation was concomitant with an increase in BDNF exon IV mRNA in the PFC of mice that achieved fear extinction.
“This hyperacetylation was concomitant with an increase in BDNF exon IV mRNA in the PFC of mice that achieved fear extinction (Bredy et al., 2007).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Bredy et al., 2007
In C57BL/6 mice with footshock paired with white noise, animals that displayed fear extinction had increased levels of histone H4 acetylation around the promoter of Bdnf exon IV compared with both naive and fear-conditioned animals without extinction controls.
“In a study using footshock paired with white noise in C57BL/6 mice (a model for PTSD and anxiety), animals that displayed fear extinction where the induced fear behavior such as freezing is lost by extinction training had increased levels of histone H4 acetylation around the promoter of Bdnf exon IV, compared with both naive and fear-conditioned animals without extinction controls.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Bredy et al., 2007
HDACs may perpetuate repressed Bdnf expression in anxiety models.
“Valproic acid (VPA), an HDAC inhibitor and mood stabilizer, was shown to potentiate long-term memory for fear extinction, suggesting that HDACs may perpetuate repressed Bdnf expression in anxiety models (Bredy et al., 2007).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Bredy et al., 2007
An increase in BDNF expression facilitated by H4 hyperacetylation likely underscores improved learning and subsequent extinction of fear-conditioned behaviors.
“It is likely that an increase in BDNF expression facilitated by H4 hyperacetylation underscores improved learning and subsequent extinction of fear-conditioned behaviors.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Bredy et al., 2007
Valproic acid (VPA) was shown to potentiate long-term memory for fear extinction.
“Valproic acid (VPA), an HDAC inhibitor and mood stabilizer, was shown to potentiate long-term memory for fear extinction, suggesting that HDACs may perpetuate repressed Bdnf expression in anxiety models (Bredy et al., 2007).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Bredy et al., 2007
An acute dose of butyrate enhances (re-)learning and memory, decreases depressive-like and perseverative behavior, and increases sociability in a mouse model of ASD.
“such an acute dose of butyrate enhances (re-)learning and memory, decreases depressive-like and perseverative behavior, and increases sociability in a mouse model of ASD”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Bredy et al., 2007
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- Authors
- Bredy, T. W., Wu, H., Crego, C., Zellhoefer, J., Sun, Y. E., & Barad, M.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Learning & Memory
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-04
- Volume
- 14
- Issue
- 4
- Pages
- 268-276
- ISSN
- 1072-0502 (ISSN-L)
- 1549-5485
- PMC
- PMC2216532
- OpenAlex
- W2137116499
- Cited by
- 548
- References
- 4
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 16 · 2023: 16 · 2022: 16 · 2021: 31 · 2020: 18 · 2019: 31 · 2018: 30 · 2017: 35 · 2016: 43 · 2015: 28 · 2014: 49 · 2013: 65 · 2012: 41
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Learning & Memory (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- brain-derived neurotrophic factor, histone modifications, histone H4 acetylation, fear extinction, fear conditioning, prefrontal cortex, valproic acid, histone deacetylase inhibitors, epigenetic regulation, gene expression, long-term memory, anxiety disorders
- MeSH terms
- Acetylation, Animals, Conditioning, Psychological, Enzyme Inhibitors, Extinction, Psychological, Fear, Histones, Male, Memory, Mice, Inbred C57BL, Promoter Regions, Genetic, RNA, Messenger, Time Factors, Valproic Acid, Prefrontal Cortex, Brain-Derived Neurotrophic Factor, Mice, Histone Deacetylase Inhibitors
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