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A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood
Open accessAbstract
Binge drinking during adolescence is a risk factor for neuropsychiatric disorders that can develop later in life. Histone acetylation is an important epigenetic mechanism that contributes to neurodevelopment. We investigated the effects of adolescent intermittent ethanol (AIE) exposure, as opposed to normal saline (AIS) exposure, on histone acetylation-mediated regulation of brain-derived neurotrophic factor (BDNF) expression and developmental stages of neurogenesis (proliferating and immature neurons) in the hippocampus in adulthood. AIE exposure increased whole hippocampal histone deacetylase (HDAC) activity and decreased binding protein of cyclic adenosine monophosphate response element binding protein (CBP) and histone H3-K9 acetylation levels in the CA1, CA2, and CA3 regions of the hippocampus. BDNF protein and exon IV mRNA levels in the CA1 and CA3 regions of the hippocampus of AIE-exposed adult rats were decreased as compared to AIS-exposed adult rats. AIE-induced anxiety-like behaviors and deficits in histone H3 acetylation at BDNF exon IV promoter in the hippocampus during adulthood, which were reversed by treatment with the HDAC inhibitor, trichostatin A (TSA). Similarly, neurogenesis was inhibited by AIE in adulthood as demonstrated by the decrease in Ki-67 and doublecortin (DCX)-positive cells in the dentate gyrus, which was normalized by TSA treatment. These results indicate that AIE exposure increases HDACs and decreases CBP levels that may be associated with a decrease in histone H3 acetylation in the hippocampus. These epigenetic changes potentially decrease BDNF expression and inhibit neurogenesis in the hippocampus that may be involved in AIE-induced behavioral abnormalities, including anxiety, in adulthood.
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“Moreover, persistent HC damage following intermittent alcohol exposure has also been documented, with alcohol exposure in rats during the adolescent period leading to decreases in doublecortin labeled neurons (marker of neurogenesis), Ki-67 labeled cells (marker of cell proliferation), and BDNF, and increases in cleaved caspase-3 (marker of cell death) in the HC in adulthood (Vetreno and Crews 201”
From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Sakharkar et al. 2016
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“Interestingly, adult reductions in doublecortin, as a result of adolescent alcohol exposure, are prevented by the inhibition of histone deacetylase, suggesting a role of epigenetic modification in the deficits produced by adolescent alcohol exposure (Sakharkar et al. 2016).”
From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Sakharkar et al. 2016
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Metadata
- Authors
- Sakharkar, A. J., Vetreno, R. P., Zhang, H., Kokare, D. M., Crews, F. T., & Pandey, S. C.
- Affiliations
- University of Illinois Chicago (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Pandey, Subhash C.
- Venue
- Brain Structure and Function
- Published
- 2016-03-03
- Volume
- 221
- Issue
- 9
- Pages
- 4691-4703
- ISSN
- 1863-2653 (ISSN-L)
- 1863-2661
- PMC
- PMC5010799
- OpenAlex
- W2290020361
- Cited by
- 122
- References
- 68
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 8 · 2023: 10 · 2022: 7 · 2021: 22 · 2020: 12 · 2019: 16 · 2018: 16 · 2017: 16 · 2016: 4
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Structure and Function (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA-019971, AA-024605, AA-010005, AA-013341, P50 AA-022538, AA020023 (NADIA project), AA020024, AA020022)
- U.S. Department of Veterans Affairs (Merit Review Grant,I01BX000143; Senior Research Career Scientist award)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- adolescent intermittent ethanol exposure, binge drinking, histone acetylation, histone deacetylase, CBP, brain-derived neurotrophic factor, hippocampal neurogenesis, dentate gyrus, anxiety-like behavior, trichostatin A, epigenetic regulation, brain development
- MeSH terms
- Doublecortin Protein, Acetylation, Ethanol, Animals, Anxiety, Hippocampus, Histones, Hydroxamic Acids, Male, Rats, Sprague-Dawley, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic, CREB-Binding Protein, Rats, Neurogenesis, Histone Deacetylase Inhibitors
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