Targeted epigenomic editing ameliorates adult anxiety and excessive drinking after adolescent alcohol exposure
Open accessAbstract
Adolescent binge drinking is a major risk factor for psychiatric disorders later in life including alcohol use disorder. Adolescent alcohol exposure induces epigenetic reprogramming at the enhancer region of the activity-regulated cytoskeleton-associated protein (Arc) immediate-early gene, known as synaptic activity response element (SARE), and decreases Arc expression in the amygdala of both rodents and humans. The causal role of amygdalar epigenomic regulation at Arc SARE in adult anxiety and drinking after adolescent alcohol exposure is unknown. Here, we show that dCas9-P300 increases histone acetylation at the Arc SARE and normalizes deficits in Arc expression, leading to attenuation of adult anxiety and excessive alcohol drinking in a rat model of adolescent alcohol exposure. Conversely, dCas9-KRAB increases repressive histone methylation at the Arc SARE, decreases Arc expression, and produces anxiety and alcohol drinking in control rats. These results demonstrate that epigenomic editing in the amygdala can ameliorate adult psychopathology after adolescent alcohol exposure.
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Restoring histone acetylation at the Arc SARE site of the central amygdala following voluntary adolescent alcohol exposure in male rats caused a reduction in anxiety-like behavior and excessive drinking to control levels.
“Bohnsack and colleagues [52] found that restoring histone acetylation at the Arc SARE site of the CeA following voluntary AAE in male rats caused a reduction in anxiety-like behavior and excessive drinking to control levels.”
From Consequences of adolescent drug use (2023) · cites this paper as [52]
The Results section (‘Activation of the Arc enhancer rescues anxiety and drinking’; page unavailable) reports that CeA dCas9-P300 plus sgRNAs restored anxiety-like behavior and excessive drinking to control levels after adolescent alcohol exposure. However, the Materials and Methods section (‘Adolescent intermittent alcohol exposure’; page unavailable) says the male rats received ethanol by intraperitoneal injection, not voluntarily. (LLM, conf=0.94)
Experimental — accuracy not yet measuredAdolescent alcohol exposure-induced epigenetic repression of the synaptic activity response element within the immediate-early gene Arc in the central amygdala is a critical mediator for anxiety-like behavior.
“Recent evidence points to AAE-induced epigenetic repression of the synaptic activity response element (SARE) within the immediate-early gene activity-regulated cytoskeleton-associated protein (Arc) in the central amygdala (CeA) [51, 52] as a critical mediator for anxiety-like behavior.”
From Consequences of adolescent drug use (2023) · cites this paper as [52]
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- Authors
- Bohnsack, J. P., Zhang, H., Wandling, G. M., He, D., Kyzar, E. J., Lasek, A. W., & Pandey, S. C.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Pandey, Subhash C.
- Venue
- Science Advances
- Published
- 2022-05-06
- Volume
- 8
- Issue
- 18
- Pages
- eabn2748-eabn2748
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC9067919
- OpenAlex
- W4229005036
- Cited by
- 68
- References
- 61
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 21 · 2023: 16 · 2022: 6
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (IK6BX006030)
- National Institutes of Health (5f32aa027410-02)
- National Institute on Alcohol Abuse and Alcoholism (U01AA019971, F32AA-027410, R01AA027231, U24AA024605, P50AA022538)
- National Institute of Mental Health (R25MH086466)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- adolescent alcohol exposure, binge drinking, alcoholism, anxiety, Arc gene, amygdala, histone acetylation, histone methylation, dCas9-KRAB, enhancer reprogramming, adult psychopathology
- MeSH terms
- Adolescent, Ethanol, Alcoholism, Animals, Anxiety, Histones, Humans, Rats, Epigenomics
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