Abstract
Background
Adolescent intermittent ethanol (AIE) exposure is an emerging risk factor for adult
psychopathology, such as anxiety disorders. Enhancer RNAs (eRNAs) are short noncoding
RNAs transcribed from enhancer regions that regulate synaptic plasticity–associated
gene expression, including Arc, but their role in AIE-induced susceptibility to anxiety in adulthood is unknown.
Methods
Rats were exposed to AIE (ethanol exposure 2 days on/off) or intermittent normal saline
during postnatal days 28 to 41 and allowed to grow to adulthood for analysis of behavior
and biochemical measures. Some AIE rats and rats with intermittent normal saline exposure
were exposed to an acute challenge with ethanol in adulthood. Cohorts of alcohol-naïve
adult rats were cannulated in the central nucleus of amygdala and infused with either
Kdm6b small interfering RNA or an antisense locked nucleic acid oligonucleotide specific
to Arc eRNA before behavioral and biochemical analysis.
Results
AIE adult rats displayed heightened anxiety and decreased Arc eRNA expression, which is regulated epigenetically through decreased Kdm6b expression. This triggered condensed chromatin at the synaptic activity response
element site and promoter of the Arc gene, facilitating increased negative elongation factor binding to the Arc promoter and decreasing Arc expression in the amygdala. Knockdown of Kdm6b or Arc eRNA expression in the central nucleus of amygdala provoked anxiety in alcohol-naïve
adult rats and recapitulated the molecular and epigenetic phenotypes of AIE.
Conclusions
These data suggest that eRNA regulation via epigenetic reprogramming in the amygdala,
particularly at the Arc synaptic activity response element site, contributes to adult anxiety after adolescent
alcohol exposure.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Effects of adolescent alcohol consumption on the brain and behaviour.Nat Rev Neurosci. 2018; 19: 197-214
- Changes in the adolescent brain and the pathophysiology of psychotic disorders.Lancet Psychiatry. 2014; 1: 549-558
- Global epigenomic reconfiguration during mammalian brain development.Science. 2013; 341: 1237905
- Age at first alcohol use: A risk factor for the development of alcohol disorders.Am J Psychiatry. 2000; 157: 745-750
- Underage alcohol use: Summary of developmental processes and mechanisms: ages 16-20.Alcohol Res Health. 2009; 32: 41-52
- Depressive and anxiety disorders predicting first incidence of alcohol use disorders: Results of the Netherlands Study of Depression and Anxiety (NESDA).J Clin Psychiatry. 2013; 74: 1233-1240
- Prevalence of comorbid substance use, anxiety and mood disorders in epidemiological surveys, 1990-2014: A systematic review and meta-analysis.Drug Alcohol Depend. 2015; 154: 1-13
- Epidemiology of DSM-5 Alcohol Use Disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions III.JAMA Psychiatry. 2015; 72: 757-766
- The comorbidity of alcoholism with anxiety and depressive disorders in four geographic communities.Compr Psychiatry. 1998; 39: 176-184
- Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood.Addict Biol. 2017; 22: 1191-1204
- Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood.Neurobiol Dis. 2015; 82: 607-619
- Alcohol intoxications during adolescence increase motivation for alcohol in adult rats and induce neuroadaptations in the nucleus accumbens.Neuropharmacology. 2013; 67: 521-531
- Adolescent alcohol exposure persistently impacts adult neurobiology and behavior.Pharmacol Rev. 2016; 68: 1074-1109
- Adolescent alcohol exposure: Burden of epigenetic reprogramming, synaptic remodeling, and adult psychopathology.Front Neurosci. 2016; 10: 222
- An operational definition of epigenetics.Genes Dev. 2009; 23: 781-783
- Non-coding RNA networks underlying cognitive disorders across the lifespan.Trends Mol Med. 2011; 17: 337-346
- Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential for synapse-to-nucleus signaling in activated neurons.Proc Natl Acad Sci U S A. 2009; 106: 316-321
- Enhancer RNA facilitates NELF release from immediate early genes.Mol Cell. 2014; 56: 29-42
- Widespread transcription at neuronal activity-regulated enhancers.Nature. 2010; 465: 182-187
- Enhancers as non-coding RNA transcription units: Recent insights and future perspectives.Nat Rev Genet. 2016; 17: 207-223
- Spatial genome organization and cognition.Nat Rev Neurosci. 2016; 17: 681-691
- Histone H3K27ac separates active from poised enhancers and predicts developmental state.Proc Natl Acad Sci U S A. 2010; 107: 21931-21936
- Chromatin modifications and their function.Cell. 2007; 128: 693-705
- Different neuronal activity patterns induce different gene expression programs.Neuron. 2018; 98: 530-546
- Genome-wide maps of chromatin state in pluripotent and lineage-committed cells.Nature. 2007; 448: 553-560
- Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions.Genome Res. 2011; 21: 1273-1283
- UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.Nature. 2007; 449: 731-734
- Polycomb complexes repress developmental regulators in murine embryonic stem cells.Nature. 2006; 441: 349-353
- Neuronal activity controls Bdnf expression via Polycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons.Nat Commun. 2016; 7: 11081
- The CBP co-activator is a histone acetyltransferase.Nature. 1996; 384: 641-643
- Adolescent alcohol exposure epigenetically regulates CREB signaling in the adult amygdala.Sci Rep. 2018; 8: 10376
- HDAC2 negatively regulates memory formation and synaptic plasticity.Nature. 2009; 459: 55-60
- The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function.Nucleic Acids Res. 2010; 38: W214-W220
- Class I histone deacetylase-mediated repression of the proximal promoter of the activity-regulated cytoskeleton-associated protein gene regulates its response to brain-derived neurotrophic factor.J Biol Chem. 2015; 290: 6825-6836
- Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism.Biol Psychiatry. 2013; 73: 763-773
- RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin alpha-subunit gene.Proc Natl Acad Sci U S A. 2015; 112: 4369-4374
- A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood.Brain Struct Funct. 2016; 221: 4691-4703
- Anxiety disorders and first alcohol use in the general population. Findings from a nationally representative sample.J Anxiety Disord. 2015; 31: 108-113
- Age at onset of alcohol use and DSM-IV alcohol abuse and dependence: A 12-year follow-up.J Subst Abuse. 2001; 13: 493-504
- Adolescent binge drinking leads to changes in alcohol drinking, anxiety, and amygdalar corticotropin releasing factor cells in adulthood in male rats.PLoS One. 2012; 7: e31466
- Periadolescent ethanol vapor exposure persistently reduces measures of hippocampal neurogenesis that are associated with behavioral outcomes in adulthood.Neuroscience. 2013; 244: 1-15
- Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain.PLoS One. 2014; 9: e113421
- Chronic intermittent ethanol exposure during adolescence: Effects on social behavior and ethanol sensitivity in adulthood.Alcohol. 2014; 48: 433-444
- The histone demethylase Kdm6b regulates a mature gene expression program in differentiating cerebellar granule neurons.Mol Cell Neurosci. 2018; 87: 4-17
- Binge-like alcohol exposure during adolescence disrupts dopaminergic neurotransmission in the adult prelimbic cortex.Neuropsychopharmacology. 2017; 42: 1024-1036
- Existing and future drugs for the treatment of the dark side of addiction.Annu Rev Pharmacol Toxicol. 2016; 56: 299-322
- Epigenetic basis of the dark side of alcohol addiction.Neuropharmacology. 2017; 122: 74-84
- Dealing with pervasive transcription.Mol Cell. 2013; 52: 473-484
- An atlas of active enhancers across human cell types and tissues.Nature. 2014; 507: 455-461
- Coexpression networks identify brain region-specific enhancer RNAs in the human brain.Nat Neurosci. 2015; 18: 1168-1174
- Transcription factor trapping by RNA in gene regulatory elements.Science. 2015; 350: 978-981
- Emerging themes in neuronal activity-dependent gene expression.Mol Cell Neurosci. 2018; 87: 27-34
- The central amygdala as an integrative hub for anxiety and alcohol use disorders.Biol Psychiatry. 2015; 77: 859-869
Article info
Publication history
Published online: March 01, 2019
Accepted:
December 19,
2018
Received in revised form:
December 18,
2018
Received:
July 12,
2018
Identification
Copyright
Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Connecting the Dots: Adolescent Alcohol, Enhancer RNA, and AnxietyBiological PsychiatryVol. 85Issue 11
- PreviewThe overwhelming drug of choice for abuse by adolescents is alcohol, and when they drink, it is often in intermittent binges, consuming more than four drinks in a few hours (1). Considerable epidemiological evidence documents that adolescent exposure to ethanol can increase the risk for drug dependence, affective disorders, or cognitive impairment in adulthood (2). Similar results from adolescent ethanol exposure have been found in animal models (3) and also occur with other drugs of abuse (4). Such findings document that adolescence is a critically sensitive developmental period whereby ethanol can evoke long-lasting changes in brain function, possibly due to alterations in ongoing synaptic pruning and maturation of myelinated fibers.
- Full-Text
- Preview