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
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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.
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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.
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