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Abstract
Transcriptomic changes in specific brain regions can influence the risk of alcohol use disorder (AUD), but the underlying mechanism is not fully understood. We investigated AUD-associated miRNA–mRNA regulatory networks in multiple brain regions by analyzing transcriptomic changes in two sets of postmortem brain tissue samples and ethanol-exposed human embryonic stem cell (hESC)-derived cortical interneurons. miRNA and mRNA transcriptomes were profiled in 192 tissue samples (Set 1) from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control European Australians. Nineteen differentially expressed miRNAs (fold-change>2.0 & P < 0.05) and 97 differentially expressed mRNAs (fold-change>2.0 & P < 0.001) were identified in one or multiple brain regions of AUD subjects. AUD-associated miRNA–mRNA regulatory networks in each brain region were constructed using differentially expressed and negatively correlated miRNA–mRNA pairs. AUD-relevant pathways (including CREB Signaling, IL-8 Signaling, and Axonal Guidance Signaling) were potentially regulated by AUD-associated brain miRNA–mRNA pairs. Moreover, miRNA and mRNA transcriptomes were mapped in additional 96 tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control European Australians. Some of the AUD-associated miRNA–mRNA regulatory networks were confirmed. In addition, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with or without ethanol exposure, and ethanol-influenced miRNA–mRNA regulatory networks were constructed. This study provided evidence that alcohol could induce concerted miRNA and mRNA expression changes in reward-related or alcohol-responsive brain regions. We concluded that altered brain miRNA–mRNA regulatory networks might contribute to AUD development.
Highlights
Alcohol use disorder (AUD) is characterized by uncontrolled alcohol drinking due to physical and psychological dependence on alcohol
By Affymetrix miRNA 4.0 microarray analysis of the 96 selected Set 2 samples, we identified 52 differentially expressed miRNAs in one or more brain regions (1 in AMY, 1 in caudate nucleus (CN), 3 in CRB, 4 in HIP, 44 in prefrontal cortex (PFC), and 4 in PUT) of AUD subjects (Fig. S6 and Table S3)
We examined ethanol-induced miRNA transcriptomic changes in human embryonic stem cell (hESC)-derived cortical interneurons by small RNA-seq
Summary
Alcohol use disorder (AUD) is characterized by uncontrolled alcohol drinking due to physical and psychological dependence on alcohol. Human postmortem brain studies have examined AUD-associated coding gene (or mRNA) expression changes in three brain regions [prefrontal cortex (PFC), NAc, and ventral tegmental area (VTA)] comprising the core reward circuitry. Expressed coding genes identified in postmortem PFC of AUD subjects are potentially involved in transcription [5], aldehyde detoxification [6], nicotine response and opioid signaling [7], oxidative stress [5, 8], mitochondrial function [5, 6], myelination [9,10,11,12], calcium signaling [11], protein trafficking [10], fatty acid metabolism [6], cell cycling [13], cell adhesion [12], and neuronal apoptosis [5, 11, 12]. Expressed coding genes identified in postmortem NAc of AUD subjects may participate in synaptic transmission [5, 8], vesicle formation and cell architecture [5], transcription and lipid metabolism [14], and oxidative phosphorylation, mitochondrial dysfunction and cytokine signaling [15]
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