Alcohol use disorder causes global changes in splicing in the human brain

Derek Van Booven,J Sunil Rao,Claes Wahlestedt,Ilya O Blokhin,Markus Heilig,Estelle Barbier,Mengying Li Mengying Li,R Dayne Mayfield

doi:10.1038/s41398-020-01163-z

Abstract

Alcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs splicing in the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). To evaluate splicing, bam files from STAR alignments were indexed with samtools for use by rMATS software. Computational analysis of affected pathways was performed using Gene Ontology Consortium, Gene Set Enrichment Analysis, and LncRNA Ontology databases. Surprisingly, AUD was associated with limited changes in the transcriptome: expression of 23 genes was altered in SFC, 14 in NA, 102 in BLA, and 57 in CNA. However, strikingly, mis-splicing in AUD was profound: 1421 mis-splicing events were detected in SFC, 394 in NA, 1317 in BLA, and 469 in CNA. To determine the mechanism of mis-splicing, we analyzed the elements of the spliceosome: small nuclear RNAs (snRNAs) and splicing factors. While snRNAs were not affected by alcohol, expression of splicing factor heat shock protein family A (Hsp70) member 6 (HSPA6) was drastically increased in SFC, BLA, and CNA. Also, AUD was accompanied by aberrant expression of long noncoding RNAs (lncRNAs) related to splicing. In summary, alcohol is associated with genome-wide changes in splicing in multiple human brain regions, likely due to dysregulation of splicing factor(s) and/or altered expression of splicing-related lncRNAs.

Highlights

1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Alcohol use disorder (AUD) is a chronic condition characterized by a problematic pattern of alcohol use, which results in clinically significant impairment
Amygdala is a part of the limbic system which projects to nucleus accumbens and is mainly involved in the formation of emotional responses[7]
Rat model of alcohol use disorder based on the vapor chamber Rats were placed in a vapor chamber with normal air for one week for habituation to a new environment

Summary

Introduction

Alcohol use disorder (AUD) is a chronic condition characterized by a problematic pattern of alcohol use, which results in clinically significant impairment. In the United States, 14% of adults currently meet the criteria for AUD, 29% met AUD criteria once during their lifetime[1]; in addition, the prevalence of AUD is increasing[2]. Because of high prevalence and lack of efficient treatment modalities as well as due to association with multiple medical and psychiatric illnesses[3,4], AUD causes a significant socioeconomic burden. Even though multiple brain regions might be involved in the pathogenesis of AUD, major sites are considered to be the frontal cortex, nucleus accumbens, and amygdala[6]. The frontal cortex is responsible for learning, decisionmaking, attention, and memory. Nucleus accumbens plays a critical role in processing rewarding stimuli, reinforcing pleasurable activities. Amygdala is a part of the limbic system which projects to nucleus accumbens and is mainly involved in the formation of emotional responses[7]

Methods

Results

Conclusion