Identification of long noncoding RNAs dysregulated in the midbrain of human cocaine abusers

Abstract

Maintenance of the drug-addicted state is thought to involve changes in gene expression in different neuronal cell types and neural circuits. Midbrain dopamine (DA) neurons in particular mediate numerous responses to drugs of abuse. Long noncoding RNAs (lncRNAs) regulate CNS gene expression through a variety of mechanisms, but next to nothing is known about their role in drug abuse. The proportion of lncRNAs that are primate-specific provides a strong rationale for their study in human drug abusers. In this study, we determined a profile of dysregulated putative lncRNAs through the analysis of postmortem human midbrain specimens from chronic cocaine abusers and well-matched control subjects (n=11 in each group) using a custom lncRNA microarray. A dataset comprising 32 well-annotated lncRNAs with independent evidence of brain expression and robust differential expression in cocaine abusers is presented. For a subset of these lncRNAs, differential expression was validated by quantitative real-time PCR and cellular localization determined by in situ hybridization histochemistry. Examples of lncRNAs exhibiting DA cell-specific expression, different subcellular distributions, and covariance of expression with known cocaine-regulated protein-coding genes were identified. These findings implicate lncRNAs in the cellular responses of human DA neurons to chronic cocaine abuse.

Cocaine alters Homer1 natural antisense transcript in the nucleus accumbens

“…Utilizing microarray analysis, previous studies have also identified several long noncoding RNAs that were altered in the NAc and midbrain dopamine neurons of human cocaine and heroin abusers (Michelhaugh et al , 2011; Bannon et al , 2015) and in the NAc of mice following cocaine conditioned place preference (Bu et al , 2012). Although NATs were not the primary focus of these previous studies, several of the long noncoding RNAs that were altered by cocaine were antisense transcripts (52/603 in the mouse NAc and 16/32 in the human midbrain) (Bu et al , 2012; Bannon et al , 2015).…”

“…Although NATs were not the primary focus of these previous studies, several of the long noncoding RNAs that were altered by cocaine were antisense transcripts (52/603 in the mouse NAc and 16/32 in the human midbrain) (Bu et al , 2012; Bannon et al , 2015). To our knowledge, Homer1-AS and other NATs examined in the current study were not investigated in previous cocaine studies.…”

“…Two recent reports, however, indicate that lncRNAs, in general, may play a role in cocaine-induced adaptations, as expression of several lncRNAs was altered in the nucleus accumbens (NAc) and midbrain of post-mortem human cocaine abusers (Michelhaugh et al , 2011; Bannon et al , 2015) and in mice following cocaine conditioned place preference (Bu et al , 2012). To better understand a role for NATs in response to repeated cocaine use, we took advantage of a recently published automated algorithm that mines the AceView transcriptomic database to identify biologically relevant sense-antisense pairs (Velmeshev et al , 2013) and revealed that numerous genes that have been previously associated with cocaine-induced neuroadaptations contain NATs.…”

Noncoding RNA Regulation of Dopamine Signaling in Diseases of the Central Nervous System

“…Investigation of midbrain dopamine neurons (mDN), which are primary responders to drugs of abuse, revealed lncRNA modulators of addiction phenotypes (Bannon et al, 2015). Bannon et al identified a subset of dysregulated lncRNAs in mDN from post-mortem tissue of cocaine addicts (Bannon et al, 2015).…”

“…Bannon et al identified a subset of dysregulated lncRNAs in mDN from post-mortem tissue of cocaine addicts (Bannon et al, 2015). One of those misregulated lncRNAs is an antisense transcript to the gene for tumor necrosis factor receptor-associated factor 3-interacting protein 2 (TRAF3IP2).…”