Circular RNA regulation and function in drug seeking phenotypes

Abstract

Drug overdoses have increased dramatically in the United States over the last decade where they are now the leading cause of accidental death. To develop efficient therapeutic options for decreasing drug consumption and overdose risk, it is critical to understand the neurobiological changes induced by drug exposure. Chronic systemic exposure to all drug classes, including opioids, psychostimulants, nicotine, cannabis, and alcohol, induces profound molecular neuroadaptations within the central nervous system that may reveal crucial information about the lasting effects that these substances impart on brain cells. Transcriptome analyses of messenger RNAs (mRNAs) have identified gene patterns in the brain that result from exposure to various classes of drugs. However, mRNAs represent only a small fraction of the RNA within the cell, and drug exposure also impacts other classes of RNA that are largely understudied, especially circular RNAs. Circular RNAs (circRNAs) are a naturally occurring RNA species formed from back-splicing events during mRNA processing and are enriched in the nervous system. circRNAs are a pleiotropic class of RNAs and have a diverse impact on cellular function, with putative functions including regulation of mRNA transcription, protein translation, microRNA sponging, and sequestration of RNA-binding proteins. Recent studies have demonstrated that circRNAs can modulate cognition and are regulated in the brain in response to drug exposure, yet very few studies have explored the contribution of circRNAs to drug seeking phenotypes. In this review, we will provide an overview of the mechanisms of circRNA function in the cell to highlight how drug-induced circRNA dysregulation may impact the molecular substrates that mediate drug seeking behavior and the current studies that have reported drug-induced dysregulation of circRNAs in the brain. Furthermore, we will discuss how principles of circRNA biology can be adapted to study circRNAs in models of drug exposure and seek to provide further insight into the neurobiology of addiction.

Keywords: Circular RNA; Cocaine; Heroin; Morphine; Opioid; Psychostimulant; Splicing.

Figure 1:

Biogenesis, classification, and regulatory functions of circRNAs. (A) circRNAs can be classified into 4 subtypes: intronic circRNAs (icircRNA), exon-intron/sense overlapping circRNAs (ELcircRNA), exonic circRNAs (EcircRNA), and intergenic circRNAs with each group undergoing discrete biogenesis processes. (B) 6 circRNA functions identified to date. (1) Regulate gene expression through 3 discrete pathways (1a) compete with canonical splicing of linear counterpart (negative regulation); (1b) interact with polymerase II (Pol II) to promote transcription of parental gene (positive regulation); (1c) inhibit protein translation via sequestration of RBPs. (2) circRNAs have been shown to have dynamic protein interactions where they can function as transporters, scaffolding, decoys, and modulate protein activity. (3) Newer research has found some circRNAs can be translated into protein. (4) circRNAs may sponge miRNAs to allow translation of miRNA-repressed genes. (5) Through a process of reverse transcription and integration into host genomes, circRNAs can generate pseudogenes and thus physiological and pathological processes at the DNA, RNA, and protein levels; the mechanisms, and functions of circRNA derived pseudogenes is unknown. (6) circRNAs can also regulate epigenetic modifications via DNA and histone methylations.