Dissertation

MicroRNAs and Cocaine Addiction: Role in Modulating Striatal TNF Signaling

Bali, Purva

2019

Overview

Addiction can be defined as compulsive drug use despite negative consequences. The negative health and economic consequence on society associated with cocaine abuse remains a key concern and currently there is no FDA-approved pharmacological intervention for the treatment of cocaine dependence. Chronic use of drugs of abuse like cocaine can perturb the reward pathways in the brain and cause changes in neuronal plasticity and function. MicroRNAs (miRNAs) are small noncoding RNA transcripts that regulate gene expression at the post-transcriptional level. Cocaine and other drugs of abuse modulate expression of miRNAs in addiction-relevant brain sites, including the striatum, which in turn influences their motivational properties by controlling expression of targeted genes. Previous studies from our group have shown that levels of miR-212, and the closely related miR-132, are increased in the striatum of rats with a history of extended access to intravenous cocaine self-administration that demonstrates compulsive-like consumption of the drug. Here we show that these cocaine-responsive miRNAs differentially modulate cocaine -associated behaviors. In our attempt to investigate the molecular signaling cascades impacted by these miRNAs to help us understand how they influence drug-taking behavior we found that they regulate TNF-α signaling, an important pathway recently shown to control cocaine-induced striatal neuroplasticity. Interestingly, even though miR-212 and miR-132 share common seed sequences and share a similar target profile, we found that miR-212 and miR-132 exert markedly different effects on TNF-α signaling through a mechanism that involves differential targeting of gene transcripts. Our data identifies one of these differentially targeted genes as CYLD (cylindromatosis), a key regulator of TNF-α signaling. CYLD is a K63 deubiquitinase that regulates non-proteolytic ubiquitin signaling, and is highly enriched in striatum. We find that miR-132 and miR-212 signaling play a critical role in regulating AMPA receptor signaling in primary striatal neurons, providing a potential mechanism by which miR-132 and miR-212 can differentially influence cocaine-induced plasticity. Finally, our in vivo studies suggest that this miR-212/132-TNF signaling axis in striatum could be important in regulating vulnerability to drug relapse.

• Publisher: ProQuest Dissertations & Theses
• Subject: Neurosciences
• ISBN: 043896358X, 9780438963580