Role of microRNA-212 in striatal plasticity underlying cocaine addiction
Funded Grant
Overview
Affiliation
View All
Overview
description
PROJECT SUMMARY/ABSTRACT Chronic cocaine exposure causes maladaptive neuroplasticity in brain reward circuitry that leads to compulsive drug use, loss of control over intake, and vulnerability to relapse, even after protracted abstinence. Initial drug reward is mediated by the nucleus accumbens in the ventral striatum, and early goal-‐directed drug intake is dependent on this structure. As drug use transitions from goal-‐directed to compulsive, there is a corresponding anatomical transition from dependence on the ventral striatum to dorsal striatum habit circuitry. MicroRNAs (miRNA) are small (~21-‐23 nucleotide) non-‐coding RNA sequences that regulate mRNA stability and translation by complementary binding to the 3’ UTR of the mRNA. Each miRNA can regulate the binding of hundreds or even thousands of mRNA. Our lab has previously identified that miR-‐212 regulates cocaine intake under extended access conditions, but not during restricted access. Specifically, overexpressing miR-‐212 in the dorsal striatum decreases cocaine intake during 6-‐hour self-‐administration sessions, whereas using a knocking down miR-‐212 in this region augments cocaine intake in rats. The precise cellular mechanism of action of miR-‐212 is not known. The dorsal striatum is primarily composed of medium spiny neurons (MSNs; 95% of cells), which can be further broken down by their receptor composition and anatomical projections. Dopamine D1 receptor (DRD1) expressing neurons form a direct pathway that innervates the substantia nigra (striatonigral pathway), and neurons expressing the D2 receptor and the adenosine A2A receptor (A2AR) project to the pallidum (striatopallidal pathway). These cell populations have opposite contributions to tasks involving movement, and more notably reward, such as cocaine conditioned place preference. This proposal seeks to examine the contributions of miR-‐212 specifically in each of these two cell populations in order to elucidate its mechanism of action in regulating cocaine seeking. To do this, in aim 1 I will use novel genetically modified mice to create conditional knockouts of miR-‐212 in either DRD1-‐expressing MSNs, or in A2AR-‐expressing MSNs. These mice will be tested under either restricted or extended access to cocaine, and the contribution of miR-‐212 during each of these phases will be assessed. In aim 2, I will use a novel high throughput screening following crosslinking immunoprecipitation (HITS-‐CLIP) technique to examine mRNA targets of miR-‐212 specifically in striatonigral vs striatopallidal neurons. Together, these aims will provide me with excellent training in mouse genetics and behavioral models, as well as advanced RNA biochemistry and large high throughput screening data sets, including bioinformatics analysis of such data sets.
