MiR-137 gain of function in the dorsomedial striatum promotes continued cocaine-taking despite punishment in rats

Drug addiction is a major public health issue that is characterised by continued drug use despite negative consequences. However, the molecular and cellular mechanisms that underlie this behaviour are not well understood. In this study we investigated the role of miR-137, a microRNA that has been previously shown to control the expression of genes necessary for neuronal development and synapse maturation, with common variants in the MIR137 gene linked to a higher risk of schizophrenia. Previously, we revealed that miR-137 expression in cocaine-trained animals exhibited spatial and temporal variability in the dorsal striatum (DS). Building upon this observation, we hypothesised that augmenting miR-137 function in the DS would impact drug-seeking behavior under punishment conditions by modulating molecular targets involved in synaptic plasticity. Male Sprague-Dawley rats were trained to self-administer cocaine and then randomly assigned to receive either lentiviral-mediated overexpression of hsa-miR-137 (miR-137OE) or an empty pCDH-vector (pCDH-EV) control in the dorsomedial striatum (DMS). Once stable cocaine self-administration was achieved, drug-taking was assessed under conditions in which lever presses were associated with a 0.25 probability of foot shock (0.5 mA). During five days of testing, pCDH-EV control animals showed a significant reduction in responding for cocaine, whereas miR-137OE animals displayed greater resistance to the suppression of cocaine responding across foot shock sessions compared to controls. RNA-sequencing analysis of striatal tissue from miR-137OE animals revealed significant enrichment of genes involved in synaptic plasticity and astrocyte signalling compared to control animals. Taken together, these findings provide insight into the mechanisms underlying addiction risk and and contribute to a better understanding of the neural substrates involved in these disorders. Overall design: mRNA sequencing of the rat dorsomedial striatum after lentiviral transduction with pre-miR-137 or pCDH empty vector constructs.