The Role of miRNAs in Neuronal Cell Survival and Function

Paul Greengard, Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University

Understanding of the molecular mechanisms of drug addiction is essential for the development of novel approaches for the treatment of this debilitating disease. Recent findings showed that development of addictive behavior in mice is associated with stable changes in gene and protein expression. We found that establishment of cocaine addiction in mice is associated with expression changes of numerous miRNAs in the striatum, a brain area responsible for drug addiction. Given the potent role of miRNAs in regulation of protein expression, we hypothesize that cocaine-regulated miRNAs contribute to the establishment of the protein expression network that supports addiction. To evaluate the contribution of cocaine induced miRNAs to the development and maintenance of cocaine addiction we propose to address the impact of striatum specific alteration of individual miRNAs on addiction. We will test whether correction of miRNA levels affected by chronic cocaine treatment affects the development of addictive behavior in vivo. Additionally, we will attempt to identify the striatal targets of individual miRNAs using a proteomic approach. Inactivation of miRNA that are induced by cocaine treatment will be achieved by injection of the RNA based cell-permeable specific miRNA inhibitors into the striatum. In turn, striatum specific normalization of miRNA that are suppressed by cocaine will be achieved by using miRNA expressing adeno-associated virus (AAV). Identification of specific miRNAs and their targets that play a role in the development and maintenance of cocaine addiction may help to reveal the molecular networks controlling dopamine signaling in health and disease. Furthermore, targeting of the addiction-associated miRNAs by synthetic miRNA antagonists may lead to development of novel and highly specific approaches for treatment of addiction.