MR Assessment of Altered Cerebral Gene Expression after Amphetamine Exposure

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DESCRIPTION (provided by applicant): This proposed project aims to validate and refine a novel MRI technique that uses targeting MR contrast probes to detect altered endogenous gene expression resulting from amphetamine exposure in living animals. We will use an animal model of addiction in C57Black6 mice. The targets to be investigated in this project are mRNA of a transcription factor fosB and the activator protein 1 (AP-1) whose altered expression is strongly implicated in drug addiction. Most current molecular imaging methods detect cell surface proteins as markers of gene expression. Our proposed technique detects intracellular products of gene expression, such as mRNA and its products that may have DNA binding ability in the brains of living mice. This method uses DNA with antisense sequence to the target mRNA or DNA with consensus sequence for AP-1 binding. In preliminary studies, we labeled these DNA with MR contrast agent and showed in a proof-of-concept study that the probe is capable of reporting elevation of c-fos mRNA live animals using MRI after acute amphetamine injection. Our goals are to extend and improve the sensitivity of this technique and establish the correlate between MR signal and histological assessment of intracellular targets. By achieving these goals, we will be able to apply this novel MR technique as a quantitative tool for the detection of endogenous gene expression of other genes such as cyclic AMP responsive elements (CREB) and a host of other products of gene expression that are implicated in drug addiction.Project Narrative: In this project, we will extend and refine a novel Magnetic Resonance Imaging (MRI) technique that we have developed to detect altered gene expression in the brains of live animal affected by addictive drugs. The goal of this project is to make this technique a quantitative tool to measure endogenous gene expression in the brains. Such enhancement will bring a step closer to real-time analysis of neurophysiologic events that occur in patients with substance abuse and addiction.