In vivo profiling of glial and neuronal activities in psychostimulant abuse (PI: Christina H Liu, PhD) Drug addiction is a chronic brain disorder that severely hampers productivity of many members of our society. One of the most used drugs of abuse is amphetamine. Most neuroscience studies on amphetamine have focused on the morphological and molecular adaptations of neurons in response to chronic drug exposure. Electrophysiological data from cell cultures or brain slice preparations show that an important component of drug abuse is the interaction that occurs between glia and neurons during neuronal activations arising from repeat exposure to amphetamine. Although we know that glial cells are essential to the survival of neurons, providing critical support, nutrition, and toxin clearance to the neurons, our understanding of the role of glia in drug addiction is very limited. To overcome this limitation, we have developed a novel in vivo probe to visualize the changes in gene activities in neurons and glia, using magnetic resonance imaging (MRI) in live brains after exposure to amphetamine. We have demonstrated the utility of this method for discrimination of cells that express different but specific gene activities;i.e., neuronal-based elevation of cfos messenger RNA (mRNA) from glia-based GFAP mRNA. Because our detection technique does not require the use of postmortem samples, we are able to study the longitudinal profiles of different cerebral gene activities during and after exposure to drugs. Here, we aim to study gene activation during amphetamine sensitization in living C57Black6 mice, which involves repeated usage of, abstinence from, and re-exposure to the drug. We will utilize our novel technique that uses mRNA-targeted MR contrast probes to detect altered endogenous gene activities that result from amphetamine exposure in neurons and glia. The targets to be investigated in this project are mRNAs of glial fibrillary acidic protein (GFAP) and neuronal cFos protein. Our goals for this project are to use this novel MRI technique to enhance current understanding of the interactions between glial and neuronal cells at different stages of amphetamine exposure. We propose the following specific aims: (1) determine the optimal dosage and retention profiles of MRI probes in live brains;(2) determine the gene activity profiles of glial and neuronal cells in mouse brains in vivo after amphetamine, at different stages of exposure;and (3) explore the neuron-mediated glial response in the development of the amphetamine addiction phenotype.

Public Health Relevance

In this project, we will utilize a novel Magnetic Resonance Imaging (MRI) technique that we have developed to detect altered gene expression in neurons and glia of live animal affected by addictive drugs. The goals of this project are to enhance current understanding of the interaction between glial and neuronal cells at different stages of amphetamine exposure. Such enhancement will bring a step closer to real-time analysis of neurophysiologic events that occur in patients with substance abuse and addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZDA1-MXH-H (11))
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Wu, Da-Yu
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Massachusetts General Hospital
United States
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Liu, Christina H; Yang, Jinsheng; Ren, Jia Q et al. (2013) MRI reveals differential effects of amphetamine exposure on neuroglia in vivo. FASEB J 27:712-24
Liu, Christina H; Ren, Jia Q; You, Zerong et al. (2012) Noninvasive detection of neural progenitor cells in living brains by MRI. FASEB J 26:1652-62
Papagiannaros, Aristarchos; Righi, Valeria; Day, George G et al. (2012) Imaging C-Fos Gene Expression in Burns Using Lipid Coated Spion Nanoparticles. Adv J Mol Imaging 2:31-37
Kida, Kotaro; Minamishima, Shizuka; Wang, Huifang et al. (2012) Sodium sulfide prevents water diffusion abnormality in the brain and improves long term outcome after cardiac arrest in mice. Resuscitation 83:1292-7
Eikermann-Haerter, Katharina; Lee, Jeong Hyun; Yuzawa, Izumi et al. (2012) Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations. Circulation 125:335-45
Minamishima, Shizuka; Kida, Kotaro; Tokuda, Kentaro et al. (2011) Inhaled nitric oxide improves outcomes after successful cardiopulmonary resuscitation in mice. Circulation 124:1645-53
Liu, Philip K; Liu, Christina H (2011) Gene targeting MRI: nucleic acid-based imaging and applications. Methods Mol Biol 711:363-77
Liu, Christina H; You, Zerong; Liu, Charng-Ming et al. (2009) Diffusion-weighted magnetic resonance imaging reversal by gene knockdown of matrix metalloproteinase-9 activities in live animal brains. J Neurosci 29:3508-17
Liu, Christina H; Ren, Jia Q; Yang, Jinsheng et al. (2009) DNA-based MRI probes for specific detection of chronic exposure to amphetamine in living brains. J Neurosci 29:10663-70
Liu, Christina H; You, Zerong; Ren, JiaQian et al. (2008) Noninvasive delivery of gene targeting probes to live brains for transcription MRI. FASEB J 22:1193-203