We propose a series of translational studies using in vivo magnetic resonance (MR) neuroimaging and spectroscopy applied across rats and humans and monkeys by a collaboration between INIA-West and INIA-Stress. The goal is to identify and explicate changes in brain morphology, neurocircuitry, and metabolism during the development and maintenance of alcohol dependence. Exploratory studies will include correlation of in vivo MR data with postmortem histological analyses in collaboration with other INIA-West sites.
Specific Aim 1 : Rat Model of Dependence-Induced Drinking and Neuroadaptation. A primary INIA animal model of high alcohol consumption is withdrawal induced-drinking demonstrated with repeated high dose binge exposure, analogous to the chronic intermittent ethanol (CIE) paradigm. The progression of brain circuitry change over the course of repeated exposure-withdrawal cycles will be demonstrable with functional neuroimaging and a change in the pattern of choline and glutamate levels.
Specific Aim 2 : Rat-Monkey-Human Translation of High Doses of Chronic Alcohol: Brain Structure and Intrinsic Neural Connectivity. We propose parallel studies in chronic alcoholics and chronically-exposed animals using analogous neuroimaging probes: structural morphometry (MRI) and fcMRI from nodes pertinent to the maintenance of alcohol dependence-"withdrawal/negative affect" circuitry. We will use a longitudinal design, and a common analysis to be conducted across species: rat, monkey, and human.
Specific Aim 3 : Rat-Monkey-Human Translation of High Doses of Chronic Alcohol: Brain Metabolites. In vivo MR spectroscopy (MRS) studies report abnormally high choline soon after alcohol withdrawal in human alcoholics and rats chronically exposed to alcohol and in rats with single binge exposures. High glutamate occurs with high chronic alcohol exposure. As potential markers of dependence, we will model this pattern of metabolite changes in collaboration with INIA-Stress and propose parallel rat, monkey, and human studies using a common MRS acquisition and analysis tuned specifically to detect glutamate. The proposed research conceptually casts some alcoholic brain damage as a disorder of neuroconnectivity with structural and functional concomitants with bidirectional translation from humans to animal models and back to humans. We bring forth a paradigm shift from observing the brain's responsivity to external demands to investigating the brain's ongoing intrinsic activity as a concept for explicating the deleterious effects of chronic alcoholism on the brain.

Public Health Relevance

Neuroadaptation is the process by which continued consumption of alcohol, initially rewarding, is replaced by withdrawal/negative affect and ultimately dependence, a condition with serious public health consequences. Processes involved in the transition from reversible to sustained changes are unknown but our proposed work will translate findings from rats and monkeys to humans to enable a mechanistic understanding of the development of dependence.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-DD (50))
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Matochik, John A
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Sri International
Menlo Park
United States
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Kroenke, Christopher D; Rohlfing, Torsten; Park, Byung et al. (2014) Monkeys that voluntarily and chronically drink alcohol damage their brains: a longitudinal MRI study. Neuropsychopharmacology 39:823-30
Billingsley, Kelvin L; Josan, Sonal; Park, Jae Mo et al. (2014) Hyperpolarized [1,4-(13)C]-diethylsuccinate: a potential DNP substrate for in vivo metabolic imaging. NMR Biomed 27:356-62
Zahr, Natalie M; Alt, Carsten; Mayer, Dirk et al. (2014) Associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of Wernicke's encephalopathy. Exp Neurol 261:109-19
Billingsley, Kelvin L; Park, Jae Mo; Josan, Sonal et al. (2014) The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-(13)C]-ketoisocaproate. Magn Reson Imaging 32:791-5
Zahr, Natalie M; Mayer, Dirk; Rohlfing, Torsten et al. (2014) Rat strain differences in brain structure and neurochemistry in response to binge alcohol. Psychopharmacology (Berl) 231:429-45
Josan, Sonal; Hurd, Ralph; Park, Jae Mo et al. (2014) Dynamic metabolic imaging of hyperpolarized [2-(13) C]pyruvate using spiral chemical shift imaging with alternating spectral band excitation. Magn Reson Med 71:2051-8
Zahr, Natalie M; Mayer, Dirk; Rohlfing, Torsten et al. (2014) Imaging neuroinflammation? A perspective from MR spectroscopy. Brain Pathol 24:654-64
Josan, Sonal; Xu, Tao; Yen, Yi-Fen et al. (2013) In vivo measurement of aldehyde dehydrogenase-2 activity in rat liver ethanol model using dynamic MRSI of hyperpolarized [1-(13) C]pyruvate. NMR Biomed 26:607-12
Gu, Meng; Zahr, Natalie M; Spielman, Daniel M et al. (2013) Quantification of glutamate and glutamine using constant-time point-resolved spectroscopy at 3 T. NMR Biomed 26:164-72
Park, Jae Mo; Josan, Sonal; Grafendorfer, Thomas et al. (2013) Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-ýýýýC]pyruvate. NMR Biomed 26:1197-203

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