C 3/3: Translational Neuroimaging Core

Christopher Kroenke

PROJECT SUMMARY
Non-invasive neuroimaging procedures have provided instrumental insights into our understanding of how chronic exposure to ethanol can affect brain structure and function. Through comparisons of brain macroscopic structure in alcoholics and age-matched controls, it has been possible to detect changes in brain tissue volume, and its recovery following abstinence from alcohol. Diffusion tensor imaging (DTI) experiments have provided information on cellular-level changes in white matter microstructure that result from chronic exposure to ethanol, often prior to the appearance of macroscopic changes. In addition to these structural changes, it has also been possible to characterize physiological changes associated with brain function in functional MRI experiments. However, in all of these neuroimaging approaches, consistent systematic confounding factors plague the biological interpretations of findings. First, it is not possible to accurately quantify ethanol exposure, beginning at the initiation of drinking, in human subjects. Second, confounding factors such as polydrug use, nutrition, frequency of withdrawals, and other environmental insults are difficult to discern from the effects of ethanol exposure on brain structure and function. Third, the interpretation of functional neuroimaging experiments can be difficult to cast in terms of neural function, e.g., as measured using traditional neurophysiological methods. In order to address these deficits in knowledge, we propose a Translational Neuroimaging Core to perform MRI experiments on nonhuman primate research subjects at the Oregon National Primate Research Center's nonhuman-primate-dedicated MRI facility. These experiments have been designed to directly support projects in the INIA-S as well as the INIA-N consortia. Aim 1 is to provide data to buttress INIA-S project 8, in which glucocorticoid antagonists will be administered to nonhuman primate research subjects, and the resting-state functional MRI changes associated with the resulting changes in drinking patterns will be determined. Aim 2 is to support an INIA-N project proposed by A. Pfefferbaum, E. Sullivan, and N. Zahr, in which brain structural and functional changes associated with repeated episodes of abstinence and drinking will be determined in rhesus macaques to bridge data acquired in rodent and human species. Aim 3 is to support INIA-S project 7, to use functional MRI to directly monitor changes in brain circuitry induced through the influence of designer receptors exclusively activated by designer drugs (DREADDs) in the striatum, and to characterize the effects of DREADDs-induced neural activity changes on functional connectivity measurements. Last, in a subset of control animals, quantitative comparisons will be performed between MRI-determined functional connectivity and connectivity assessed with focal infrared neural stimulation of regions known to be sensitive to previous exposure to ethanol, with the goal of assessing the validity of common interpretations of resting-state fMRI experiments.