Laetitia Degiorgis1, Tanzil Mahmud Arefin2, Sami Ben-Hamida3, Vincent Noblet4, Cristina Antal5, Thomas Bienert6, Marco Reisert6, Dominik von Elverfeldt6, Brigitte L Kieffer7, Laura-Adela Harsan8. 1. Integrative Multimodal Imaging in Healthcare team, UMR 7357, Laboratory of Engineering, Informatics and Imaging (ICube); Department of Psychiatry, University of Strasbourg, Strasbourg, France. 2. Department of Radiology, Medical Physics, University Medical Center Freiburg, Faculty of Medicine, University Freiburg, Freiburg, Germany; Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, New York. 3. INSERM U1114, University Hospital of Strasbourg, Strasbourg, France; INSERM U1247, research group on alcohol and pharmacodependance (GRAP), University of Picardie Jules-Verne, Amiens, France. 4. Images, Learning, Geometry and Statistics team, UMR 7357, Laboratory of Engineering, Informatics and Imaging (ICube); Department of Psychiatry, University of Strasbourg, Strasbourg, France. 5. Integrative Multimodal Imaging in Healthcare team, UMR 7357, Laboratory of Engineering, Informatics and Imaging (ICube); Department of Psychiatry, University of Strasbourg, Strasbourg, France; Faculty of Medicine, Histology Institute and Unité Fonctionnelle de Foetopathologie, University Hospital of Strasbourg, Strasbourg, France. 6. Department of Radiology, Medical Physics, University Medical Center Freiburg, Faculty of Medicine, University Freiburg, Freiburg, Germany. 7. INSERM U1114, University Hospital of Strasbourg, Strasbourg, France. 8. Integrative Multimodal Imaging in Healthcare team, UMR 7357, Laboratory of Engineering, Informatics and Imaging (ICube); Department of Psychiatry, University of Strasbourg, Strasbourg, France; Department of Biophysics and Nuclear Medicine, University Hospital of Strasbourg, Strasbourg, France. Electronic address: harsan@unistra.fr.
Abstract
BACKGROUND: Alcohol acts as an addictive substance that may lead to alcohol use disorder. In humans, magnetic resonance imaging showed diverse structural and functional brain alterations associated with this complex pathology. Single magnetic resonance imaging modalities are used mostly but are insufficient to portray and understand the broad neuroadaptations to alcohol. Here, we combined structural and functional magnetic resonance imaging and connectome mapping in mice to establish brain-wide fingerprints of alcohol effects with translatable potential. METHODS: Mice underwent a chronic intermittent alcohol drinking protocol for 6 weeks before being imaged under medetomidine anesthesia. We performed open-ended multivariate analysis of structural data and functional connectivity mapping on the same subjects. RESULTS: Structural analysis showed alcohol effects for the prefrontal cortex/anterior insula, hippocampus, and somatosensory cortex. Integration with microglia histology revealed distinct alcohol signatures, suggestive of advanced (prefrontal cortex/anterior insula, somatosensory cortex) and early (hippocampus) inflammation. Functional analysis showed major alterations of insula, ventral tegmental area, and retrosplenial cortex connectivity, impacting communication patterns for salience (insula), reward (ventral tegmental area), and default mode (retrosplenial cortex) networks. The insula appeared as a most sensitive brain center across structural and functional analyses. CONCLUSIONS: This study demonstrates alcohol effects in mice, which possibly underlie lower top-down control and impaired hedonic balance documented at the behavioral level, and aligns with neuroimaging findings in humans despite the potential limitation induced by medetomidine sedation. This study paves the way to identify further biomarkers and to probe neurobiological mechanisms of alcohol effects using genetic and pharmacological manipulations in mouse models of alcohol drinking and dependence.
BACKGROUND: Alcohol acts as an addictive substance that may lead to alcohol use disorder. In humans, magnetic resonance imaging showed diverse structural and functional brain alterations associated with this complex pathology. Single magnetic resonance imaging modalities are used mostly but are insufficient to portray and understand the broad neuroadaptations to alcohol. Here, we combined structural and functional magnetic resonance imaging and connectome mapping in mice to establish brain-wide fingerprints of alcohol effects with translatable potential. METHODS: Mice underwent a chronic intermittent alcohol drinking protocol for 6 weeks before being imaged under medetomidine anesthesia. We performed open-ended multivariate analysis of structural data and functional connectivity mapping on the same subjects. RESULTS: Structural analysis showed alcohol effects for the prefrontal cortex/anterior insula, hippocampus, and somatosensory cortex. Integration with microglia histology revealed distinct alcohol signatures, suggestive of advanced (prefrontal cortex/anterior insula, somatosensory cortex) and early (hippocampus) inflammation. Functional analysis showed major alterations of insula, ventral tegmental area, and retrosplenial cortex connectivity, impacting communication patterns for salience (insula), reward (ventral tegmental area), and default mode (retrosplenial cortex) networks. The insula appeared as a most sensitive brain center across structural and functional analyses. CONCLUSIONS: This study demonstrates alcohol effects in mice, which possibly underlie lower top-down control and impaired hedonic balance documented at the behavioral level, and aligns with neuroimaging findings in humans despite the potential limitation induced by medetomidine sedation. This study paves the way to identify further biomarkers and to probe neurobiological mechanisms of alcohol effects using genetic and pharmacological manipulations in mouse models of alcohol drinking and dependence.