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Brain-wide functional architecture remodeling by alcohol dependence and abstinence

Kimbrough, Adam and Lurie, Daniel J. and Collazo, Andres and Kreifeldt, Max and Sidhu, Harpreet and Macedo, Giovana Camila and D’Esposito, Mark and Contet, Candice and George, Olivier (2020) Brain-wide functional architecture remodeling by alcohol dependence and abstinence. Proceedings of the National Academy of Sciences of the United States of America, 117 (4). pp. 2149-2159. ISSN 0027-8424. PMCID PMC6994986. doi:10.1073/pnas.1909915117.

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Alcohol abuse and alcohol dependence are key factors in the development of alcohol use disorder, which is a pervasive societal problem with substantial economic, medical, and psychiatric consequences. Although our understanding of the neurocircuitry that underlies alcohol use has improved, novel brain regions that are involved in alcohol use and novel biomarkers of alcohol use need to be identified. The present study used a single-cell whole-brain imaging approach to 1) assess whether abstinence from alcohol in an animal model of alcohol dependence alters the functional architecture of brain activity and modularity, 2) validate our current knowledge of the neurocircuitry of alcohol abstinence, and 3) discover brain regions that may be involved in alcohol use. Alcohol abstinence resulted in the whole-brain reorganization of functional architecture in mice and a pronounced decrease in modularity that was not observed in nondependent moderate drinkers. Structuring of the alcohol abstinence network revealed three major brain modules: 1) extended amygdala module, 2) midbrain striatal module, and 3) cortico-hippocampo-thalamic module, reminiscent of the three-stage theory. Many hub brain regions that control this network were identified, including several that have been previously overlooked in alcohol research. These results identify brain targets for future research and demonstrate that alcohol use and dependence remodel brain-wide functional architecture to decrease modularity. Further studies are needed to determine whether the changes in coactivation and modularity that are associated with alcohol abstinence are causal features of alcohol dependence or a consequence of excessive drinking and alcohol exposure.

Item Type:Article
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URLURL TypeDescription Information CentralArticle
Kimbrough, Adam0000-0001-9434-4987
Macedo, Giovana Camila0000-0001-7443-3026
Additional Information:© 2020 National Academy of Sciences. Published under the PNAS license. Edited by Huda Akil, University of Michigan, Ann Arbor, MI, and approved December 16, 2019 (received for review June 10, 2019). PNAS first published January 14, 2020. We thank Dr. Nicolas Renier for technical guidance, Michael Arends for editorial assistance, and Lauren C. Smith for assistance with illustrations. Light-sheet imaging was performed at the California Institute of Technology Beckman Institute. This work was supported by the National Institutes of Health (Grants AA006420, AA026081, AA022977, AA026685, AA024198, NS79698, AA027301, and AA007456), the Pearson Center for Alcoholism and Addiction Research, and the Arnold and Mabel Beckman Foundation. Data Availability: Data will be made available upon request. Author contributions: A.K. and O.G. designed research; A.K., A.C., M.K., H.S., G.C.M., and C.C. performed research; D.J.L. and M.D. contributed new reagents/analytic tools; A.K., D.J.L., M.D., and C.C. analyzed data; and A.K. and O.G. wrote the paper. The authors declare no competing interest. This article is a PNAS Direct Submission. This article contains supporting information online at
Funding AgencyGrant Number
Pearson Center for Alcoholism and Addiction ResearchUNSPECIFIED
Arnold and Mabel Beckman FoundationUNSPECIFIED
Subject Keywords:iDISCO; network analysis; graph theory; Fos; dependence
Issue or Number:4
PubMed Central ID:PMC6994986
Record Number:CaltechAUTHORS:20200114-104948499
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Official Citation:Brain-wide functional architecture remodeling by alcohol dependence and abstinence. Adam Kimbrough, Daniel J. Lurie, Andres Collazo, Max Kreifeldt, Harpreet Sidhu, Giovana Camila Macedo, Mark D’Esposito, Candice Contet, Olivier George. Proceedings of the National Academy of Sciences Jan 2020, 117 (4) 2149-2159; DOI: 10.1073/pnas.1909915117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100716
Deposited By: Tony Diaz
Deposited On:14 Jan 2020 20:56
Last Modified:16 Nov 2021 17:56

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