Suppression of binge alcohol drinking by an inhibitory neuronal ensemble in the mouse medial orbitofrontal cortex

Pablo Gimenez-Gomez^{1

2}, Timmy Le^{3

4

5}, Max Zinter^{4

5}, Peter M'Angale⁴, Violeta Duran-Laforet⁴, Timothy G Freels^{3

4}, Rebecca Pavchinskiy^{3

4

5}, Susanna Molas^{6

7}, Dorothy P Schafer⁴, Andrew R Tapper^{3

4}, Travis Thomson⁴, Gilles E Martin^{8

9}

Affiliations

¹ Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA. Pablo.gimenezgomez@umassmed.edu.
² Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA. Pablo.gimenezgomez@umassmed.edu.
³ Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁴ Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁵ Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁶ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
⁷ Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
⁸ Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA. gilles.martin@umassmed.edu.
⁹ Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA. gilles.martin@umassmed.edu.

PMID: 40495064
DOI: 10.1038/s41593-025-01970-x

Suppression of binge alcohol drinking by an inhibitory neuronal ensemble in the mouse medial orbitofrontal cortex

Pablo Gimenez-Gomez et al. Nat Neurosci. 2025 Aug.

. 2025 Aug;28(8):1741-1752.

doi: 10.1038/s41593-025-01970-x. Epub 2025 Jun 10.

Authors

Affiliations

¹ Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA. Pablo.gimenezgomez@umassmed.edu.
² Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA. Pablo.gimenezgomez@umassmed.edu.
³ Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁴ Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁵ Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁶ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
⁷ Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA.
⁸ Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA. gilles.martin@umassmed.edu.
⁹ Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA. gilles.martin@umassmed.edu.

PMID: 40495064
DOI: 10.1038/s41593-025-01970-x

Abstract

Alcohol consumption remains a significant global health challenge, directly and indirectly causing millions of deaths annually. Alcohol abuse causes dysregulated activity of the prefrontal cortex, yet effects on specific prefrontal circuits remain to be elucidated. Here, we identify a discrete GABAergic neuronal ensemble in the mouse medial orbitofrontal cortex (mOFC) that is selectively recruited in response to binge alcohol drinking and limits further drinking behavior. Optogenetic silencing of this population, or its ablation, results in uncontrolled binge alcohol consumption. This neuronal ensemble is specific to alcohol and is not recruited by other rewarding substances. Neurons in this ensemble project widely throughout the brain, but projections specifically to the mediodorsal thalamus regulate binge alcohol drinking. Together, these results identify a brain circuit in the mOFC that serves to protect against binge drinking by reducing alcohol intake, which may offer avenues for the development of mOFC neuronal ensemble-targeted interventions.

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Conflict of interest statement

Competing interests: All authors declare no competing interests.

References

1. World Health Organization. Global Status Report on Alcohol and Health 2018 (World Health Organization, 2019).
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Suppression of binge alcohol drinking by an inhibitory neuronal ensemble in the mouse medial orbitofrontal cortex

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Suppression of binge alcohol drinking by an inhibitory neuronal ensemble in the mouse medial orbitofrontal cortex

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