Sex differences in insular cortex function in persistent alcohol drinking despite aversion in mice

1. Mol Psychiatry. 2026 Jun 26. doi: 10.1038/s41380-026-03716-y. Online ahead of print.

Sex differences in insular cortex function in persistent alcohol drinking
despite aversion in mice.

Fornari C(1)(2), Ricci D(1), Couderc Y(1), Guerrero-Márquez C(1), Namburi P(3),
Penet C(1), Nicolas C(#)(4)(5), Beyeler A(#)(6).

Author information:
(1)University of Bordeaux, INSERM 1215, Neurocentre Magendie, 146 rue Léo
Saignat, 33000, Bordeaux, France.
(2)University of Bordeaux, CNRS UMR 5287, Institut de Neurosciences Cognitives
et Intégratives d’Aquitaine, 2 rue Dr Hoffmann Martinot, 33000, Bordeaux,
France.
(3)Institute for Medical Engineering & Science, Massachusetts Institute of
Technology, 77 Massachusetts Ave, Cambridge, MA, 02139, USA.
(4)University of Bordeaux, INSERM 1215, Neurocentre Magendie, 146 rue Léo
Saignat, 33000, Bordeaux, France. .
(5)University of Bordeaux, CNRS UMR 5287, Institut de Neurosciences Cognitives
et Intégratives d’Aquitaine, 2 rue Dr Hoffmann Martinot, 33000, Bordeaux,
France. .
(6)University of Bordeaux, INSERM 1215, Neurocentre Magendie, 146 rue Léo
Saignat, 33000, Bordeaux, France. .
(#)Contributed equally

One major hallmark of alcohol use disorder (AUD) is the persistence of drinking
despite negative consequences. Among indicators of AUD vulnerability, binge
drinking has been identified as one of the strongest risk factors. Although the
lifetime prevalence of both binge drinking and AUD has historically been higher
in men than women, this gap has dramatically narrowed in the last decade.
Additionally, sex differences in AUD and binge drinking have been found in
clinical and preclinical studies. At the neurobiological level, the insular
cortex plays an important role in AUD, with the anterior (aIC) and posterior
(pIC) divisions supporting different functions. However, the contributions of
the aIC and pIC sections in sexual dimorphism of alcohol binge drinking and the
persistence of alcohol drinking despite aversion remain to be uncovered. Using
the drinking in the dark model in mice, we validated that female mice have a
higher binge ethanol intake compared to males. To evaluate persistent ethanol
consumption despite aversion, we supplemented ethanol with the bitter compound
quinine, and found a higher persistent drinking in females compared to males.
Using fiber photometry recordings, we revealed that aIC activity was increased
during binge and persistent ethanol consumption independently of sex, whereas
pIC glutamatergic neuron activity was higher during persistent ethanol drinking,
specifically in female mice. Using chemogenetics, we revealed that inhibition of
aIC glutamatergic neurons reduced intake of bitter solutions independently of
the solvent (ethanol or water) in both sexes. In addition, inhibition of pIC
glutamatergic neurons exclusively reduced persistent ethanol drinking in
females, while decreasing quinine consumption only in males. These findings
suggest a sex-dependent function of the pIC in the persistence of ethanol
consumption, providing a starting point in understanding sex-specific functions
of the insular cortex in the neurobiology of AUD.

© 2026. The Author(s).

DOI: 10.1038/s41380-026-03716-y
PMID: 42362767

Conflict of interest statement: Competing interests: The authors declare that
they do not have any competing interests or conflicts of interest (financial or
non-financial) related to the material presented in this manuscript. Ethics
approval: Animal maintenance, treatments and experimental procedures were
conducted according to French governmental regulations, and approved by the
ethical committee and the Ministry of Education, Research and Innovation
(Saisines #22122, #53819) in accordance with the guidelines of the European
Communities Council Directives.

Auteurs Bordeaux Neurocampus