Venue: BBS
Claudia Fornari
équipe :Addiction, Intéroception et dimorphisme sexuel (NEED)
Céline Nicolas INCIA
Title
Neurobiological and Hormonal Mechanisms of Sex Differences in Alcohol Consumption and Cocaine Relapse in rodents
Abstract
Addiction is characterized by persistent drug use despite negative consequences and a high risk of relapse, two major obstacles to its treatment. Both clinical and preclinical research have consistently reported sex differences in alcohol consumption and cocaine relapse. However, the neurobiological mechanisms driving these differences are still poorly understood.
Over the past decade, the prevalence of alcohol use disorders increased in both men and women, but more dramatically among women, emphasizing the need to investigate sex-specific neural mechanisms underlying alcohol addiction. In this context, the first objective of my thesis was to elucidate sex differences in antero-posterior insular cortex function during persistent alcohol consumption despite aversion in mice. At the behavioral level, we revealed that females had a higher persistent ethanol intake compared to males, and this effect was independent of the hormonal cycle. At the neuronal level, using fiber photometry recordings, we showed that glutamatergic neurons of the anterior insular cortex (or insula) increased their activity during persistent ethanol intake independently of sex. Furthermore, chemogenetic inhibition of anterior insula neurons significantly reduced persistent ethanol intake in both males and females. In contrast, activity of posterior insula excitatory neurons was increased during persistent ethanol drinking exclusively in females, and inhibition of this neuronal population selectively reduced persistent ethanol intake in females. Together, our findings reveal an antero-posterior and sex-dependent insular function in the regulation of persistent ethanol drinking in mice.
In the context of cocaine relapse, previous studies suggested that relapse vulnerability fluctuates across the female hormonal cycle, especially in the context of cue-induced cocaine relapse. In this context, progesterone has emerged as a potential protective factor. Thus, the second axis of my PhD deciphered the behavioral and neurobiological mechanisms underlying progesterone’s effect on cue-induced cocaine relapse in female rats. We demonstrated that females with low endogenous progesterone levels have a greater level of relapse than those with high levels, indicating a protective role of this hormone. Moreover, acute progesterone treatment markedly reduced relapse in vulnerable females. By quantifying the neuronal activity marker cFos in several brain regions involved in drug relapse, we highlighted that progesterone treatment in vulnerable females, decreased the neuronal activation of the posterior insula and the central amygdala, demonstrating that they could be key neuronal target of progesterone’s protective effect. Finally, relapse levels positively correlate with the number of cFos-positive neurons in the posterior insula and the central amygdala, and progesterone abolished this correlation. Collectively, our results provide a solid foundation for understanding the neuronal basis underlying progesterone protective effects on relapse vulnerability in females.
Keywords: Drug addiction, Sex differences, Hormonal cycle
Publication
Claudia Fornari, Carmen Guerrero-Márquez, Praneeth Namburi, Yoni Couderc, Céline Nicolas* and Anna Beyeler*. Sexual dimorphism of posterior insular cortex function in alcohol drinking despite aversion in mice. BioRxiv 2023 and under revision.
Jury
- Stéphanie DAUMAS – Professeure – CNRS, Sorbonne Université, France – Présidente
- Liana FATTORE – Senior research scientist – Istituto di Neuroscienze, Italie – Rapportrice
- Anne-Noël SAMAHA Professeure – Université de Montréal, Canada – Rapportrice
- François GEORGES – Directeur de recherche – CNRS, Université de Bordeaux, France – Examinateur
- Fuschia SERRE – Chercheure – Université de Bordeaux, France – Examinatrice
- Céline NICOLAS – Chargée de recherche – CNRS, Université de Bordeaux, France – Directrice de thèse
- Anna BEYELER – Invitée