ED Sciences de la Vie et de la Santé
Neurobiological and hormonal mechanisms of sex differences in alcohol intake and cocaine relapse in rodents.
by Claudia FORNARI (Institut de neurosciences cognitives et intégratives d'Aquitaine)
The defense will take place at 14h30 - Amphithéâtre bâtiment Bordeaux Biologie Santé Bâtiment Bordeaux Biologie Santé 2 rue Dr Hoffmann Martinot 33000 Bordeaux France
in front of the jury composed of
- Céline NICOLAS - Chargé de recherche - Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA) - Directeur de these
- Anne-Noël SAMAHA - Professeur - Université de Montréal - Rapporteur
- Liana FATTORE - Professeur - Istituto di Neuroscienze - Rapporteur
- François GEORGES - Professeur - Institut des Maladies Neurodégénératives (IMN) - Examinateur
- Fuschia SERRE - Ingénieur de recherche - Laboratoire SANPSY - Examinateur
- Stéphanie DAUMAS - Professeur - Institut de Biologie Paris Seine (IBPS) - Examinateur
Addiction is characterized by persistent drug use despite negative consequences and a high risk of relapse, two major obstacles to its treatment. Clinical and preclinical studies reveal sex differences in alcohol consumption and cocaine relapse, however, the underlying neurobiological mechanisms remain to be understood. In the last decade, alcohol use disorders (AUDs) prevalence increased in both sexes, but more dramatically in women, highlighting the importance of studying sex-specific mechanisms. Thus, the first aim of my thesis was to study the sexually dimorphic functions of the insular cortex in persistent alcohol intake despite aversion. We showed a higher persistent ethanol intake in females compared to males. Fiber photometry recordings revealed that anterior insula (aIC) activity increased during persistent ethanol intake independently of sex, and the chemogenetic inhibition of the same neuronal population reduced persistent drinking regardless of sex. In contrast, during persistent ethanol intake, posterior insula (pIC) activity was higher in females compared to males, and inhibition of this neuronal population reduced persistent ethanol intake only in females. Altogether, our results show an antero-posterior and sex -dependent function of the insula in persistent ethanol drinking in mice. In the context of cocaine relapse, sex differences have been shown to depend on the hormonal cycle, and progesterone is identified as a potential protective factor. The second axis of my PhD deciphered the behavioral and neurobiological mechanisms underlying progesterone's effect on cocaine relapse. We demonstrated that females with low progesterone levels have a greater level of relapse than those with high levels, confirming a protective role of this hormone. Additionally, acute progesterone injection protected vulnerable females from relapse by reducing the number of neurons expressing the activity marker c-fos in the pIC and the central amygdala (CeA). Finally, relapse levels positively correlate with c-fos+ neurons in the pIC and CeA, and progesterone abolished this correlation. Our results provide a basis for understanding neuronal mechanisms of progesterone-dependent relapse vulnerability.