Thesis supervisor: Marie-Pierre Moisan

Sophie Layé Lab: NutriNeurO

Team of Marie-Pierre Moisan and Guillaume Ferreira : Nutrition, memory and glucocorticoïds

Members of the jury:

Dr Beracochea Daniel, Université de Bordeaux, Président

Pr Roozendaal Benno, Professeur, Radboud University, the Netherlands, Rapporteur

Pr Ruiz-Gayo Mariano, Professeur, Universidad CEU San Pablo, Spain, Rapporteur

Dr Castanon Nathalie, Chargée de recherche, Université de Bordeaux, Examinateur

Dr Moisan Marie-Pierre, Directrice de recherche, INRA Bordeaux, Directrice de thèse

Abstract

 The great diversity in the response to stress observed among individuals originates from their genetic background in interaction with environmental factors. Some responses can be less adaptive and increase the vulnerability to develop stress-associated disorders. CBG is a plasma glycoprotein that regulates the bioavailability of glucocorticoids, one of the main mediators of the stress response. Genetic studies pointed out variations in the gene coding for CBG as a major factor influencing the glucocorticoid response to stress. To better understand the mechanisms involved and the consequences on endocrine and behavioral responses to stress, our team has developed a mouse model of CBG deficiency. These mice present blunted glucocorticoid response to stress associated with increased despair-like behaviors. This thesis aimed at further exploring the physiological and behavioral alterations presented by the Cbg ko mice. We showed that the lower glucocorticoid levels observed in Cbg ko mice stems from their higher clearance from plasma. A study performed on Cbg ko female mice revealed that estrogens outpass CBG deficiency in inducing despair-like behavior. Additionally, we evidenced that CBG deficiency leads to lower behavioral and endocrine sensitivity to chronic stress, and we observed impairment of hippocampal-dependent long-term memory in these mice. Finally, we found that chronic stress combined to high-fat diet leads to alteration in glucose metabolism in CBG deficient animals. These findings reinforce the important role of CBG influencing the broad range of actions of glucocorticoids by modulating their levels and availability.

Keywords : transcortin, CBG, HPA axis, glucocorticoids, stress, memory consolidation, emotional behavior, western lifestyle.