We have previously shown that the consumption of an obesogenic diet during the adolescence period induces memory alterations in adulthood, in particular hippocampus-dependent memory tasks. Because glucocorticoid hormones (GC) regulate memory processes and their receptors (glucocorticoid receptor=GR and mineralocorticoid receptor) are highly expressed in hippocampus, we have examined the potential role of GC in the memory alterations observed in adolescent mice fed a high fat-high sucrose diet (HFD) for 12 weeks compared to age-matched mice fed normal chow. In basal conditions, the circadian secretion of corticosterone was not different between groups after 12 weeks of either diet. However, HFD abolished the circadian oscillatory expression of the GR mRNA in hippocampus. Interestingly, this alteration of circadian gene expression is rescued if the mice under HFD have their food temporally restricted to the active phase for the last 4 weeks of HFD. Hippocampal GR protein and its phosphorylation at serine 211 and Serine 284 was then studied in basal condition and during memory consolidation. Phosphorylation of GR increased both in basal conditions and after contextual fear conditioning, especially at Serine 284 in HFD mice compared to controls. We also studied hippocampal neuronal spine dynamics in wild-type animals and in a mouse knock-in harboring mutation in the Serine 284 phosphorylation site of GR. Wild-type mice under HFD as well as the KI mouse mutant display decreased spine formation and enhanced spine elimination after contextual fear conditioning compared to their respective controls. Finally, to investigate the functional role of hippocampal GR in obesity-induced memory alterations, we infused within the dorsal hippocampus the GR antagonist RU38486 in HFD mice and controls immediately after training of an object recognition memory task, known to be impaired by HFD. Blockade of the GR specifically within hippocampus prevented the long-term memory alterations in HFD fed mice. Overall, these data point to an important role of GR signaling in the memory alterations observed in mice fed HFD during adolescence.This project is supported by Fondation Carrefour and the scientific expertise ensured by the scientific committee of Fédération de Recherche sur le Cerveau.Read less <