Transcriptional effects of glucocorticoid receptors in the dentate gyrus increase anxiety-related behaviors.
The Glucocorticoid Receptor (GR) is a transcription factor ubiquitously expressed in the brain. Activation of brain GRs by high levels of glucocorticoid (GC) hormones modifies a large variety of physiological and pathological-related behaviors. Unfortunately the specific cellular targets of GR-mediated behavioral effects of GC are still largely unknown. To address this issue, we generated a mutated form of the GR called DeltaGR. DeltaGR is a constitutively transcriptionally active form of the GR that is localized in the nuclei and activates transcription without binding to glucocorticoids. Using the tetracycline-regulated system (Tet-OFF), we developed an inducible transgenic approach that allows the expression of the DeltaGR in specific brain areas. We focused our study on a mouse line that expressed DeltaGR almost selectively in the glutamatergic neurons of the dentate gyrus (DG) of the hippocampus. This restricted expression of the DeltaGR increased anxiety-related behaviors without affecting other behaviors that could indirectly influence performance in anxiety-related tests. This behavioral phenotype was also associated with an up-regulation of the MAPK signaling pathway and Egr-1 protein in the DG. These findings identify glutamatergic neurons in the DG as one of the cellular substrate of stress-related pathologies.
Sarrazin
Nadège
N
Pathophysiology of Addiction group, Neurocenter Magendie, INSERM U862, Bordeaux, France.
Di Blasi
Francesco
F
Roullot-Lacarrière
Valérie
V
Rougé-Pont
Françoise
F
Le Roux
Anne
A
Costet
Pierre
P
Revest
Jean-Michel
JM
Piazza
Pier Vincenzo
PV
D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014158:Transcription, Genetic
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D011965:Receptors, Glucocorticoid