Abstract
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 ΔGR. ΔGR 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 ΔGR in specific brain areas. We focused our study on a mouse line that expressed ΔGR almost selectively in the glutamatergic neurons of the dentate gyrus (DG) of the hippocampus. This restricted expression of the ΔGR 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.
Highlights
Glucocorticoid hormones (GC) are the end product of the activation of the hypothalamus-pituitary-adrenal (HPA) axis
We used a bidirectional construct allowing the co-expression of the Enhanced Green Fluorescent Protein (EGFP) and DGR under the control of Tetracycline Response Elements (TRE), which can be activated by the tTA protein in the absence of tetracycline’s analogue doxycycline (Dox) [8,12] (Figure 1B)
The transgenic mice integrating this bidirectional construct (Tet-DGR/EGFP) were crossed with regulatory mice in which the tTA transgene was controlled by the Eno2 (Neuron Specific Enolase: Neuron-Specific Enolase (NSE)) promoter [12,13] (Figure 1C)
Summary
Glucocorticoid hormones (GC) are the end product of the activation of the hypothalamus-pituitary-adrenal (HPA) axis. The secretion of these hormones increases during the active phase of the circadian cycle and in response to stress [1,2]. Glucocorticoids through their action on the brain have large effects on adaptive behaviors and are involved in the pathophysiology of several stress-related disorders such as drug abuse, depression and anxiety [2,3,4,5,5,6,7,8,9]. Molecular mechanisms of glucocorticoid-mediated pathologies can only be understood once the specific cellular targets of these hormones have been identified
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