2005/06/29 by Stephanie Ridder, Sabine Chourbaji, Rainer Hellweg +9 · 378 citations
Neuroscience · Medicine · Psychology · #Stress Responses and Cortisol #Hormonal Regulation and Hypertension #Neuroendocrine regulation and behavior #Learned helplessness #Glucocorticoid receptor #Endocrinology #Internal medicine #Pathogenesis #Context (archaeology) #Glucocorticoid #Corticotropin-releasing hormone #Receptor #Biology #Psychology #Hormone #Medicine #Developmental psychology
paper · pdf · doi:10.1523/jneurosci.0736-05.2005
published in Journal of Neuroscience 25(26), 6243-6250 (Society for Neuroscience)
openalex publication_date 2005/06/29 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/- mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/- mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression.