title: Blunted HPA axis reactivity reveals glucocorticoid system dysbalance in a mouse model of high anxiety-related behavior.
abstract: Depression and anxiety disorders are often characterized by altered hypothalamic-pituitary-adrenal (HPA) axis re-/activity. However, the presence of a molecular link between dysbalanced neuroendocrine regulation and psychopathologies is not yet fully established. Earlier, we reported that high (HAB), normal (NAB) and low (LAB) anxiety-related behavior mice express divergent anxiety-related and passive/active coping phenotypes. Here, we studied mechanisms that might contribute to the different HPA axis reactivity observed in HAB, NAB and LAB mice and their involvement in the regulation of anxiety-related behavior and passive/active coping style. We found that HAB mice respond with significantly reduced corticosterone (CORT) secretion to an acute stressful stimulus and a blunted response in the Dex/CRH test compared to NAB and LAB mice. At the molecular level, higher expression of the glucocorticoid receptor (GR/Nr3c1) and decreased corticotropin-releasing hormone receptor 1 (CRHR1) expression were observed in the pituitary of HAB mice. We further analyzed whether these stress mediators differed between the HAB, NAB and LAB lines in limbic system-associated brain regions and whether their interplay contributes to the phenotype. Interestingly, not only in the pituitary but also in almost all brain regions investigated, GR expression was significantly higher in HAB mice. In contrast, the amount of CORT in the brain structures analyzed was significantly lower in these animals. The expression of CRHR1 varied in the prefrontal cortex only. Since glucocorticoids regulate both GR and CRHR1, we treated HAB and NAB mice chronically with CORT. After 6 weeks of administration, reduced anxiety- and depression-like behaviors were observed in HAB mice, whereas increased anxiety was found in NABs. In both groups, GR, but not CRHR1, were significantly reduced. Taken together, our study proposes HAB mice as an animal model of simultaneous features of increased anxiety-related and depression-like behaviors with blunted HPA axis reactivity suggesting a dysregulated GR/CORT system as one key mechanism behind their phenotype.
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany; Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia. Electronic address: sotnikov_sv@list.ru.
authors.forename: Sergey
authors.initials: S
authors.lastname: Sotnikov
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Wittmann
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Bunck
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany; Clinical Cooperation Group Molecular Neurogenetics, Institute of Developmental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Deussing
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Chadi
authors.initials: C
authors.lastname: Touma
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Landgraf
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Czibere
mesh_terms: D000818:Animals; D001008:Anxiety Disorders / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003348:Cortisone / Q000378:metabolism; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009490:Neurosecretory Systems / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000378:metabolism* / Q000503:physiopathology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D000099052:CRF Receptor, Type 1
chemical_list: D005938:Glucocorticoids; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D003348:Cortisone
keywords: Anxiety; CRHR1; Corticosterone; Depression; Dex/CRH; GR; HAB; HPA axis; Nr3c1; Stress