title: Mice selected for extremes in stress reactivity reveal key endophenotypes of major depression: a translational approach.
abstract: Clear evidence has linked dysregulated hypothalamus-pituitary-adrenocortical (HPA) axis function to the aetiology and pathophysiology of major depression (MD), as observed in the majority of patients. Increased stress reactivity and hyperactivity of the HPA axis seem characteristic for psychotic/melancholic depression, while the atypical subtype of depression has been connected with the opposing phenotypes. However, the underlying molecular-genetic mechanisms are poorly understood. In the present study, mouse lines selectively bred for extremes in stress reactivity (SR), i.e. presenting high (HR) or low (LR) corticosterone secretion in response to stressors, were used to characterise the molecular alterations on all levels of the HPA axis. Results were contrasted with clinical phenotypes of MD patients from the Munich Antidepressant Response Signature project, stratified according to their cortisol response in the Dex/CRH test. Distinct differences between HR and LR mice were found in the expression of HPA axis-related genes in the adrenals, pituitary and selected brain areas. Moreover, HR animals presented an enhanced adrenal sensitivity, increased stress-induced neuronal activation in the PVN and an overshooting Dex/CRH test response, whereas LR animals showed a blunted response in these paradigms. Interestingly, analogous neuroendocrine, morphometric, psychopathological and behavioural differences were observed between the respective high and low HPA axis responder groups of MD patients. Our findings suggests that (i) the SR mouse model can serve as a valuable tool to elucidate HPA axis-related mechanisms underlying affective disorders and (ii) a stratification of MD patients according to their HPA axis-related neuroendocrine function should be considered for clinical research and treatment.
authors.affiliation: Research Group of Psychoneuroendocrinology, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Jan-Michael
authors.initials: JM
authors.lastname: Heinzmann
authors.affiliation: Research Group of Psychiatric Pharmacogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kloiber
authors.affiliation: Research Group of Psychoneuroendocrinology, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ebling-Mattos
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ziemssenstr. 1, 80336 Munich, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Bielohuby
authors.affiliation: Research Group of Neurobiology of Stress, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
authors.affiliation: Department of Biomedical Sciences, Institute of Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Rupert
authors.initials: R
authors.lastname: Palme
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Research Group of Pharmacokinetics and Liquor Analysis, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: Research Group of Molecular Psychology, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: Research Group of Psychoneuroendocrinology, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany. Electronic address: touma@mpipsykl.mpg.de.
authors.forename: Chadi
authors.initials: C
authors.lastname: Touma
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism / Q000494:pharmacology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone; D003865:Major Depressive Disorder / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003907:Dexamethasone; D004195:Disease Models, Animal; D058068:Endophenotypes / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D010902:Pituitary Gland / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D057170:Translational Research, Biomedical
chemical_list: D000450:Aldosterone; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D006854:Hydrocortisone
keywords: Atypical depression; Dex/CRH test; HPA axis; Melancholic depression; Mouse model; Stress reactivity