title: Genetic predisposition for high stress reactivity amplifies effects of early-life adversity.
abstract: A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) axis and the experience of early-life adversity are both well-established risk factors for the development of affective disorders, such as major depression. However, little is known about the interaction of these two factors in shaping endophenotypes of the disease. Here, we studied the gene-environment interaction of a genetic predisposition for HPA axis dysregulation with early-life stress (ELS), assessing the short-, as well as the long-lasting consequences on emotional behavior, neuroendocrine functions and gene expression profiles. Three mouse lines, selectively bred for either high (HR), intermediate (IR), or low (LR) HPA axis reactivity, were exposed to one week of ELS using the limited nesting and bedding material paradigm. Measurements collected during or shortly after the ELS period showed that, regardless of genetic background, ELS exposure led to impaired weight gain and altered the animals' coping behavior under stressful conditions. However, only HR mice additionally showed significant changes in neuroendocrine stress responsiveness at a young age. Accordingly, adult HR mice also showed lasting consequences of ELS, including hyperactive stress-coping, HPA axis hyperreactivity, and gene expression changes in the Crh system, as well as downregulation of Fkbp5 in relevant brain regions. We suggest that the genetic predisposition for high stress reactivity interacts with ELS exposure by disturbing the suppression of corticosterone release during a critical period of brain development, thus exerting lasting programming effects on the HPA axis, presumably via epigenetic mechanisms. In concert, these changes lead to the emergence of important endophenotypes associated with affective disorders.
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-University, Großhaderner Str. 2, 82152 Munich, Germany.
authors.forename: Silja
authors.initials: S
authors.lastname: McIlwrick
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rechenberg
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Mariana
authors.initials: M
authors.lastname: Matthes
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Burgstaller
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzbauer
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-University, Großhaderner Str. 2, 82152 Munich, Germany; Department of Neurobiology, Weizmann Institute of Science, PO Box 26, 76100 Rehovot, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-University, Großhaderner Str. 2, 82152 Munich, Germany. Electronic address: touma@psych.mpg.de.
authors.forename: Chadi
authors.initials: C
authors.lastname: Touma
mesh_terms: D000223:Adaptation, Psychological; D000818:Animals; D001921:Brain / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004644:Emotions; D058068:Endophenotypes / Q000378:metabolism; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D051379:Mice; D019964:Mood Disorders / Q000235:genetics* / Q000378:metabolism; D009490:Neurosecretory Systems / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011247:Pregnancy; D011897:Random Allocation; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
chemical_list: D003345:Corticosterone
keywords: Crh; Early-life stress; Gene-environment interaction; HPA axis; Major depressive disorder; Stress reactivity mouse model