Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states
Autor: | Miroslav Adzic, Ivan Soldatovic, Milos Mitic, Zorana Pavlovic, Marina Mihaljevic, Milica J Nesic, Zorica Petrovic, Zeljka Brkic, Jelena Radulovic, Minja Milosavljevic, Emilija Glavonic, Nadja P. Maric, Ester Francija |
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Rok vydání: | 2019 |
Předmět: |
Adult
Male medicine.medical_specialty Plasticity Alpha (ethology) Fear conditioning Pilot Projects Glucocorticoid receptor Childhood trauma Article Extinction Psychological Cohort Studies Random Allocation 03 medical and health sciences Receptors Glucocorticoid 0302 clinical medicine Internal medicine Conditioning Psychological Neuroplasticity Animals Humans Protein Isoforms Medicine Biological Psychiatry Cell Nucleus Pharmacology DASS business.industry Fear Extinction (psychology) 030227 psychiatry Mice Inbred C57BL Affect Disease Models Animal Endocrinology Adult Survivors of Child Adverse Events Protein Biosynthesis Anxiety Female FKBP5 medicine.symptom business 030217 neurology & neurosurgery |
Zdroj: | Progress in Neuro-Psychopharmacology and Biological Psychiatry |
ISSN: | 0278-5846 |
Popis: | Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα their interactions and FKBP5 explained 22%–35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα and emphasized its role in fear extinction and neural plasticity. © 2018 Elsevier Inc. Free Author Manuscript available at PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383671/] |
Databáze: | OpenAIRE |
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