title: Effects of repeated adolescent stress and serotonin transporter gene partial knockout in mice on behaviors and brain structures relevant to major depression.
abstract: In humans, exposure to stress during development is associated with structural and functional alterations of the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HC) and their circuits of connectivity, and with an increased risk for developing major depressive disorder particularly in carriers of the short (s) variant of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR). Although changes in these regions are found in carriers of the s allele and/or in depressed patients, evidence for a specific genotype × developmental stress effect on brain structure and function is limited. Here, we investigated the effect of repeated stress exposure during adolescence in mice with partial knockout of the 5-HTT gene (HET) vs. wildtype (WT) on early-adulthood behavioral measures and brain structure [using magnetic resonance imaging (MRI)] relevant to human major depression. Behaviorally, adolescent stress (AS) increased anxiety and decreased activity and did so to a similar degree in HET and WT. In a probabilistic reversal learning task, HET-AS mice achieved fewer reversals than did HET-No-AS mice. 5-HTT genotype and AS were without effect on corticosterone stress response. In terms of structural brain differences, AS reduced the volume of two long-range white matter tracts, the optic tract (OT) and the cerebral peduncle (CP), in WT mice specifically. In a region-of-interest analysis, AS was associated with increased HC volume and HET genotype with a decreased frontal lobe volume. In conclusion, we found that 5-HTT and AS genotype exerted long-term effects on behavior and development of brain regions relevant to human depression.
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich Zurich, Switzerland ; Neuroscience Center, University and ETH Zurich Zurich, Switzerland ; Zurich Center for Integrative Human Physiology, University of Zurich Zurich, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Spinelli
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich Zurich, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Müller
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children Toronto, Canada.
authors.forename: Miriam
authors.initials: M
authors.lastname: Friedel
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich Zurich, Switzerland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Sigrist
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg Würzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children Toronto, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Henkelman
authors.affiliation: Neuroscience Center, University and ETH Zurich Zurich, Switzerland ; Institute for Biomedical Engineering, University and ETH Zurich Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rudin
authors.affiliation: Neuroscience Center, University and ETH Zurich Zurich, Switzerland ; Zurich Center for Integrative Human Physiology, University of Zurich Zurich, Switzerland ; Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich Zurich, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Seifritz
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich Zurich, Switzerland ; Neuroscience Center, University and ETH Zurich Zurich, Switzerland ; Zurich Center for Integrative Human Physiology, University of Zurich Zurich, Switzerland.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pryce
keywords: adolescent stress; development; magnetic resonance imaging; major depression; mouse model; serotonin transporter gene