Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala
Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mec...
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00460/full |
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| author | Magdalena T. Weidner Magdalena T. Weidner Magdalena T. Weidner Roy Lardenoije Roy Lardenoije Roy Lardenoije Lars Eijssen Lars Eijssen Floriana Mogavero Lilian P. M. T. De Groodt Sandy Popp Rupert Palme Konrad U. Förstner Konrad U. Förstner Konrad U. Förstner Tatyana Strekalova Tatyana Strekalova Tatyana Strekalova Harry W. M. Steinbusch Angelika G. Schmitt-Böhrer Jeffrey C. Glennon Jonas Waider Daniel L. A. van den Hove Daniel L. A. van den Hove Klaus-Peter Lesch Klaus-Peter Lesch Klaus-Peter Lesch |
| author_facet | Magdalena T. Weidner Magdalena T. Weidner Magdalena T. Weidner Roy Lardenoije Roy Lardenoije Roy Lardenoije Lars Eijssen Lars Eijssen Floriana Mogavero Lilian P. M. T. De Groodt Sandy Popp Rupert Palme Konrad U. Förstner Konrad U. Förstner Konrad U. Förstner Tatyana Strekalova Tatyana Strekalova Tatyana Strekalova Harry W. M. Steinbusch Angelika G. Schmitt-Böhrer Jeffrey C. Glennon Jonas Waider Daniel L. A. van den Hove Daniel L. A. van den Hove Klaus-Peter Lesch Klaus-Peter Lesch Klaus-Peter Lesch |
| author_sort | Magdalena T. Weidner |
| collection | DOAJ |
| description | Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2-/-) and heterozygous (Tph2+/-) mice, and their wildtype littermates (Tph2+/+) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2-/- mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2+/- mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2+/- mice when compared to their Tph2-/- littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability. |
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| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-12T20:23:22Z |
| publishDate | 2019-05-01 |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-e9bfdfc3a3f543148df4c4b9e9207fcb2022-12-22T00:13:12ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-05-011310.3389/fnins.2019.00460456914Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the AmygdalaMagdalena T. Weidner0Magdalena T. Weidner1Magdalena T. Weidner2Roy Lardenoije3Roy Lardenoije4Roy Lardenoije5Lars Eijssen6Lars Eijssen7Floriana Mogavero8Lilian P. M. T. De Groodt9Sandy Popp10Rupert Palme11Konrad U. Förstner12Konrad U. Förstner13Konrad U. Förstner14Tatyana Strekalova15Tatyana Strekalova16Tatyana Strekalova17Harry W. M. Steinbusch18Angelika G. Schmitt-Böhrer19Jeffrey C. Glennon20Jonas Waider21Daniel L. A. van den Hove22Daniel L. A. van den Hove23Klaus-Peter Lesch24Klaus-Peter Lesch25Klaus-Peter Lesch26Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, NetherlandsDivision of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, GermanyDepartment of Psychiatry and Psychotherapy, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, GermanyDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, NetherlandsDepartment of Psychiatry and Psychotherapy, Universitätsmedizin Göttingen, Georg-August-Universität, Göttingen, GermanyDepartment of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, United StatesDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, NetherlandsDepartments of Bioinformatics, Psychiatry & Neuro Psychology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, NetherlandsDonders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, NetherlandsDonders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, NetherlandsDivision of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, GermanyDepartment of Biomedical Sciences, University of Veterinary Medicine, Vienna, AustriaCore Unit Systems Medicine, Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany0ZB MED – Information Centre for Life Sciences, Cologne, Germany1TH Köln, Faculty of Information Science and Communication Studies, Cologne, GermanyDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, NetherlandsDivision of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, Germany2Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I. M. Sechenov First Moscow State Medical University and Institute of General Pathology and Pathophysiology, Moscow, RussiaDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands3Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, GermanyDonders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, NetherlandsDivision of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, GermanyDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, NetherlandsDivision of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, GermanyDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, NetherlandsDivision of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Würzburg, Würzburg, Germany2Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I. M. Sechenov First Moscow State Medical University and Institute of General Pathology and Pathophysiology, Moscow, RussiaConverging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2-/-) and heterozygous (Tph2+/-) mice, and their wildtype littermates (Tph2+/+) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2-/- mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2+/- mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2+/- mice when compared to their Tph2-/- littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.https://www.frontiersin.org/article/10.3389/fnins.2019.00460/fullserotoninmaternal separationmouseemotional behaviorDNA methylationRNA expression |
| spellingShingle | Magdalena T. Weidner Magdalena T. Weidner Magdalena T. Weidner Roy Lardenoije Roy Lardenoije Roy Lardenoije Lars Eijssen Lars Eijssen Floriana Mogavero Lilian P. M. T. De Groodt Sandy Popp Rupert Palme Konrad U. Förstner Konrad U. Förstner Konrad U. Förstner Tatyana Strekalova Tatyana Strekalova Tatyana Strekalova Harry W. M. Steinbusch Angelika G. Schmitt-Böhrer Jeffrey C. Glennon Jonas Waider Daniel L. A. van den Hove Daniel L. A. van den Hove Klaus-Peter Lesch Klaus-Peter Lesch Klaus-Peter Lesch Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala Frontiers in Neuroscience serotonin maternal separation mouse emotional behavior DNA methylation RNA expression |
| title | Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala |
| title_full | Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala |
| title_fullStr | Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala |
| title_full_unstemmed | Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala |
| title_short | Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala |
| title_sort | identification of cholecystokinin by genome wide profiling as potential mediator of serotonin dependent behavioral effects of maternal separation in the amygdala |
| topic | serotonin maternal separation mouse emotional behavior DNA methylation RNA expression |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00460/full |
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