TY - JOUR
T1 - Identification of Cholecystokinin by Genome-Wide Profiling as Potential Mediator of Serotonin-Dependent Behavioral Effects of Maternal Separation in the Amygdala
AU - Weidner, Magdalena T.
AU - Lardenoije, Roy
AU - Eijssen, Lars
AU - Mogavero, Floriana
AU - De Groodt, Lilian P. M. T.
AU - Popp, Sandy
AU - Palme, Rupert
AU - Foerstner, Konrad U.
AU - Strekalova, Tatyana
AU - Steinbusch, Harry W. M.
AU - Schmitt-Boehrer, Angelika G.
AU - Glennon, Jeffrey C.
AU - Waider, Jonas
AU - van den Hove, Daniel L. A.
AU - Lesch, Klaus-Peter
N1 - Funding Information:
This work was funded by the Deutsche Forschungsgemeinschaft (DFG CRC TRR 58/A1 and A5 to K-PL, DvdH, and AS-B, and WA 3446/2-1 to JW), the European Union’s Seventh Framework Programme under grant no. 602805 (Aggressotype) to K-PL, TS, JG, and DvdH, EC: MATRICS FP7/No. 603016 to JG, the Horizon 2020 Research and Innovation Programme under grant no. 728018 (Eat2beNICE) to K-PL and JG, the Innovative Medicines Initiative 2 Joint Undertaking No. 115916 (PRISM) to JG, the 5– 100 Russian Academic Excellence Project to K-PL and TS. MW was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences (GSLS), University of Würzburg. RL was supported by a fellowship as part of the Netherlands Organization for Scientific Research (NWO) grant 022.005.019. This publication was funded by the German Research Foundation (DFG) and the University of Würzburg in the funding programme Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2019 Weidner, Lardenoije, Eijssen, Mogavero, De Groodt, Popp, Palme, Förstner, Strekalova, Steinbusch, Schmitt-Böhrer, Glennon, Waider, van den Hove and Lesch.
PY - 2019/5/10
Y1 - 2019/5/10
N2 - 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.
AB - 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.
KW - serotonin
KW - maternal separation
KW - mouse
KW - emotional behavior
KW - DNA methylation
KW - RNA expression
KW - BRAIN 5-HT SYNTHESIS
KW - C-FOS EXPRESSION
KW - GENE-EXPRESSION
KW - PRENATAL STRESS
KW - PLUS-MAZE
KW - HYPOTHALAMIC VASOPRESSIN
KW - DEAKIN/GRAEFF HYPOTHESIS
KW - EPIGENETIC MECHANISMS
KW - RECEPTOR ANTAGONISTS
KW - AGGRESSIVE-BEHAVIOR
U2 - 10.3389/fnins.2019.00460
DO - 10.3389/fnins.2019.00460
M3 - Article
C2 - 31133792
SN - 1662-453X
VL - 13
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
IS - MAY
M1 - 460
ER -