The circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders

Mariana Astiz; Isabel Heyde; Mats Ingmar Fortmann; Verena Bossung; Claudia Roll; Anja Stein; Berthold Grüttner; Wolfgang Göpel; Christoph Härtel; Jonas Obleser; Henrik Oster

doi:10.1038/s41467-020-17429-5

The circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders

Mariana Astiz^*, Isabel Heyde, Mats Ingmar Fortmann, Verena Bossung, Claudia Roll, Anja Stein, Berthold Grüttner, Wolfgang Göpel, Christoph Härtel, Jonas Obleser, Henrik Oster

^*Korrespondierende/r Autor/-in für diese Arbeit

40 Zitate (Scopus)

Abstract

During pregnancy, maternal endocrine signals drive fetal development and program the offspring’s physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child’s risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.

Originalsprache	Englisch
Aufsatznummer	3593
Zeitschrift	Nature Communications
Jahrgang	11
Ausgabenummer	1
Seiten (von - bis)	3593
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-020-17429-5
Publikationsstatus	Veröffentlicht - 17.07.2020

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Study approval. All experiments in mice were ethically approved by the Committee on Animal Health and Care of the Government of Schleswig-Holstein (V 242–7224.122-4(45-4/15) and V 242–7604/2017 (37-3/17) and were performed according to international guidelines on the ethical use of animals. The GNN is supported by the German Federal Ministry for Education & Research (BMBF; code: 01ER1501; https://www.gesundheitsforschung-bmbf.de/de/deutsches-fruhgeborenen-netzwerk-german-neonatal-network-gnn-3798.php) and approved by the University of Lübeck ethics committee (08–022) and the institutional review boards of all participating sites. The study protocol can be accessed at https://www. vlbw.de/ (in German). English translations of the study protocol and the informed consent form are provided in the Supplementary Material 2 and 3. The authors would like to thank Dr. Mathias V. Schmidt (Munich Center for Neurosciences, Ludwig-Maximilians-Universität, Munich) for GR in situ hybridization probes, Drs. Christiane Koch, Anthony Tsang, and Isa Kolbe (Institute of Neurobiology) for fruitful discussions, Nadine Oster, Cécile Demarez, and Ludmila Skrum for excellent technical assistance. This work was supported by German Research Foundation (DFG) grants AS547-1/1 (to M.A.) and OS353-7/1 and OS353-10/1 (to H.O.), an IBRO (International Brain Research Organization)-ISN (International Society for Neurochemistry) research fellowship 2016 (to M.A.) and an EMBO (European Molecular Biology Organization) short-term fellowship (to M.A.). J.O. is partly funded by the European Research Council (ERC-CoG-2014 646696). H.O. is a Lichtenberg fellow of the Volkswagen Foundation. The German Neonatal Network is funded by the German Ministry for Education and Research (BMBF-grant-Nos.: 01ER0805 and 01ER1501).

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Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

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10.1038/s41467-020-17429-5

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title = "The circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders",

abstract = "During pregnancy, maternal endocrine signals drive fetal development and program the offspring{\textquoteright}s physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child{\textquoteright}s risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.",

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AU - Astiz, Mariana

AU - Heyde, Isabel

AU - Fortmann, Mats Ingmar

AU - Bossung, Verena

AU - Roll, Claudia

AU - Stein, Anja

AU - Grüttner, Berthold

AU - Göpel, Wolfgang

AU - Härtel, Christoph

AU - Obleser, Jonas

AU - Oster, Henrik

PY - 2020/7/17

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N2 - During pregnancy, maternal endocrine signals drive fetal development and program the offspring’s physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child’s risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.

AB - During pregnancy, maternal endocrine signals drive fetal development and program the offspring’s physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child’s risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.

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The circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders

Abstract

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