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STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology
The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural fun...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505245/ https://www.ncbi.nlm.nih.gov/pubmed/33046834 http://dx.doi.org/10.1038/s41380-020-00904-2 |
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author | Reisinger, Sonali N. Sideromenos, Spyros Horvath, Orsolya Derdak, Sophia Cicvaric, Ana Monje, Francisco J. Bilban, Martin Häring, Martin Glat, Micaela Pollak, Daniela D. |
author_facet | Reisinger, Sonali N. Sideromenos, Spyros Horvath, Orsolya Derdak, Sophia Cicvaric, Ana Monje, Francisco J. Bilban, Martin Häring, Martin Glat, Micaela Pollak, Daniela D. |
author_sort | Reisinger, Sonali N. |
collection | PubMed |
description | The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology. |
format | Online Article Text |
id | pubmed-8505245 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85052452021-10-14 STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology Reisinger, Sonali N. Sideromenos, Spyros Horvath, Orsolya Derdak, Sophia Cicvaric, Ana Monje, Francisco J. Bilban, Martin Häring, Martin Glat, Micaela Pollak, Daniela D. Mol Psychiatry Article The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology. Nature Publishing Group UK 2020-10-12 2021 /pmc/articles/PMC8505245/ /pubmed/33046834 http://dx.doi.org/10.1038/s41380-020-00904-2 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Reisinger, Sonali N. Sideromenos, Spyros Horvath, Orsolya Derdak, Sophia Cicvaric, Ana Monje, Francisco J. Bilban, Martin Häring, Martin Glat, Micaela Pollak, Daniela D. STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology |
title | STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology |
title_full | STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology |
title_fullStr | STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology |
title_full_unstemmed | STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology |
title_short | STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology |
title_sort | stat3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505245/ https://www.ncbi.nlm.nih.gov/pubmed/33046834 http://dx.doi.org/10.1038/s41380-020-00904-2 |
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