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Understanding the Molecular Mechanisms of Aggression in BALB/C and TPH2-Deficient Mice Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice Citation for published version (APA): Gorlova, A. (2020). Understanding the molecular mechanisms of aggression in BALB/c and TPH2- deficient mice. OneBook.ru. https://doi.org/10.26481/dis.20200305ag Document status and date: Published: 01/01/2020 DOI: 10.26481/dis.20200305ag Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 04 Oct. 2021 MAASTRICHT UNIVERSITY Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice Anna Gorlova 1 © A. Gorlova, Maastricht 2020 M.: OOO “Sam Poligraphist”, 2019. – 326 p., ILL Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice ISBN 978-5-00166-023-1 Cover: Scene from Homer’s The Iliad on wine-drinking bowl, c. 530 bc, from Pharsalos, Greece. National Archaeological Museum, Athens Number of copies: 30 Order # 89610. Printed by «OneBook.ru» ООО “Sam Poligraphist” 129090 Moscow, Protopovsky lane 6 www.onebook.ru All rights reserved. No parts of this book may be reproduced or transmitted in any form or by any means, without prior permission in writing by the author, or when appropriate, by the publishers of the publication. 2 Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice DISSERTATION to obtain the degree of Doctor at Maastricht University, on the authority of the Rector Magnificus, Prof.dr. Rianne M. Letschert in accordance with the decision of the Board of Deans, to be defended in public on Thursday, March 5th 2020, at 10:00 hours by Anna Gorlova 3 Promotor: Prof. dr. K.P. Lesch Co-promotors: Dr. T. Strekalova Prof. dr. L. Bettendorff, University of Liege, Belgium Assessment Committee: Prof. dr. J. Prickaerts (Chairman) Prof. dr. Th. van Amelsvoort Dr. A. Jahanshahi Prof. dr. E. Budygin, Wake Forest School of Medicine, Winston- Salem, NC, USA Dr. J. Glennon, Radboud University Nijmegen Medical Centre, Nijmegen 4 Table of Contents Propositions .................................................................................... 7 Abbreviations ................................................................................. 9 Chapter 1. General introduction ................................................. 11 1.1. Aggression and its neuroanatomical basis in human and rodents ....................................................................................... 12 1.2. Excessive aggression as a symptom of psychiatric conditions, including depression and anxiety disorders .......... 16 1.3. Neuronal serotonin in the regulation of aggression ......... 18 1.4. Role of the glutamatergic system in the regulation of excessive aggression .................................................................. 20 1.5. Changes in neuronal plasticity, oxidative stress and neuroinflammation as mechanisms of excessive aggression ... 22 1.6. Animal models of aggression ............................................. 25 1.7. Challenges in management of excessive aggression in the clinical setting and therapeutic potential of psychoactive antioxidant and anti-inflammatory compounds ...................... 28 Hypothesis and aim .................................................................. 31 References.................................................................................. 32 Chapter 2. Thiamine and benfotiamine counteract ultrasound- induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice ............ 45 Chapter 3. Ultrasound stress compromises the correlates of emotional-like states and brain AMPAR expression in mice: effects of antioxidant and anti-inflammatory herbal treatment .................................................................................................... 155 Chapter 4. Stress-induced aggression in heterozygous TPH2 mutant mice is associated with alterations in serotonin metabolism and expression of 5-HT6 and AMPA subunit 2A receptors ..................................................................................... 231 Chapter 5. General discussion .................................................. 275 5 5.1. Environmental factors leading to excessive aggression: impact of emotional stress ....................................................... 276 5.2. The role of serotonin, its receptors and Tryptophan hydroxylase-2 in pathological aggression ............................... 279 5.3. Altered internalization and expression of AMPA receptor subunits in the mechanisms of neuropsychiatric disorders ... 284 5.4. Interplay between oxidative stress, neuroinflammation and altered neuroplasticity in excessive aggression, depressive-like and anxiety-like behavior: evidence from clinical data .......... 288 5.5. Antioxidant compounds as potential treatment of excessive aggression and associated conditions: perspectives of clinical use of thiamine compounds and herbal treatments ............... 295 References ................................................................................ 299 Summary .................................................................................... 308 Samenvatting ............................................................................. 311 Valorization ................................................................................ 314 Acknowledgements ..................................................................... 317 About the author ........................................................................ 321 6 Propositions 1. Alterations in the expression of 5-HT6-R and AMPA-R subunits GluA1-3 and internalization of the latter are implicated in excessive aggression in the ultrasound mouse model of ‘emotional stress’ (this thesis); 2. In mice with partial genetic deficit of tryptophan hydroxylase-2 (Tph2-het), predation stress evokes aggression and changes in the expression of 5-HT6-R, GluA2 and serotonin metabolism (this thesis); 3. Ultrasound-induced aggression in BALB/c mice is associated with neuroinflammation, decreased hippocampal plasticity and oxidative stress (this thesis); 4. Compounds with antioxidant properties, including vitamin B1 (thiamine), benfotiamine and herbs, normalize ultrasound-induced aggression and accompanying molecular changes (this thesis); 5. New paradigms of aggressive behaviour, evoked by ‘emotional stress’ in BALB/c mice and by predation in Tph2-het mice are useful for fundamental and pre-clinical studies (valorization); 7 6. Gene-environment interactions underpin manifestations of many psychopathologies; 7. The use of multiple tests and a variety of experimental conditions is the must with the validation of animal models of psychiatric disorders; 8. A balance between oxidative stress and inflammation on one hand and counteracting detoxifying and anti- inflammatory factors on another hand determines healthy state; 9. Aggression unopposed becomes a contagious disease (Jimmy Carter); 10. War is sweet to those who have not experienced it (Desiderius Erasmus). 8 Abbreviations 5-HIAA 5-hydroxyindoleacetic acid 5-HT 5-hydroxytryptamine 5-HTP 5-hydroxytryptophan Akt Protein kinase B α-amino-3-hydroxy-5-methyl- AMPA isoxazolepropionic acid BBB Blood-brain barrier BDNF Brain-derived neurotrophic factor CNS Central nervous system COX-2 Cyclooxigenase-2 CRP C-reactive protein CSF Cerebrospinal fluid DLPFC Dorsolateral prefrontal cortex DNA Deoxyribonucleic acid ELS Early-life stress GSK Glycogen synthase kinase HAB High anxiety-like behavior HPA Hypothalamic–pituitary–adrenal IFN Interferon IL Interleukin iNOS Inducible nitric oxide synthase LAB Low anxiety-like behavior L-DOPA L-3,4-dihydroxyphenylalanine MAOA Monoamine oxidase A mPFC Medial prefrontal cortex NAD Nicotinamide adenine dinucleotide 9 NMDA N-methyl-D-aspartate receptor NOX NADPH oxidase OFC Orbitofrontal cortex PFC Prefrontal cortex PSA-NCAM
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