The role of estrogen receptors in anxiety disorders: an investigation in zebrafish

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dc.contributor.advisorSmith, Carineen_ZA
dc.contributor.advisorPretorius, Leshaen_ZA
dc.contributor.authorBalshaw, Aidan Glennen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Dept. of Medicine. Division of Clinical Pharmacologyen_ZA
dc.date.accessioned2023-11-06T13:44:55Zen_ZA
dc.date.accessioned2024-01-08T15:35:55Zen_ZA
dc.date.available2023-11-06T13:44:55Zen_ZA
dc.date.available2024-01-08T15:35:55Zen_ZA
dc.date.issued2023-11en_ZA
dc.descriptionThesis (MSc)--Stellenbosch University, 2023.en_ZA
dc.description.abstractENGLISH ABSTRACT: Background & Aim Anxiety disorders are the most prevalent psychiatric disorders with approximately twice the prevalence in females compared to males. Clinical studies on the exacerbation of anxiety symptoms in the premenstrual phase of the menstrual cycle implicate the role of declining estradiol levels. Preclinical evidence most consistently indicating the anxiolytic effect of increased estrogen receptor beta-signalling exacerbations in anxiety symptoms have been demonstrated in clinical studies. This thesis aimed to simulate estrogen-linked anxiety behaviour in larval zebrafish to assess the role of estrogen receptors (ER) in this phenomenon. Methods Using an estradiol-treatment-withdrawal-model, behaviour of zebrafish larvae was determined in the LDTT on 7 days post-fertilisation (dpf) in a series of experiments. Firstly, the estradiol treatment withdrawal model was optimised by increasing the duration of treatment withdrawal and reducing the number of estradiol concentrations used. Further optimisation included comparing behaviour after estradiol washout with behaviour after prolonged tamoxifen, an ER modulator, administration. Secondly, ER modulators (WAY-200070, PHTPP, and tamoxifen) were administered for 45 minutes, in the presence of absence of exogenous estradiol exposure, before behavioural analysis. Thirdly, ERβ expression was determined after estradiol treatment. Lastly, redox status (hydrogen peroxide levels, antioxidant capacity, and lipid peroxidation) and behaviour of estradiol-treated larvae were evaluated. Results Estradiol withdrawal decreased basal and anxiety-like behaviour. The accuracy of the estradiol washout model was not improved by longer durations of treatment withdrawal or refinement of estradiol concentrations used. Prolonged tamoxifen administration reduced basal and anxiety-like behaviour. ER modulation did not alter anxiety-like behaviour, while basal activity slightly altered by supraphysiological concentrations of WAY-200070 in the absence of estradiol. WAY-200070 and tamoxifen altered basal activity when administered in the presence of exogenous estradiol exposure. ERβ expression was not upregulated in larvae exposed to low concentrations of estradiol. Longer exposure to low concentrations of estradiol increased antioxidant capacity and slightly decreased lipid peroxidation while hydrogen peroxide levels were unaltered. In addition, acute exposure to low concentrations of estradiol increased basal activity in the LDTT. Conclusion Current data suggest that developing zebrafish larvae are likely not suitable for modelling exacerbations in anxiety symptoms associated with fluctuating estrogen levels. Rather, current investigations demonstrated that increased activity levels were not linked to anxiety but better redox status, in the context of free estrogen availability. Considering the effect of redox status on larval behaviour, it is recommended that behavioural analysis be conducted in parallel with mechanistic studies in the context of ER signalling.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Agtergrond & Doelwitte Angsversteurings is die mees algemene psigiatriese versteurings en affekteer ongeveer dubbel die hoeveelheid vroue in vergelyking met mans. Kliniese studies wat fokus op die erger angstigheidssimptome in die premenstruele/menstruele fase van die menstruele siklus dui daarop dat ‘n afname in estradiol vlakke moontlik ‘n rol mag speel. Prekliniese bewyse dui ook daarop dat die angsverligtingseffekte van toenemende estrogeenreseptor-beta (ERβ) seinoordrag beklemtoon is in angstigheid simptome. Dit word selfs in kliniese studies gedemonstreer. Die doelwit van hierdie studie was dus om estrgeen-verwante vehoogde angstigheid na te boots in zebravis larwes om estrogenreseptor (ER) seinoordrag te bestudeer. Metodes Die gedragspatrone van zebravislarwe (7 dpf) onder die invloed van ‘n eksperimentele model waar estradiol behandelling onttrek is, is deur middel van ‘n lig-donker verwisselingstoets (LDTT) geassesseer in ‘n reeks eksperimente. In die eerste plek was die estradiolbehandelingonttrekkingsmodel geoptimiseer deur verskillende tydsdure van onttrekkking en konsentrasies estradiol in ag te neem. Verdere verfyning het die vergelyking van gedragspatone na verlengde toediening van tamoxifen (‘n moduleerder van ER seinoordrag) ingesluit. Tweedens, is estrogeenreseptor moduleerders (WAY-200070, PHTPP en tamoxifen) vir ‘n tydsduur van 45 minute toegedien in beide die teenwoordigheid en afwesigheid van eksogene estradiol, waarna gedragspatoonanalise uitgevoer is. In die derde plek is ERβ uitdrukking bepaal na afloop van estradiol behandeling. Laastens is redoksstatus van die zebravislarwes ge-evalueer deur waterstofperoksied vlakke, antioksidant kapasiteit en lipiedperoksidasie, as ook die gedragspatrone van zebravislarwes. Resultate Estradiolonttrekking het die basale- en angstigheids- gedragspatrone in die zebravislarwes verminder. Die akkuraatheid van die estradiolbehandeling-onttrekkingsmodel het nie verbeter met langer behandelingstydperke of verfynde estradiolkonsentrasies wat gebruik is nie. Langdurige tamoxifen behandeling het die basale- and angstigheids- gedragspatrone verlaag. ER modulasie het geen effek op die angstigheids-gedragspatrone gehad nie, terwyl basale gedragspatrone effense veranderinge ondergaan het onder die invloed van suprafisiologiese konsentrasies van WAY-200070 in die afwesigheid van estradiol. Langer blootstelling aan laer estradiol konsentrasies het die antioksidant kapasiteit verhoog terwyl die lipiedperoksidasie afgeneem het en waterstofperoksied konsentrasies onveranderd gebly het. Verder het akute blootstelling aan lae estradiolkonsentrasies die basale akstwiteitsvlakke van die zebravislarwes in die LDTT verhoog. Gevolgtrekking Huidige data dui daarop dat ontwikkende zebravislarwes moonlik nie ‘n geskikte model vir die modellering van verhoogde angssimptome wat met wisselende estrogeenvlakke gepaardgaan, is nie. Verhoogde aktiwiteitsvlakke in die huidige model dui nie op verhoogde angstigheid nie, maar eerder op beter redoksstatus, in die konteks waar vrye estrogen beskikbaar is. Inaggenome die effekte van redoksstatus op die zebravislarwes se gedragspatrone, is die aanbeveling dat gedragsanalise in parallel met meganistiese studies in die konteks van ER seinoordrag uitgevoer word.af_ZA
dc.description.versionMastersen_ZA
dc.format.extentix, 98 pages : illustrationsen_ZA
dc.identifier.urihttps://scholar.sun.ac.za/handle/10019.1/128913en_ZA
dc.language.isoen_ZAen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshAnxiety disorders -- Animal modelsen_ZA
dc.subject.lcshEstrogen -- Receptorsen_ZA
dc.subject.lcshLogperch -- Larvae -- Behavioren_ZA
dc.subject.lcshEstradiol -- Treatment -- Complicationsen_ZA
dc.subject.lcshRedox reactionen_ZA
dc.titleThe role of estrogen receptors in anxiety disorders: an investigation in zebrafishen_ZA
dc.typeThesisen_ZA
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Masters Degrees (Clinical Pharmacology)