Chronic Unpredictable Stress CUS)-Induced Anxiety and Related Mood Disorders in a Zebrafish Model Altered Brain Proteome Profile Implicates Mitochondrial Dysfunction.docVIP

ChronicUnpredictableStress(CUS)-InducedAnxietyand RelatedMoodDisordersinaZebrafishModel:Altered BrainProteomeProfileImplicatesMitochondrial Dysfunction SumanaChakravarty1*,BommanaR.Reddy1,SreeshaR.Sudhakar2,SandeepSaxena2,TapateeDas1, VuppalapatyMeghah2,CherukuvadaV.BrahmendraSwamy2,ArvindKumar2,MohammedM.Idris2* 1ChemicalBiologyDivision,CSIR-IndianInstituteofChemicalTechnology(IICT),Hyderabad,India,2CSIR-CentreforCellularandMolecularBiology(CCMB),Habsiguda, Hyderabad,India Abstract Anxietyanddepressionaremajorchronicmooddisorders,andtheetiopathologyforeachappearstoberepeatedexposure todiverseunpredictablestressfactors.Mostofthestudiesonanxietyandrelatedmooddisordersareperformedinrodents, andagoodmodelischronicunpredictablestress(CUS).Inthisstudy,wehaveattemptedtounderstandthemolecularbasis oftheneuroglialandbehavioralchangesunderlyingCUS-inducedmooddisordersinthesimplestvertebratemodel,the zebrafish,Daniorerio.ZebrafishweresubjectedtoaCUSparadigminwhichtwodifferentstressorswereuseddailyfor15 days,andthoroughbehavioralanalyseswereperformedtoassessanxietyandrelatedmooddisorderphenotypesusingthe noveltanktest,shoalcohesionandscototaxis.Fifteendaysofexposuretochronicstressorsappearstoinduceananxiety and related mood disorder phenotype. Decreased neurogenesis, another hallmark of anxiety and related disorders in rodents,wasalsoobservedinthiszebrafishmodel.Thecommonmolecularmarkersofrodentanxietyandrelateddisorders, corticotropin-releasing factor (CRF), calcineurin (ppp3r1a) and phospho cyclic AMP response element binding protein (pCREB), were also replicated in the fish model. Finally, using 2DE FTMS/ITMSMS proteomics analyses, 18 proteins were foundtobederegulatedinzebrafishanxietyandrelateddisorders.Themostaffectedprocesswasmitochondrialfunction,4 of the18differentially regulatedproteins weremitochondrial proteins: PHB2,SLC25A5, VDAC3 andIDH2, as reportedin rodent and clinical samples. Thus, the zebrafish CUS model and proteomics can facilitate not only uncovering