A Hypomorphic Vasopressin Allele Prevents Anxiety-Related Behavior 英文参考文献.docVIP

AHypomorphicVasopressinAllelePreventsAnxiety- RelatedBehavior MirjamBunck1.,LudwigCzibere1.*,CharlotteHorvath1,CorneliaGraf1,ElisabethFrank1¤,MelanieS. Ke?ler1,ChrisMurgatroyd1,BertramMu¨ller-Myhsok1,MariyaGonik1,PeterWeber1,BennoPu¨tz1 ,Patrik Muigg2,MarkusPanhuysen3,NicolasSingewald2,ThomasBettecken1,JanM.Deussing1,4 ,Florian Holsboer1,DietmarSpengler1,RainerLandgraf1 1Max Planck Institute of Psychiatry, Munich, Germany, 2University of Innsbruck, Innsbruck, Austria, 3Affectis Pharmaceuticals, Martinsried, Germany, 4Helmholtz Zentrum,InstituteofDevelopmentalGenetics,Munich/Neuherberg,Germany Abstract Background: To investigate neurobiological correlates of trait anxiety, CD1 mice were selectively bred for extremes in anxiety-relatedbehavior,withhigh(HAB)andlow(LAB)anxiety-relatedbehaviormiceadditionallydifferinginbehavioral testsreflectingdepression-likebehavior. Methodology/ Principal Findings: In this study, microarray analysis, in situ hybridization, quantitative real-time PCR and immunohistochemistry revealeddecreasedexpressionofthevasopressingene(Avp)inthehypothalamic paraventricular (PVN)andsupraoptic(SON)nucleiofadultLABmicecomparedtoHAB,NAB(normalanxiety-relatedbehavior)andHABxLAB F1intercrosscontrols,withoutdetectingdifferencesinreceptorexpressionordensity.Bysequencingtheregions2.5kbp up-anddownstreamoftheAvpgenelocus,wecouldidentifyseveralpolymorphicloci,differingbetweentheHABandLAB lines.Inthegenepromoter,adeletionoftwelvebpD(22180–2191)isparticularlylikelytocontributetothereducedAvp expression detected in LAB animals under basal conditions. Indeed, allele-specific transcription analysis of F1 animals revealed a hypomorphic LAB-specific Avp allele with a reduced transcription rate by 75% compared to the HAB-specific allele,thusexplainingline-specificAvpexpressionprofilesandphenotypicfeatures.Accordingly,intra-PVNAvpmRNAlevels were found to correlate with anxiety-related and depression-like behaviors. In addition to this correlative evidence, a sig