PACAP-Deficient Mice Exhibit Light Parameter–Dependent Abnormalities on Nonvisual Photoreception and Early Activity Onset 英文参考文献.docVIP

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PACAP-Deficient Mice Exhibit Light Parameter–Dependent Abnormalities on Nonvisual Photoreception and Early Activity Onset 英文参考文献.doc

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PACAP-Deficient Mice Exhibit Light Parameter–Dependent Abnormalities on Nonvisual Photoreception and Early Activity Onset 英文参考文献

PACAP-DeficientMiceExhibitLightParameter– DependentAbnormalitiesonNonvisualPhotoreception andEarlyActivityOnset ChihiroKawaguchi1,YasushiIsojima2,3*,NorihitoShintani1,MichiyoshiHatanaka1,XiaohongGuo1, NobuakiOkumura2,KatsuyaNagai2,HitoshiHashimoto1,4,5,AkemichiBaba1 1GraduateSchoolofPharmaceuticalSciences,OsakaUniversity,Osaka,Japan,2InstituteforProteinResearch,OsakaUniversity,Osaka,Japan,3GenomicScienceCenter, RIKEN,Yokohama, Japan,4TheOsaka-Hamamatsu JointResearchCenter forChild MentalDevelopment,OsakaUniversity,Osaka,Japan, 5United Graduate School of ChildDevelopment,OsakaUniversity,KanazawaUniversity,andHamamatsuUniversitySchoolofMedicine,Osaka,Japan Abstract Background: The photopigment melanopsin has been suggested to act as a dominant photoreceptor in nonvisual photoreceptionincludingresettingofthecircadianclock(entrainment),directtuningormaskingofvitalstatus(activity,sleep/ wakecycles,etc.),andthepupillarylightreflex(PLR).Pituitaryadenylatecyclase-activatingpolypeptide(PACAP)isexclusively coexpressedwithmelanopsininasmallsubsetofretinalganglioncellsandispredictedtobeinvolvedextensivelyinthese responses;however,therewereinconsistenciesinthepreviousreports,anditsfunctionalrolehasnotbeenwellunderstood. Methodology/PrincipalFindings:HereweshowthatPACAP-deficientmiceexhibitedseveredysfunctionsofentrainmentin atime-dependentmanner.Theabnormalitiesinthemutantmicewereintensity-dependentinphasedelayandduration- dependent in phase advance. The knockout mice also displayed blunted masking, which was dependent on lighting conditions,butnotcompletelylost.ThedysfunctionsofmaskinginthemutantmicewererecoveredbyinfusionofPACAP- 38.Bycontrast,thesemutantmiceshowanormalPLR.Weexaminedtheretinalmorphologyandinnervationsinthemutant mice, and no apparent changes were observed in melanopsin-immunoreactive cells. These data suggest that the dysfunctionsofentrainmentandmaskingwerecausedbythelossofPACAP,notbythelossoflightinputitself.Moreover, PACAP-deficientmiceexpressanunusua