Rhythmicity in Mice Selected for Extremes in Stress Reactivity Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression 英文参考文献.docVIP

RhythmicityinMiceSelectedforExtremesinStress Reactivity:Behavioural,EndocrineandSleepChanges ResemblingEndophenotypesofMajorDepression ChadiTouma1.*,ThomasFenzl1.,Jo¨rgRuschel1,RupertPalme2,FlorianHolsboer1,MayumiKimura1, RainerLandgraf1 1MaxPlanckInstituteofPsychiatry,Munich,Germany,2DepartmentofBiomedicalSciences,UniversityofVeterinaryMedicine,Vienna,Austria Abstract Background:Dysregulationofthehypothalamic-pituitary-adrenal(HPA)axis,includinghyper-orhypo-activityofthestress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biologicalhallmarksofMDaredisturbancesincircadianrhythmsandsleeparchitecture.Applyingatranslationalapproach, ananimalmodelhasrecentlybeendeveloped,focusingonthedeviationinsensitivitytostressfulencounters.Thisso-called ‘stressreactivity’(SR)mousemodelconsistsofthreeseparatebreedinglinesselectedforeitherhigh(HR),intermediate(IR), orlow(LR)corticosteroneincreaseinresponsetostressors. Methodology/PrincipleFindings:InordertocontributetothevalidationoftheSRmousemodel,ourstudycombinedthe analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and explorationtowardstheendoftherestingperiod),resemblingsymptomslikerestlessness,sleepcontinuitydisturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibitioninHRmice. Conclusion/Significance:Thus,wecouldshowthatbyselectivelybreedingmiceforextremesinstressreactivity,cl