Insomniaisthemostcommonsleepdisorderamongolderadults,affecting50%ofpeopleovertheageof65. Amongthisolderpopulation,sleepdisturbancesareoftenthefirstpresentingsymptomofAlzheimer?sdisease, aswellasotherformsofdementia.ThelinkbetweensleepandAlzheimer?sdiseaseisbidirectional: progressionofdiseaseisassociatedwithworsenedsleep,andpoorsleepcausesworseningcognitive function.Therefore,improvingsleephastherapeuticpotentialinpatientssufferingfromAlzheimer?sdisease. CognitiveBehavioralTherapyforInsomnia(CBT-I)isthefirst-linetherapytotreatsleepdisturbances,but limitedaccessibilityofpractitionersandlongdurationoftherapyarebarriersthatlimitimplementation.Hypnotic medications,a2nd-lineinsomniatreatment,areavoidedinAlzheimer?sdiseasepatientsbecausetheymay exacerbatecognitivedecline.Withwell-validatedmodelsofchronicinsomnia,aging,andAlzheimer?sdisease, anduniquegenetictools,Drosophilaprovidesadynamicsystemtoinvestigatetheunderlyingcellular mechanismsofbehavioralsleepmodification.Idesignedbehavioralparadigmstomodelsleeprestriction,one oftheprimarytenetsofCBT-I,inmutantfliesthatrecapitulatethefeaturesofchronicinsomnia.Sleep restrictioninDrosophilaisachievedbyshorteningthedarkperiodfrom12to4hours,followedbysequential darkperiodexpansionby2hourseveryotherday.Preliminarydatarevealsthataftersleeprestriction,animals exhibitthreefoldincreasesinsleepefficiencyandsleepconsolidation.Thus,thecentralhypothesisofthis proposalisthatbehavioralsleeptherapyaltersactivityofsleeppromotingcenters,allowingformoreefficient andconsolidatedsleep,whichcanbeleveragedtoproducesleepimprovementinagingandAlzheimer?s diseasemodels.Thishypothesiswillbepursuedthrough3specificaims.
Aim1 willinvestigatehowactivityin sleepcenterschangeswithsleeprestriction,andwhichbrainregionsarenecessaryforimprovementsinsleep.
Aim2 willelucidatetheeffectsofbehavioralsleepmodificationontheagedbrain.
Aim3 willanalyzethe changeinbehavioralandmolecularoutcomeswithsleeprestrictioninamodelofAlzheimer?sdisease. Successfulcompletionoftheseaimswillelucidatethecellularmechanismsofbehavioraltherapy,validate sleeprestrictionasatherapeuticstrategyforagingandAlzheimer?sdisease,andserveasafoundationto searchformoleculartargetsthatcanbetranslatedintolong-termtreatmentsforhumanpatients.
Sleepdegradeswithaging,andsleepdisturbancesareoftenthefirstclinicalsignsofAlzheimer?s disease.IwillseektoreversesleepfragmentationduetoagingandAlzheimer?sdiseasethrough behavioralsleepmodificationinDrosophila.Iwillusethismodelsystemtoprovideawindowinto thecellularchangesoccurringwithbehavioraltherapy,pioneeringnewsleep-basedtherapeutic strategiestoameliorateneurologicchangesassociatedwithagingandAlzheimer?sdisease.
