Abstract

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.

Public Health Relevance

Sleepdegradeswithaging,andsleepdisturbancesareoftenthefirstclinicalsignsofAlzheimer?s disease.IwillseektoreversesleepfragmentationduetoagingandAlzheimer?sdiseasethrough behavioralsleepmodificationinDrosophila.Iwillusethismodelsystemtoprovideawindowinto thecellularchangesoccurringwithbehavioraltherapy,pioneeringnewsleep-basedtherapeutic strategiestoameliorateneurologicchangesassociatedwithagingandAlzheimer?sdisease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AG058409-02
Application #
9663195
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mackiewicz, Miroslaw
Project Start
2018-03-01
Project End
2019-09-30
Budget Start
2019-03-01
Budget End
2019-09-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104