Abstract

Sleepapneaisassociatedwithautonomic,cardiovascular,metabolicandcognitiveco?morbidities.The incidenceofsleepapneaintheUnitedStatesrangesfrom2?4%inthegeneralpopulation,andisupto15times greaterinindividualswithspinalcordinjury(SCI).Adjustmentsintheneuralmodulationofthearousal threshold(AT),chemoreflexsensitivitytohypoxiaandhypercapnia(CS)andupperairwaypatencyarethree criticalfactorsthatcontributetoexacerbationofsleepapnea.Theexactneuromodulatorsthatcontrolthese variablesareenigmatic,butonepossibilityisserotonin(5HT)anditstargetreceptors.Thus,plasticityof5HT neuronsmayaccountformodificationsintheAT,CS,upperairwaypatencyandultimatelybreathingstability inintactandspinalcordinjured(SCI)animals.Wewillexploretheroleof5HTinmodulatingthecritical factorsthatexacerbatesleepapneainintactandSCImice.
Aim1 ofourproposalwillexaminetheimpactof 5HTontheATandCStoultimatelydeterminetheimpactonsleepdisorderedbreathing.
Aim2 willexplore whethermodificationsin5HTlevelsand/orreceptorsub?typesfollowingSCI,arecoupledtomodificationsin theATandCSleadingtohypoventilation,bluntingofupperairwaymusclefunctionandincreasesinthe frequencyanddurationofapneaevents.
Aim3 willdeterminewhethermodificationsin5HTlevelsand/or receptorsub?typesfollowingSCI,arecoupledtoincreasesinupperairwaycollapsibility.Toexplorethese relationshipsunanesthetized,spontaneouslybreathingintactandSCItryptophanhydroxylase2knockout (TPH2?/?)andwildtype(TPH2+/+)micewillbeemployed.TheabsenceofTPH2resultsinthedepletionof centralnervoussystem5HT,whiletherapheneuronsremainintact.Wewillmeasureventilatoryparameters, theATandCSbeforeandafterSCIinTPH2+/+andTPH2?/?mice.Breathingeventswillbedetectedduringsleep viaelectroencephalograms.Apneiceventswillbeuncoveredbymonitoringventilationanddiaphragmatic electromyography,whilemonitoringofgenioglossusmuscleactivitywillbeusedtodetectmodificationsin upperairwaymusclefunctionbeforeandafterSCI.Ourresultswillestablishifmodificationsin5HT modulation,eitherviageneticdepletionorSCI,leadstoalterationsintheAT,CS,upperairwaymuscle functionandultimatelybreathingstability.

Public Health Relevance

Sleepdisorderedbreathingisassociatedwithanumberofhealthproblems.Theincidenceofsleepdisordered breathingisincreasedsignificantlyinindividualswithspinalcordinjury.However,thereasonsforthis increaseareunknown.Theincreasemayberelatedtoabluntingofthearousalandventilationresponseto decreasesinoxygenlevelsandincreasesincarbondioxidelevelsbecauseofchangestoserotoninneurons followingspinalcordinjury.Ourstudywillexplorethesepossibilitiesusinganon?anesthetizedspontaneously breathingmousemodelwithorwithoutgeneticdepletionofcentralnervoussystemserotonin,beforeand afterspinalcordinjury.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX003946-02
Application #
9591289
Study Section
Respiration (PULM)
Project Start
2018-01-01
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
John D Dingell VA Medical Center
Department
Type
DUNS #
002643443
City
Detroit
State
MI
Country
United States
Zip Code
48201