SleepdeprivationisachronicandwidespreadhallmarkoflifeinmodernAmerica.Oneofthestrongestand mostcostlyeffectsofsleepdeprivationisitseffectonmemory.Multiplelinesofevidenceindicatethatsleep promotestheformationandstabilizationofmemoriesthroughchangesinthesynapsesofindividualneurons mediatedbycyclicadenosine3?,5?monophosphate(cAMP)proteinsignaling(aprocessknownas?cellular memoryconsolidation?),andthroughchangesintheoscillatoryactivitiesofneuronalcircuitsduringwhichother brainregionssynchronizewiththehippocampus(aprocessknownassystemsmemoryconsolidation).When animalsaredeprivedofsleep,theyshowbothanimpairedabilitytoformnewmemoriesandareductionin cAMP-dependentformsofsynapticplasticityinthehippocampus.However,thecausallinkbetweencellular andsystemsconsolidationofmemoryremainsunknown.Recently,Havekes,Abel,andcolleaguesdeveloped aviralvectorwhichintroducesaGs-coupledDrosophilaoctopaminereceptortoincreasecAMPlevelsin excitatoryneuronsinspecificregionsofthebrain(1).Byinfusingthisvectorintothehippocampusofmiceand activatingitwithoctopamineinjectionsduringsleepdeprivation,Havekesetalwereabletopreventtheusual effectsofsleepdeprivationonbothsynapticplasticityandobjectlocationmemory,ataskwhichisknownto dependonthehippocampusandonsleepafterlearning.Inthisproposal,weaimtocombinethisnovel chemogeneticmanipulationforenhancingneuronalcAMPsignalingwithlarge-scaleextracellularrecordings fromthehippocampusandprefrontalcortexofratsduringtraining,sleepdeprivation,recoverysleep,and memoryretrieval.Wewilldetectandmeasurethenetworkoscillationswhichhavebeenimplicatedinsystems memoryconsolidationduringsleepaswellaswakingrest,includinghippocampalsharp-waveripples,sleep spindles,corticalslow-waveactivity,andthetaoscillations.Basedonourownandothers?previouswork,we hypothesizethatsharp-waveripplesarethemostimportantmechanismfortheconsolidationofmemories,and thatenhancedcAMPsignalingwillspecificallyincreasetherateandreplaycontentoftheseeventsduringboth sleepandwakingrest.Theseexperimentswillbecriticallyvaluableforscientistsworkingtoexplainhow molecularchangesinthesleepingbraintranslateintochangesinthebehaviorofneuronswhichconsolidate memories,andforresearchersdevelopingpharmacologicalinterventionstoovercomethedetrimentaleffects ofsleepdeprivationinhumans.
Evidenceindicatesthatspecifichippocampaloscillationshelptoformandstabilizememories.Usinga novelchemogenetictool,wewillinvestigatehowtheseoscillationsrespondtoatransientincreaseinneuronal cyclicadenosinemonophosphatesignalingwhichhasbeenshowntoovercomethedetrimentaleffectsofsleep deprivationonmemoryandplasticity.
