PTSD is a stress-induced disorder characterized by a cluster of symptoms, including persistent, extinction- resistant memory. Behavior modification, such as exposure therapy, and pharmaceuticals have had limited success in treating PTSD, with outcomes ranging from unresponsive to an exacerbation of symptoms. As a result, there is an urgent need to develop improved therapeutics. However, therapeutic development cannot progresswithoutabetterunderstandingoftheneurobiologicalmechanismsthatunderliePTSD.Toaddressthis gap,anovelmousemodelofPTSDemployingstress-enhancedfearlearning(SEFL)willbeused.Thismodel hashighfaceandconstructvalidity,withasubgroupofmalesfromtheinbredC57BL/6Jmouselinedisplaying severalPTSD-likefeatures,including(1)extinctiondeficits,(2)feargeneralization,(3)heterogeneousresponse tostress,suchthat?resilient?and?susceptible?phenotypesdevelopwithinthesameSEFLtreatedgroup,(4) persistenceofthetraumaticmemoryformorethan30days,and(5)exaggeratedstartlereflex.Consistentwith the human literature on PTSD, these mice also show altered Fos activation in two PTSD-associated brain regions;?hypoactivationoftheinfralimbiccortex(IL)andhyperactivationinthebasolateralamygdala(BLA)with remotememoryretrieval.ItiswellestablishedthattheBLAandIL,whicharereciprocallyconnected,playavital role in the regulation of fear memories. Therefore, the central hypothesis of this proposal is that altered communicationbetweentheBLAandILunderliesthepersistent,extinction-resistantfearmemoriespresentin micetrainedinthisSEFLmodelofPTSD.GiventhatwomenaretwiceaslikelytodevelopPTSD,itisimperative thatanimalmodelsbeusedthateffectivelyrecapitulatethedisorderinbothsexes.Therefore,inthefirstaim, theSEFLprotocolwillbevalidatedinfemalesusingaseriesofbehavioralandphysiologicaltests,withthegoal ofidentifyingaprotocolthatproducesinterindividualvariabilityinstresssusceptibility,asisthecaseinmales. TheworkinghypothesisforthisaimisthatSEFLwillproduceaPSTD-likephenotypeinasubgroupoffemale mice.
Inthe secondaim, theSEFLparadigmwillbeappliedtobothsexestointerrogatetheneurocircuitrythat supportsthepersistenceofextinction-resistantfearmemories.Theworkinghypothesisisthatdysregulationof celltype-specificBLAinputsontotheILsupportstress-enhanced,extinction-resistantfearmemories.Toassess the functional importance of the IL to extinction of PTSD-like memories, following identification of the cellular identityofactivatedneuronsintheILandBLA,achemogeneticapproachwillbeemployedtodeterminethe functionaleffectofmanipulatingthisregion?sactivityonfearmemoryexpressionfollowingSEFLtraining.Activity ofmonosynaptic,celltype-specificILinputswillthenbeidentifiedusingmodifiedrabiesvirus.Thisproposalis expectedtogreatlyexpandourknowledgeoftheneurobiologysupportingPTSD-likememories.
PTSD is a stress-induced disorder with higher prevalence among women and characterized by traumatic, extinction-resistant memories. Using a novel mouse model of stress enhanced-fear learning that recapitulates several hallmark features of the disorder in males, we will extend validation to females and interrogate the underlying brain circuitry to gain insight into the neurobiology for improved therapeutic development.
Sillivan, Stephanie E; Joseph, Nadine F; Jamieson, Sarah et al. (2017) Susceptibility and Resilience to Posttraumatic Stress Disorder-like Behaviors in Inbred Mice. Biol Psychiatry 82:924-933 |