Seite - 77 - in Advances in Neuroimmunology

BrainSci. 2016,6, 16 usedasevendayabstinenceperiod toallowrats to recover fromfourdaysof intoxicationand the significantwithdrawalsequelae thatoccurs in thismodel [40].Moreover,becausesomeweight loss is observed in theMajchrowiczmodel [40], repetitivegavagemaybestressful [81], andbothof these aspectsmodulatemicroglial reactivity [78,82],agroupwithad libitumaccess to foodandwaterwas included.Noneof themeasuresofmicrogliaactivationweredifferentbetweenthead libitumgroup andtheCon/Congroupdespite theirslightweight lossandexperiencewithgavage.Moreover,weight lossdidnotcorrelatewithanymeasureofmicroglialactivation inanimals receivingethanol. Thepotentiatedmicroglia activation seen in this double bingeAUDmodel suggests that the microglialresponsecanbealteredbyethanolaloneandsupportstheideathatchronicethanolexposure canelicitamorepro-inflammatorystate thanasingleboutofbingeexposure. The lackofexpressionof ED-1andmorphologyofOX-42+andIba-1+cells support thatevenwith the twobinges, cellsarenot fullyorclassicallyactivated.However,microgliaare“further”downthespectrumtowardsclassical activation than a single binge alone. These data coupledwith the lack of evidence for classically activatedmicroglia inhumanalcoholicbrain—whether themarkersarenotexpressedornoonehas examinedthoseparticularmarkers—supports that initiallymicrogliaactivation is likelyaconsequence of alcoholic neuropathology and not a cause. Whether this increased response causesmicroglia to over-respond to insult or if itmakes thebrainmore susceptible to ongoingneuroinflammation should be considered in future experiments. In addition, how these effects relate to changes in neurodegeneration, specificallyneuronalorvolumeloss, isan importantareafor futurestudy. Because microgliahavethecapacity tomaintain lowgradeactivationoraprimedstate forextensiveperiods following insult, includingalcoholexposure [22,83], theepisodicnatureofbingedrinkingwould lead toa cycleof repeatedprimingandover-response in individuals suffering fromanAUD[18,38,65]. Understandingthemechanismsthatunderlieorcontribute toalcohol-inducedneurodegenerationmay provideanovel therapeutic target toamelioratedamageandprevent thedownwardspiral intoan AUD[14,84]. 5.Conclusions In summary, these studies present a novel viewof the impact of alcohol abuse onmicroglial activity. Specifically,datapresentedherein indicate thatalcoholcausesashift inmicroglialphenotypes to a primed state. Although this study focuses on how later bouts of alcohol can exacerbate the microglial response, the implicationsofanalcohol-inducedprimedmicroglial statealsoextendtohow themicrogliaofalcoholicsmayrespondto infectionsorotheralcohol related immuneresponses in the peripheral system.This researchprovidesacontext inwhich toconsider the implicationsofmicroglia onalcohol-inducedneurodegenerationandfurther indicates that targeting theneuroimmunesystem mayalleviatedeficitscausedbyexcessivealcoholconsumption. Acknowledgments:Theauthorsgratefullyacknowledgesupport fromNIAAA(R01AA016959;F31AA023459), NIDA(T32DA016176),andNIGMS(K12GM000678). Author Contributions: Alex Marshall and Kimberly Nixon conceived and designed the experiments; AlexMarshall andChelseaGeilperformedtheexperiments;AlexMarshall analyzedthedata; andall authors contributedto the interpretationof thedata,writingandediting themanuscript. Conflictsof Interest:Theauthorsdeclarenoconflictof interest. Abbreviations Thefollowingabbreviationsareusedin thismanuscript: AALAC Associationfor theAssessmentandAccreditationofLaboratoryAnimalCare ANOVA AnalysisofVariance AUD AlcoholUseDisorder BBB BloodBrainBarrier BEC BloodEthanolConcentration 77