感觉神经元感知消化系统的伸展及营养

ArticleSensoryNeuronsthatDetectStretchandNutrientsintheDigestiveSystemGraphicalAbstractHighlightsdGeneticdeconstructionofvagalafferenttypesthatmonitorandcontroldigestiondGPR65neuronstargetintestinalvilli,detectnutrients,andcontrolgutmotilitydGLP1RneuronsformspecializedterminalsthatdetectstomachandintestinestretchdCodingofautonomicinputsinvagalganglionandbrainstemAuthorsErikaK.Williams,RuiB.Chang,DavidE.Strochlic,BenjaminD.Umans,BradfordB.Lowell,[e-mail]onssendingsignalsfromtheguttothebraincontroldigestion.Onedenselyinnervatesintestinalvillianddetectsfood,whileanothertargetsstomachandintestinalmuscleandsensesstretch.Williamsetal.,2016,Cell166,1–13June30,2016ª2016ElsevierInc.*1DepartmentofCellBiology,HarvardMedicalSchool,Boston,MA02115,USA2DivisionofEndocrinology,DiabetesandMetabolism,DepartmentofMedicine,BethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,MA02115,USA3Co-firstauthor*Correspondence:[e-mail](GPR65neurons)andmechanicaldistensionofthestomachandintestine(GLP1Rneurons).Optogenetics,invivoganglionimaging,andgeneticallyguidedanatomicalmappingprovidedirectlinksbetweenneuroniden-tity,peripheralanatomy,centralanatomy,conduc-tionvelocity,responsepropertiesinvitroandinvivo,andphysiologicalfunction.Thesestudiesclarifytherolesofvagalafferentsinmediatingparticularguthormoneresponses.Moreover,geneticcontrolovergut-to-brainneuronsprovidesamolecularframe-workforunderstandingneuralcontrolofgastrointes-tinalphysiology.INTRODUCTIONInadditiontoourexternalsensesofsight,smell,sound,touch,andtaste,internalsensorysystemswithinourbodyrelayvitalin-formationtothebrainaboutphysiologicalstate.Thevagusnerveisamajorinformationhighwayfromtheperipherythatinner-vates,surveys,andcontrolsseveralprincipalphysiologicalsystems.Withinthegastrointestinaltract,vagalsensoryneuronsmonitorstomachvolumeandintestinalcontents,andresponsiveneuralcircuitsregulatedigestivephysiology(Brookesetal.,2013).However,amolecularandgeneticclassificationofgastro-intestinalfiberswithinthevagusnerveisnotavailableandwouldfacilitatemechanisticstudiesofgut-to-brainsignalinginhealthanddisease.Themousevagusnervecontains
2,300sensoryneuronswithcellbodiesingangliaatthebaseoftheskull,aswellasasmallergroupofmotorneuronswithsomainthebrainstem.Eachsensoryneuronhasbothaperipheralterminalthatinter-faceswithaninternalorganandacentralbrainstemterminal.Classicalanatomicaltracingstudiesrevealedavarietyoftermi-naltypeswithinthegastrointestinaltract(Berthoudetal.,2004).Stomachterminalsincludemucosalendings,intraganglioniclaminarendings(IGLEs),andintramusculararrays.GastricIGLEscontactentericgangliabetweenlayersofstomachmuscle(Foxetal.,2000)andareproposedtosensestomachstretch,astheyarenearsitesofmechanosensation(Zagorodnyuketal.,2001).Intheintestine,vagalafferentsformIGLEs,endingsnearintestinalcrypts,andfreeterminalsembeddedwithinthelaminapropriaofintestinalvilli(Berthoudetal.,2004).Vagalafferentshavebeenproposedtodetectnutrientsatseverallocations,includinginproximalanddistalintestineandthehepaticportalsystem(Maljaarsetal.,2008;Ru¨ttimannetal.,2009).Becausevagalafferentsdonotdirectlycontacttheintestinallumen,vagalnutrientdetectorsarelikelytobesecond-orderchemosensoryneurons.Terminalsinintestinalvilliareexcellentcandidatestocontributetonutrientdetection;how-ever,specificcharacterizationofsensoryneuronswithvillousterminalshasbeentechnicallychallenging.Lumen-proximalendingsweredefinedinsomestudiesbysensitivitytomucosalstrokingorluminalanesthetics(BlackshawandGrundy,1990;Richardsetal.,1996);however,thesemanipulationsmaynotselectivelyimpactallvillousterminals.Additionalinsightscouldbeprovidedbygeneticallydefiningnutrient-responsivevagalafferentsandsubsequentlyexaminingtheirterminalfieldsintheperiphery.Differentmodelshavebeenraisedforhowthevagusnervere-ceivesandencodesinformationaboutingestednutrients.Somestudiesreportedpolymodalresponsesofsinglevagalafferentstointestinalnutrients,aswellastochangesinosmolarityandpH(MeiandGarnier,1986;Zhuetal.,2001).Otherstudiesconcludedthatvagalafferentsarehighlytunedforspecificnutrients,withdifferentfibersdedicatedforsugars,aminoacids,andfats(Jean-ningros,1982;Laletal.,2001;Mei,1978).Ingestednutrientsacti-vat