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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4693_Библиотеки_им_академика_М_И_Перельмана

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☆
epitheliuminfiltratingthesensoryregions.
31,76
However,theextentanddegreeofdegenerationishighly
variable amongindividuals, andis probablyinfluencedbyexposures, infections,andotherfactors that
impairtheabilityofthetissuetoregenerate.
Fig. 2.9 Immunofluorescent staining of human olfactory epithelial biopsies. Nuclei are stained blue with DAPI. Scale bars are 20 μm.
(MethodsasinKern2000.
10
ImagescourtesyofKarenKYee,MonellChemicalSensesCenter,Philadelphia,PA.)
aTissueexhibitingalteredmorphologyduetochronicinflammation, withhorizontallyalignedsquamouscellsalongthesurface.AnnexinV,a
markerofapoptoticcelldeathisshowningreen.Ki67,amarkerofcelldivision,islabeledinred.
bSupportingcelllocalizationofcytokeratin18(CK18).
cOlfactorymarkerprotein(OMP)immunostainingincellsthataredysmorphicandabnormallysituatedininflamedtissue.
OdorantsaredetectedviaalargefamilyofG-protein-coupledreceptorsthatuseasignalingcascade
that amplifies eachbinding eventtoenable detectionofextremely low concentrationsof volatile
stimuli.
Odorantsare boundtoreceptorsoftheG-protein-coupledreceptor(GPCR)class,which,inhumans,is
estimated to have 300 to 400 functional members with perhaps twice as many pseudogenes.
77,78
 The
majority of these putative ORs remain orphans, although data suggest that each OR binds to a small
numberofodorantligands,andthateachodorantligandisrecognizedbyasmallnumberofORs.
79
Each
matureORNappearstoexpressonlyasingletypeofOR,althoughexpressionofmultipleORsmayoccur
transiently.
80,81
This structuralconfigurationprovides thebasisforodor recognitionviaactivationofa
uniquepatternofORNsprojectingtodistinctglomeruliintheolfactorybulb(seeChapter3).Bindingto
these receptors is transduced to an action potential in the majority of ORNs via a cascade involving
activationof adenylatecyclase, opening of a cyclic nucleotide-gated,nonselective cationchannel, and
cellulardepolarization(Fig.2.10).Thispathwayisrelativelyinefficientasaresultofthelowaffinityof
odorantbindingandrelativelyinefficientsynthesisofcyclicadenosinemonophosphate.Toaccommodate
this,ORNsaccumulatechloride,particularlywithinthecilia,andrapidchlorideeffluxviaNa
+
/K
+
/2Cl
-
co-transport
82
 and a calcium-gated chloride channel
83
 enable a depolarization of significant rate and
magnitudetotriggeranactionpotentialalongtheaxon.Thissignaldetectionandamplificationprocess,
togetherwith theconvergence ofsignals in the olfactorybulb,supportsdetectionofvolatile stimulias
low as parts per trillion for certain odorants, even by the often underappreciated human nose!
84
TerminationofthesignaloccursascalciumisremovedviaCa
2+
/ATPaseand,toalesserdegree,through
Na
+
/Ca
2+
exchange(Fig. 2.10).
85
Calciumalsoresultsinadaptation viacalcium-dependentkinases and
subsequentphosphorylationofproteinswithinthesignalingcascade.
86
InadditiontoORs,ORNsexpress
over30othertypesofGPCRs,includingnoradrenergic,cholinergic,
87
dopaminergic,
88,89
andpurinergic
90
receptors.Thus,modulationofORNfunctioniscomplex,evenattheinitialstepsinodorperception,and
it is easy to envision why many pharmaceuticals, xenobiotics, and health conditions affecting these
pathwaysmayalsohaveadisruptiveimpactonoursenseofsmell.
Olfactory epithelial biopsies can be obtained from living subjects for primary culture and as a
sourceofstemcell–likecellswithmultipotentdifferentiationcapacity.
Inhumans,theolfactoryneuroepitheliumisaccessibleviabiopsyusingrelativelysimpleprocedures,and
olfactoryepithelialbiopsieshavebeenestablishedasaviableapproachtoobtainfreshsensoryepithelial
tissue for physiological and molecular studies.
34,69,91
 Such tissue represents a uniquely accessible
neuroepitheliumavailablefromlivingsubjects,andstudiesusingthistissuehaveprovidednovelinsights
intotheneuropathologyofpsychiatricdisorderssuchasbipolardepression,
92
schizophrenia
93,94
andRett
syndrome.
95
Whileexvivopreparationsprovidetheabilitytoexaminethenativecells,theyaresubjectto
the effectsofdissociationandtissueextractiontrauma,whichmaycompromiseandaltertheircellular
physiology. Accordingly, methods have been developed to use biopsied epithelium as the source of
precursor cells, which may be grown under conditions conducive tothe generationofneuronal
63,64
 or
non-neuronal
96,97
 cells. In these cultures, cells may be generated that express both molecular and
functional properties of the desired cell type. The OE-derived precursor cells express markers and
multipotentcapacityindicativeofmesenchymalstemcells.
97–101
Rapidadvancesarebeingmadeinour
understandingofthegrowthfactorsandconditionsunderwhichthesecellsfunctioninvivo,andmaybe
differentiated in vitro to express functional characteristics of osteogenic, adipogenic, audiogenic, or
neurogenic cells. The ability to obtain such cells from a living patient for their own use, avoiding
concernsofrejection,makeitlikelythatthesecellswillserveaprominentroleinregenerativemedicine
inthefuture.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Fig.2.10Signalingcascadeofeventsoccurringwithintheolfactoryciliainvolvedin translatingthe odorantbindingeventintoanelectrical
signalcarriedalongtheaxontotheolfactorybulbandterminationoftheodorantbindingsignal.(ArtworkbyCourtneyLoveless.)
AMP,adenosinemonophosphate;ATP, adenosinetriphosphate;Ca
2+
,calciumions; cAMP,cyclic AMP; Cl
-
,chloride ions;GDP,guanosine
diphosphate;GTP,guanosinetriphosphate;Na
+
,sodiumions.
Whileremarkableinitsabilitytoovercomethedailyonslaughtofenvironmentalexposure,thehuman
OEisalsosensitivetodamagefrominfection,irritation,aging,andthedirectandindirectconsequences
of many diseases and their treatments. Being aware of these consequences will help the clinician
understandthepotentialcausesfortheirpatient'solfactorydysfunctionandthefactorsthatmaycontribute
toimprovement.
Acknowledgments
The author acknowledges the fine technical assistance of Grant J. Currie and Lucas D.Wright of St.
Lawrence University in the preparation of Figs. 2.1, 2.2 and 2.3 and the generosity of Dr. Steven
YoungentobofSUNY,UpstateMedicalUniversity,Syracuse,NY,forprovidingFigs.2.5and2.6.
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3FunctionalAnatomyoftheOlfactorySystemII:CentralRelays,
Pathways,andtheirFunction
JessicaFreiherr,MartinWiesmann,MartinWitt
Introduction
Thefirststepsofcentralolfactoryprocessingareaccomplishedinphylogeneticallyoldbrainstructures
located in the basal forebrain and medial temporal lobe, which are activated simultaneously or
consecutively.Higherorderolfactoryprocesses,includingconsciousolfactoryperception,convergence,
lateral inhibition, adaptation/habituation, and central integration ofolfactory inputs with other sensory
stimuli (e.g.,gustatory,trigeminal,mechanosensory, auditory,andvisualafferents), aremediatedinthe
mentionedbrainstructuresaswellasinneocorticalareasthatarenotspecificforolfactoryprocessing.
Collectively, these processes enable an individual to create adequate reaction patterns to a changing
externalenvironment.
This chapter aims to provide insights into the anatomical brain structures involved in olfactory
processing. Most canonical features of the central olfactory anatomy were studied in animals in a
laboratorysetting;dataderivedfromobservationsinhumansarementioned whennecessary.Moreover,
theauthorsintendtolinktherespectivefunctionalityofabrainareatoitsanatomicalfeatures.
KeyHypothesesofCentralOlfactoryProcessing
• In contrast to other ascending sensory systems, olfactory fibers project directly to the
telencephalon, mainly without a thalamic relay. Thus, incoming olfactory information is not
filteredandmonitoredinthethalamusbeforeenteringneocorticalareas.
•Themaincentralgateforolfactoryinputsistheolfactorybulb,inwhichthefirsttopicalmapfor
odorrepresentationisgenerated.
•Theolfactorysystemisorganizedinananatomicallyunilateralmanner.Veryfew,ifany,canonical
olfactoryfibersusecommissuraltractstoentercontralateralbrainareas.
• Evidence of olfactory lateralization (i.e., representation of specific olfactory tasks within one
hemisphere)isprovided.
OutlineofOlfactoryPathways
Olfactory pathways subdivide into bulbofugal fibers originating in the olfactory bulb (OB) and
terminating incortical areas andcorticofugal fibers in reversed orientation (arising in the cortex and
projectingtothe OB). Thelatterprobablymediatetop-downmodulation ofolfactory perception at an
earlyprocessinglevel.
BulbofugalFibers
Axons of olfactory receptor neurons (ORNs) collect into~20 bundles, the olfactory fila, which pass
through 1- to 2-mm-wide holes in the cribriform plate and connect to mitral/tufted cells in the OB.
Collectively,theseprojectionsmakeuptheolfactorynerve(cranialnerveI).Axonsofmitral/tuftedcells
formtheolfactory tract. Thefactthat the olfactory tract divides into a medial, anintermedial, and a
lateral portion, or stria, has been derived from animal observation and cannot be found in humans.
1
Therefore,inhumans, thelateral olfactorytract(LOT)is consideredthe onlyprojectionfrom the OB
terminatinginasetofstructures.Thecommonlyusedterminology,primary/secondary/tertiaryolfactory
cortex,forprojectionareasfromtheOBissomewhat misleading,astheOBalreadycomprises typical
corticallayersand accomplishesfunctionalprocessescomparable tothose ofprimarycorticesinother
modalities.
2
Therefore,inouropinion,theOBshouldbeconsideredaprimaryolfactorystructure.The
targetareasofthebulbarmitral/tuftedcellsassecondaryolfactorystructuresaretheanteriorolfactory
nucleus(AON),piriformcortex(pirC),medialnucleioftheamygdala,periamygdaloidcortex,andthe
entorhinal cortex (Figs. 3.1 and 3.2). The entorhinal cortex occupies the anterior part of the
parahippocampal gyrus (Brodmann area 28), and probably targets an area underlying the anterior
perforated substance, namely the ventral striatum, especially its major structure, the nucleus
accumbens.
3
Theentitiesofthoseareasarecommonlynamed“olfactorycortex.”
Fig.3.1 Simplified schematic drawing of the essentialbulbofugalolfactory pathways, deriving frommitralcells of the olfactory bulb. The
lateralolfactorytractcarriesdirectconnectionstosecondaryolfactorystructures(“olfactorycortex”),beforetertiaryolfactorystructuresare
reached.Contralateralprojectionsandotherafferentstotheolfactorybulbarenotindicated.
Fiber connections from the above-mentioned structures project to associated neocortical areas,
tertiary olfactory structures,whichare not exclusivelyspecificolfactory areas:theorbitofrontal gyri
and,incloseproximity, theanterior insula, which is reachedeither directlyor througha relayin the
dorsomedial thalamic nucleus.
4
 Aseries ofeitherdiencephalic or telencephalic structures is reached
from theamygdala or entorhinalcortices, for example, septal nuclei, bed nucleus of stria terminalis
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(BNST)inthehypothalamus,andhippocampalformation.
Furthermore, a subset of mitral cell collaterals project from the anterior olfactory nucleus to the
contralateralolfactorybulbusingtheanteriorcommissure.
The entity oftheolfactory fila inthe olfactoryepithelium in the upper nose is termedthenervus
olfactoriusorfirstcranialnerve.
Fig.3.2a,bProjectionsfromthemitralcellsoftheolfactorybulbtocentralolfactoryareas.
aOlfactoryprojectionsattherighthumanbasalforebrain(top,anterior;right,medial).Mostolfactorystructuresarevisibleonthesurfaceof
thebrain withoutfurtherdissection. The lefthemisphere isremoved.Redlineindicates projectionsfromthe olfactory bulb(OB) via the
lateralolfactory tract(LOT) tothe piriform (Pir)and entorhinal(Ent)cortexand tothe medialamygdalaandperiamygdalar cortex(A).
From there,the blueline indicates projectionsintoneocortical targets:insula (Ins)and orbitofrontalgyri(aOF,anterior; lOF,lateral; mOF,
medialorbitofrontal gyrus), and probably to the ventral striatum (dotted blue lines dorsalto the anterior perforated substance, which is
indicatedbythedottedrectangle).Thewhitedottedlineindicatesprojectionstothecontralateralolfactorybulbviatheanteriorcommissure.
Theanteriorolfactorynucleus(AON)issituateddiffuselywithintheovaloftheolfactorypeduncle(OP).CM,corpusmamillare;GR,rectal
gyrus;OT,opticaltract;Po,Pons.TheasteriskanteriortotheOTmarksthediagonalbandofBroca,carryingfibersfromtheamygdalato
septalnuclei.Therighttemporalpole issomewhatrepositionedtoshowthesharpbendoftheolfactorytractintothepiriform cortexand
projectionstotheinsula.
bCentralolfactoryprojectionsandcorticalareasoverlaidonastructuralT1-weightedmagneticresonanceimage(coronalplaneattheanterior
commissure[AC]).Thelateralolfactorytractprojectsintothepiriformcortex(Pir,red)andinmedialamygdalarregions(A,yellow)ending
intheentorhinalcortex(Ent,red).Underneaththestriatum(CN,caudatenucleus;Pu,putamen)andpallidum(Pa),onecanfindtheventral
pallidum(vPa)situatedmoremediallyandtheventralstriatum(vPu)situatedmorelaterally.OS,olfactorysulcus;Ins,insula.
CorticofugalFibers
Though not entirely established in humans, animal data provide evidence for several glutamatergic,
adrenergic,cholinergic,andserotonergicprojectionsterminatingintheAONandOB.Theyarebelieved
topartlytakethe samerouteasthe “medialolfactorytract(stria)” in animals,althoughitsexistencein
humanshasbeenquestioned(seeabove).Thefunctionalsignificanceofcorticofugalfibershasnotbeen
investigated yet; however,they are assumedtomediate top-downmodulationof olfactoryinformation,
suchasolfactorylearningormemory.
5
CorticalOlfactoryAreasandtheirFunction
TheFirstOlfactoryProcessingRelay:OlfactoryBulb
TheOBisthefirstrelayforincomingORNsandisresponsibleforacondensationandamplificationof
olfactory information. It is located bilaterally upon the cribriform plate and is surrounded by the
subarachnoidspacefilledwithcerebrospinalfluid.Inhumans,itssizevariesconsiderably(rangingfrom
0.5 to 1.5 mm; Fig. 3.3) depending on individual olfactory performance.
6,7
 As an extension of the
prosencephalon,theOB presents a laminar structurethat is similar tothe laminarstructure of cortical
areas(Fig.3.4).Occasionally,avesiclemaybepreservedasadevelopmentalrelict.
8,9
Fig.3.3Olfactorybulb(OB)ofarat(left)andahumanbrain(right).TheabsolutesizeofthehumanOBisverysimilartothatoftherat,but,
inrelationtothetotalbrainmass(1500gversus2g),rathersmall.(OBsdelineatedinbrackets.)
Fig.3.4a–cSummaryofthesynapticorganizationofthemammalianolfactorybulb.(Fig.3.4aadaptedfromMorietal.
2
)
aSchematic organization ofthe olfactory bulb. Arabic numbers indicate the cortical structure: 1,nerve fiber layer;2,glomerular layer;3,
externalplexiformlayer;4,mitral/tuftedcelllayer;5,internalplexiformlayer;6,granulecelllayer.Glomerularcoding:Axonsofreceptorcell
expressingthe same olfactory receptorproject toonly a few analogousglomeruli (e.g.,“blue”olfactoryreceptorneurons converge with
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