NEUR3005–Semester1BefamiliarwiththemajorcellularbuildingblocksofthecentralnervoussystemNeurons–DerivedfromNeuralStemcells
• 100billionneurons(butonlymakeuponly10%ofallbraincells)
• Mostneuronalproliferationinfirst5mths• Mostneuronaldifferentiation4-9mths
• Neuronalconnectionscontinuetoformpostnatally(afterbirth)
Glialcells(“glue”) Function
Astrocytes • Homeostaticfunctions(recycleglutamate)+respondstoinjury• Structuralsupportofbrain
• ContributetoBBB
Oligodendrocytes Myelinationofaxonsforfasterconduction(occurspostnatally)
Microglia • ResidentimmunecellsofCNS�phagocytosis+responsetoinjuryo Atrest=manymobileprocessesthatsurveyareao Active=fewprocessestocompletephagocytosis
Ependymalcells • Lineventriclesandchoroidplexus• ProduceCSF
*Glialcells(exceptmicroglia)arederivedfromneuralstemcellsbutdifferentiatelaterthanneurons
Befamiliarwiththedevelopmenttimelineof:theneuraltube,primaryandsecondaryvesicles,theventricularsystem,thetelencephalon,cerebralconvolutionsandwhitematter
• Neuronsarederivedfromtheectoderm(outerlayeroftrilaminarembryo)
Formationoftheneuralgroove(3rd
week)
• Midlinemesodermreleasessignallingmoleculeswhichleadtothickeningoftheoverlyingectodermtoformtheneuralplate
• Neuralplatesfoldsinwardstoformtheneuralgroove
Primaryneurulationandformationoftheprimaryvesicles(4th
week)
• Neuraltubecloses(Day20-26)+detachesfromtheectodermalsurface(theskin)o Day24:Rostralendcloses�brain
o Day26:Caudalendcloses�spinalcord
• Remainingneuralcrestcellsformperipheralnervoussystem(e.g.dorsalrootganglion,glialcells)
Neuraltubedefects• Failureoftherostralendoftheneuraltubetoclose=
catastrophicdevelopmentaldefect(miscarriage)• Failureofthecaudalendoftheneuraltubetoclose=
spinabifida
Understandtheoriginsofdorsal/ventral(spinalcord)versusmedial/lateral(metencephalon)organisationofsensoryandmotorsystems
Dorsal-ventralpatternsofdifferentiation• Ectodermnexttotheneuralplateproducesanopposingsignallingmoleculebonemorphogeneticproteins(BMPs)
o Differentiationintosensoryneurons
• Midlinemesoderm(andlaterthenotochord)releasesasignallingmoleculecalledsonichedgehog(SHH)o differentiationintomotorneurons
Alarplatevs.basalplatederivatives• Differentmorphologicalgradientsofsignalling
moleculesestablishafunctionalorganisation,whichpersistsintheadultspinalcord
• Alar(dorsal)derivatives=becomesensoryneurons
• Basal(ventral)derivatives=becomemotorneurons
Understandthegenepatterningwhichdrivesrostrocaudalorganisationofrhombomeres
• FGF8andRetinoicacid(RA)concentrationgradientestablishesarostral–caudalorientationthatdifferent
rhombomerestohavedifferentpatternsofdevelopment(giverisetodifferentcranialnerves)
Developmentofpartsofbrain
Notochordclosestoformprimaryvesiclesforms3parts:1. Prosencephalon2. Mesencephalon3. Rhombencephlon
Secondaryvesiclesdevelopfrom:
1. Prosencephalon�telencephalon,diencephlaon
2. Mesencephalon�midbrain(nochange)
3. Rhombencephlon�metencephalon,mylencephlon
Pontineflexure(formationof4thventricle)• Theneuraltubespreadsaparttoformadiamond-shapedcavity,withathinmembraneroof• Theopeningoftheneuraltubecausesthe:
o Dorsal(sensory)/ventral(motor)orientationinthespinalcord�becomeslateral(sensory)/medial(motor)inthebrainstem
• Sulcuslimitanspersistsasanimportantboundary
Shapingthetelencephalon(wks6-12)• Rostraltipoftheneuraltubeformsathinmembranecalled“laminaterminalis”
• Laminaterminalisistheoriginofthebridgebetweenthetwohemisphereswherebundlesofinterconnectingfibresbegintogrow(e.g.corpuscallosumandanteriorcommissure)
o Basalpartofthetelencephalonthickens�formpre-cursorofthebasalganglia
o Diencephalonthickens�formthalamusandhypothalamus,separatedbyhypothalamicsulcus
• ENDof3rdmonth=diencephalonandtelencephalonhavefused
Formationoftemporalandfrontallobes
• Eachcerebralhemisphereassumestheshapeofagreatarcaroundtheinsula�formsinsularlobe
o Insularcortexgrowsslower
• Partsofthehemisphereoriginallydorsaltotheinsulagetpushedaroundintothetemporallobe(i.e.thehippocampus)
• Sulci(fissures)+gyri(folds)areconvolusionstoincreaseSAofbrain
Progressivedevelopmentofcorticalconvolutions(ageinweeks)
ContinuedgrowthofthetelencephalonFurtherrapidgrowthleadstotheinsulacortexbeingovergrown
bythefrontal,parietalandtemporallobes
Cavityoftheneuraltubebecomestheventricularsystem
Understandtheprocessesofcellproliferation,migrationanddifferentiation
NeuronalProliferation(peak5wks�5mths)• Proliferationofneuroblasts
o Occursinventricularzone• Cleavageplaneduringcelldivisiondeterminesfate
• Verticalcleavage(early)=increasedproliferationcapacity
• Horizontalcleavage(late)=reducedproliferationasonedaughtercellmigratestopiasurfaceaslackingNumbgene
Notch-1cellmigratesawayandstopsdivisionwhileNumbcell
continuestodivide
Note:NumbusuallyinhibitsNotch-1
MigrationInside-Out’developmentofthecortex
• Neuroblastscrossthesubplatetoarriveinthecorticalplate(1stcellsbecomelayerVIneurons)
o Subplatedisappears
• Radialglialcells:Providescaffoldonwhichcortexisbuilttohelpneuroblastsmigratealongtheirthinfibrestothepiasurface
6layersofneuraoninadultcerebralcortex(VI→I)
Differentiation• Neuroblastsdifferentiateintoaneuronofaspecific
phenotype• Differentiationofastrocytes�peaksatbirth
• DifferentiationofOligodendrocytes�postnatal
Postnatalproductionofmyelin(T2weightedMRICSF=bright/Myelin=dark)• Mostmyelinationoccurspost-natally(alongwithsynaptic
connections)
• Blackareasofinternalcapsule,corpuscallosumandcortexappearmoremyelinatedasbabyages
L2:Bloodsupply,ventricles+theBloodBrainBarrierBloodsupply:generaloutlineofthearterialbloodsupplyandvenousdrainageofbrain
Brainbloodsupplycomesfrom:
• Internalcarotidartery(2/3)
• Vertebralarteries(1/3)
Internalcarotidarterysystem:
• Middlecerebralarteriesandtheirbranches�lateral
• Anteriorcerebralarteriesandtheirbranches�2/3anterior
Vertebralarteriessystem(ventralview):
• Posteriorinferiorcerebellararteries(PICA)
• Anteriorinferiorcerebellararteries(AICA)
• Superiorcerebellararteries(SCA)
• Posteriorcerebralarteriesandtheirbranches
• Anteriorandposteriorspinalarteries(difficulttoidentify)
Venousdrainage(ingeneraltermsonly)
*Superficial&deepcerebralveins(A,BandC)�drainintotheduralsinuses:
Ventricles:brainishollowandthecavitiesformfourdistinctventricles
LateralVentricles:• anteriorhorn
• body
• collateraltrigone
• posteriorhorn
• inferiorhorn
Fourthventricleandcerebralaqueduct: • Surroundedbybrainstemandcerebellum• Roofof4thventriclecreatedbysuperiorandinferiorcerebellum
Brainstem SurroundedbyMesencephalon(midbrain),ponsandmedulla
Schematicpictureofcisternsascavitiesinsubarachnoidspace
Cerebrospinalfluid(CSF)isformedinsidetheventricularsystem(ependymalcells,choroidplexus)andpassesthrough:
1. Interventricularforamen
2. 3rdventricle
3. Cerebralaqueduct
4. 4thventricle
5. Themedianforamen(ofMagendie)orlateralforamina(ofLuschka)*intothesubarachnoidspace
6. Cerebellomedullarycistern
7. Pontineorsuperiorcistern
8. Interpeduncularcistern
9. Cisternofthelateralcerebralfossa
10. Arachnoidgranulationsofsuperiorsagittalsinus
Cisternsofsubarachnoidspace:
Allventriclesarelinedbychoroidplexus(flooroflateralventricle,roofof3rdventricle,inferiormedullaryvenumliningposterior/inferioraspectof4thventricle),but*maybeblockedbychoroidplexus
Bloodbrainbarrier�“HematoencephalicBarrier”:
Whatisitsnature? Non-fenestratedendothelialcellswithtightjunctions
Howisitmaintained? Tightjunctionsaremaintainedbyadjacentastrocytes
Whatisitsrole? Toprotectbrainfromneuroactive/neurotoxicsubstancesentering
• Largemolecules(proteins)donotnormallygetthroughbutsometimesdo(includingviruses;HIV)
Canitgetdamaged? Yes,inpathologicalconditionssuchas:
• highBP
• infections
• braintumours+brainoedemas(stroke)
• multiplesclerosis
• specificcompounds(NAAG,Quinolinicacid,hormones)
Howtosubstancesgetacross?
1. ByActivetransport(fast)�D-glucose(butnotL-glucose)+essentialAA
2. Viacerebrospinalfluid(CSF)�vitamins+hormones
3. Bybecomingmorelipophilic
o Createdrugsthatarelipophilic(e.g.addingaromaticcomponent)tocrosstheBBB�e.g.caffeine,nicotine
o UseHighIntensityFocusedUltrasoundtocrossBBB
*DeVivodisease:Glucosetransport(viaGLUT1)iscompromised,patientstendtohaveseriousproblems,incl.mentalretardation