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