Discharge
properties
of
neurons
recorded
in
the
parvalbumin-positive
(PV1)
nucleus
of
the
rat
lateral
hypothalamus
Alessandra
Lintas
a,b,∗aDepartmentofMedicine/UnitofAnatomy,UniversityofFribourg,Switzerland bNeuroheuristicResearchGroup,HECLausanne,UniversityofLausanne,Switzerland
h
i
g
h
l
i
g
h
t
s
•Random-likefiringcharacterizedthemajorityofPV1cells.
•OscillationsinthedeltarangewereobservedintheposteriorpartofPV1nucleus. •Theasynchronousactivityproducesanetwork-driveneffectonthePV1-targetarea.
Thisstudyreportsforthefirsttimetheextracellularactivityrecorded,inanesthetizedrats,fromcells locatedinanidentifiedclusterofparvalbumin(PV)-positiveneuronsofthelateralhypothalamusforming thePV1-nucleus.Random-likefiringcharacterizedthemajority(21/30)ofthecells,termedregularcells, withamedianfiringrateof1.7spikes/s,Fanofactorequalto1,andevenlydistributedalongthe rostro-caudalaxis.Fourcellsexhibitinganoscillatoryactivityintherange1.6–2.1Hzwereobservedonlyin theposteriorpartofthePV1-nucleus.TheasynchronousactivityofPV1neuronsislikelytoproducea “network-driven”effectontheirmaintargetwithintheperiaqueductalgraymatter.Thehypothesisis raisedthatbackgroundrandom-likefiringofPV1-nucleusisassociatedwithfunctionalnetworkactivity likelytocontributedynamicinformationrelatedtoconditiontransitionsofawarenessandnon-conscious perception.
1. Introduction
Severaltypesofcellsintermingledwiththeaxonsofthemedial forebrainbundlearelocatedinthelateralhypothalamicarea(LHA). Thesecellgroupshavetendencytobewidelydispersed,ratherthan confinedwithinanatomicallydistinctnuclei,despitethefactthey oftenformgroupsoffunctionallyrelatedneurons[1,2].Onthe con-trarytothistendency,inthelateralhypothalamusofrodentsawell identifiedclusterofparvalbumin(PV)-positiveneuronshasbeen described[3].InrodentsthePV-positiveneuronsrepresentthevast majorityofthecellsbelongingtoaclearlydistinct cytoarchitecton-icallyandneurochemicallydefinedlateralhypothalamicarea,for
∗ Correspondenceto:UniversityofLausanne,Internef138.2,CH-1015Lausanne, Switzerland.Tel.:+41216923587.
E-mailaddresses:Alessandra.Lintas@neuroheuristic.org,
Alessandra.Lintas@unil.ch
theyareconsideredtoformanentitytermedPV1-nucleus[4,5]. Inprimatesthisregionisreferredtoasthelateraltuberalnucleus (LTN)[7].
Three cell types were observed in the rodent PV1-nucleus: smallPV immunoreactiveneurons preferentially locatedin the anteriorpart of thenucleus, largePV immunoreactiveneurons preferentiallylocated in the posterior part of thenucleus, and PV-negativeneurons[4].Accordingtotopographicalmappingof thegene expression and double-labeling for glutamateand for PVitisextremelylikelythatthePV-positiveneuronsofthe PV1-nucleusareglutamatergicprojectingneurons[4,8].Glutamateis anexcitatoryaminoacidassumedtorepresentthemain neuro-transmitterusedfordistributionandtransmissionofinformation in the brain [9]. The recent study of the PV1-nucleus efferent projectionsrevealedthatitsmajortargetisanarrowcolumnof terminalfieldslocatedipsilaterallyattheedgeofthe periaqueduc-talgray(PAG),ventrolateraltotheaqueduct,notcoincidingwith anyknownsubdivisionofthePAG[5].Itisinterestingtonoticethat
Published in 1HXURVFLHQFH/HWWHUV ±
which should be cited to refer to this work.
elsewhereinthebrainPV-stainedneuronscorrespondto GABAer-gic cells [3] mediating an inhibitory effect through GABA(A) receptors,thusexertingaregulatoryfunction,eitherviaadirect inhibitionoranindirectdisinhibition[10].Hence,GABAergic neu-ronsandPVaregenerallyassociatedandtheirroleincontrolling synapticplasticity,modulatingthefiringpattern,andthe spike-timing-dependentplasticityhasbeenclearlyestablished[11–15]. The factthat thePV1-nucleusis likely tobecomposedby glu-tamatergiccells expressingPVandthatitsmaintargetisawell delimitedcolumnofcellsontheedgeoftheipsilateralPAGraises thequestionwhetheritsfunctionistointegrate,relayandtransmit aninformationorrathertoregulatetheactivityofthetargetcells. TheaimofthisstudyistoinvestigatePV1-nucleusfiringpattern andtosuggestitsfunctionalrole.
2. Materialsandmethods
All experimental procedures were conducted in accordance withethicalprinciplesandguidelinesforexperimentsonanimals mandatedbytheSwissAcademyofMedicalSciencesandSwiss AcademyofSciences(3rded.,2005)undercontrolofthe Veteri-naryCommissionforAnimalResearchoftheCantonofFribourg, Switzerland.
2.1. Subjectsandsurgicalprocedure
AdultWistarratswerehousedinpairsona12h/12hlight/dark cycle,andfoodand wateravailableadlibitum.Therats, weigh-ing 280–350g, were anesthetized with a mixture of ketamine (75mg/kgBW)and xylazine(10mg/kgBW)dilutedinsaline. All surgicalwoundswereinfiltratedsubcutaneouswithScandicaine 0.5%(AstraZeneca)forlocalanesthesia.Theanimalsweremounted in a stereotaxic frame,a hole wasdrilled in theskull and one microelectrodewasadvancedverticallyby5mstepsaimedtothe lateralhypothalamicPV1-nucleus[4].Thebodytemperaturewas monitoredandmaintainedintherange38–39◦C.Thepedal with-drawalreflexwasperiodicallycheckedand supplementaldoses ofketaminewereprovidedduringthewholerecordingsessionif necessary.
2.2. Electrophysiologicalrecordings
The recordingswereperformed inthe lefthemisphere with glass-coatedplatinum-platedtungstenmicroelectrodeshavingan impedance in the range 0.5–2M measured at a frequency of 1kHz. Signalsfromthemicroelectrodeswereamplified, filtered (400Hz–20kHz)viewedonanoscilloscope,anddigitallyrecorded in WAV format(44,100Hzsampling rate,16 bitresolution)for computerizedofflineanalysiswithtemplatematchingspike sor-tingalgorithmatatimeresolutionof1ms[16].Thefirstrecording sessionstartedapproximately90minaftertheendofthesurgical preparation.Thedataweregatheredduringspontaneousactivity, i.e.intheabsenceofanyoperator-inducedstimulation,fora con-tinuousintervalof300–600s.Allrecordingsstartedatleast15min afteranysupplementarydoseofanestheticandterminatedatleast 20minbeforeanewinjection,thusassumingtherecording condi-tionscorrespondedtoasteadylevelofanesthesia.
2.3. Histologicalandimmunohistologicalprocedures
Attheendoftherecordingsessions(lasting4–6h)electrolytic lesionswereplacedatspecificdepthsoftheelectrodetrackusing10 currentpulsesof8Afor7satregularintervalsof10s.Atthe con-clusionoftheexperiments,animalsweredeeplyanesthetizedand transcardiallyperfusedwithisotonicsalineimmediatelyfollowed by fixative solution (4% paraformaldehydein phosphate buffer
Fig.1. Histologicalanalysis.(A)Microphotographofacoronalsection(atInteraural level6.1stainedwithcresylvioletandPV-immunostainingshowinga represen-tativeelectrodepenetrationaimingthePV1-nucleus.Theentireelectrodetrackis representedbyadottedline.(B)Enlargementofthepreviouspanelemphasizing theelectrolyticlesionwithinthePV1-nucleusatthecenterofthecircle.Scalebaris 1mm.
0.1M,pH7.3).Brainswereremovedandplacedin18%solutionof sucroseinphosphatebufferedcontaining0.1%sodiumazideforone dayat4◦C.Theywerethenfrozeninpulverizeddryice.The speci-menswerecryosectionedinto50m-thicksectionsandcollected in 0.1M phosphate buffer (pH 7.3). Immunofluorescence- and immunoperoxidase-stainingtechniqueswereconducted accord-ingtopublishedprotocols[4].Thesectionswerestainedwithcresyl violetforthereconstructionoftheelectrodetracksandlocalization oftheelectrolyticlesions.
2.4. Statisticalanalysis
Spike trains were analyzed by renewal density histograms scaledinrateunits(spikes/s).Foreachhistogram,the99% con-fidencelimitswerecalculated, assumingthat spikeoccurrences followedaPoissondistribution.TheFanofactor(equalto1fordata followingaPoissonprocess)wasusedtocharacterizethe variabil-ityofthespiketrain[17].Statisticalanalyseswereperformedwith theRProjectforStatisticalComputing(http://www.r-project.org/).
3. Results
Animalsfoundtohavetrackswithplacementsoutsideofthe targeted areacorrespondingto thePV1-nucleuswere excluded fromanalysis.Thefinal sampleincludeda totalof 15electrode penetrationsperformedinthelefthemisphereof8 rats.Taking into consideration the tissue retraction during the histological processing, thebacklashof theelectrode advancement and the stereotaxic positioningoftheelectrodes,it is assumedthat the siteofasingleunitrecordingcanbeestimatedwithamarginof 50–80mofuncertaintyalongtheverticaltrack.Fig.1illustrates anexampleofarecordingtrackwithanelectrolyticlesionwithin thePV1-nucleus.Atotalof30singleunitswereclearlylocalized intheareaofthePV1-nucleus.Thesecellswerecharacterizedby stablefiringactivity,i.e.samefiringrateduringthefirst100sand thelast100softherecordingsession.Additional25singleunits wererecordedalongthesametracks,buttheirlocationwasclearly notinthePV1-nucleusafterhistologicalcheck.
ThreetypesoffiringpatternsofPV1cellswereidentifiedduring thespontaneousactivitybytheanalysisoftheautocorrelograms. Thefirstpatternistypicalofthoseneuronswithaconstant prob-ability to spike, corresponding to a flat autocorrelogram, thus formingthe“regular”(REG)typeclassofcells(Fig.2A).Thisclass wasthemostfrequentlyobserved(70%,n=21)withamedianfiring rateequalto1.7spikes/s.Cellsshowingatendencytodeviatefrom aconstantprobabilityoffiringwereclassifiedeitherin“bursting cells”(BC,n=5),characterizedbyahumpintheautocorrelogram neartimezero(Fig.2C),orin“oscillatorycells”(OSC,n=4),inthe range1.6–2.1Hz(Fig.2D).
Fig.2.Firingpatternsduringspontaneousactivity.(A,C,D)Intheupperpartof eachpanelthereisarasterdisplayofthespiketrainandinthelowerpartthereare theoscilloscopetraceoftheextracellularlyrecordedsingleunitandthe autocorrel-ogramsmoothedbyaGaussianbinof25msshowingthefiringrate(spikes/s)asa functionofthelag(ms).(A)Aregularcell(#PA1D02c1).(B)Distribution(in loga-rithmicscale)oftheregularcells’firingratewiththekerneldensityplot(solidline) andtheGaussianfit(dottedline).(C)Aburstingcell(#PA1D01nc3).(D)An oscilla-torycell(#PA6D03c2).(E)DistributionofPV1cellstypes(REG,blackdots;BC,grey dots;OSC,whitedots)alongtherostro-caudalaxis,(Interauralcoordinates5.0–7.0). Abbreviations:3dv:thirdventricule;DMH:dorsomedialhypothalamicnucleus;fx: fornix;IHA1:partoftheintermediatehypothalamicarea;ISM:interstitialnucleusof thestriaterminalis;ot:optictract;sm:medullarystria;TUL:lateraltuberalnucleus; TUMM:tuberomammillarynucleus;VMH:ventromedialhypothalamicnucleus. Modifiedfrom[4].
Table1 shows thevaluesof thefiringrates and Fanofactor forallcellclasses.ThefiringrateswerenotGaussiandistributed (D’Agostino–Pearson normalitytest, omnibusK2=2.97, p<0.01),
but taking the logarithm of the firing rates of all cell groups weobservedanormaldistribution(D’Agostino–Pearson normal-itytest,omnibusK2=1.61,p=0.45).Itisinterestingtonoticethe Table1
Firingrate(median,mean±S.E.M.)andFanofactorofPV1-nucleusspiketrains. Statisticsaredescribedinthetext.
Celltype Total REG BC OSC
N 30 21 5 4 (100%) (70%) (17%) (13%) Firingrate 1.7 1.7 1.5 2.5 (spikes/s) (2.2±0.2) (2.0±0.2) (2.2±0.9) (2.9±0.8) Fanofactor 1.0 1.0 1.6 1.1 (1.1±0.1) (1.0±0.1) (1.6±0.1) (1.1±0.1)
log-normaldistributionofthefiring ratesof classREG neurons (Fig.2B).AFanofactorvaluenear1suggeststhatthedynamics oftheprocessesproducingtheneuronaldischargeisessentially random.TheREGandOSCFanofactorvalueswereGaussian dis-tributed(D’Agostino–Pearson normalitytest, omnibus K2=1.26,
p=0.53).
Thefiringratesofthethreecellgroupswerecomparedwitha one-wayANOVA.Bartlett’stestdidnotshowaviolationof homo-geneityofvariances(K2(2)=1.12,p=0.57)andnosignificanteffect
wasfoundofthecelltypeonthelogarithmicdistributionofthe fir-ingrate((2,27)=0.70,p=0.51).Thecomparisonbetweenthethree groupsusingnonparametricKruskal–Wallistestrevealeda signifi-canteffectofthecelltypeonFanofactor(2=12.34,p<0.01).A
post-hoctest usingMann–WhitneytestswithHolm–Bonferroni correctionshowednodifferencebetweenREGandOSCcellsand significantdifferencesbetweenOSCandBCcells(p<0.05,r=0.66) and betweenREG and BC cells (p<0.01, r=0.82).These results shouldneverthelessbeconsideredwithcautionbecausethesample sizeofBCandOSCgroupsisextremelysmall.ThePV1nucleuswas subdivedonthebasisoftheanatomicalsampling.Thefourmost anteriortracks(intheInterauralrange6.3–6.8)andthefourmost posteriortracks(intheInterauralrange5.4–6.2)weregroupedin twosamples.Fig.2Eshowsthatregularcellswereevenlysampled throughoutthenucleus,whereas theBCcells tendedtoappear intheanteriorpartandOSCcellsintheposteriorpart.The like-lihoodofobtainingtheobserveddistributions offiringpatterns acrossthetwoparts ofPV1-nucleuswasestimatedby comput-ingthelikelihood-ratiostatistics(2=7.39,p<0.05)thatrejected
thehypothesisthatnodifferenceexistedbetweentheanteriorand posteriorpart.
Pairsofcellswererecordedfromthesameelectrodetipin8 sites.Intwoofthesesitesthreecellswererecordedsimultaneously. Overallthirteencrosscorrelogramscouldbecomputedandallwere characterizedbyaflatcurve,thusshowingtheindependanceof firingandnointeractionbetweenpairsofsimultaneouslyrecorded cells.
4. Discussion
Themainfindingofthisstudyisthatregularcells,withamedian firingrateof1.7spikes/sandFanofactorequalto1,representthe typicalclass(70%oftherecordings)ofPV1cellsevenlydistributed alongtherostro-caudalaxis.Theregularcellsfiringpatternis char-acterizedbyarandomspiketrainsothatsuccessivespikeintervals arestatisticallyindependentandgenerateaflatautocorrelogram [18].Pairsofcellsrecordedsimultaneouslydidnotshowanysignof functionalinteractionandfourcellsexhibitinganoscillatory activ-itywithinanarrowrangeoftheı-frequencyband(0.5–4Hz)were observedonlyintheposteriorpartofthePV1-nucleus.
Ifaneuronfiresrandomly,itislikelytohavelittleeffect,ifany, onitstargetunlessitsactivityistime-lockedtoaseriesofother spikesconvergingtothesamecell[19].Asynchronousactivityin anunstructured,sparselyconnectednetworkwithweaksynaptic couplingsfallsinastatesuchthatanexternalinputmayfavor infor-mationtransmissioninthetargetstructure[20,21]andtriggerthe transitionofanactivitypatterninaneuralnetwork[22–24].The randomfiringpropertiesofPV1neuronssuggestthatglutamate isreleasedasynchronously atsynapticterminalsand that “net-workdriven”PV1excitatoryactivitymightcontributetoachieve temporal frequency modulation of selectedpatterns of activity [25–27].Noticethatallcellswererecordedundergeneral anes-thesiainducedbyketamineandxylazineandnotbyurethane,but thisdoesnotdiscardthatquitedifferentactivitycouldoccurduring normalbehavior.
Spontaneousactivityis determinedbya combination of cir-cuitandcellularelectrophysiologicalproperties.Sourcesofcellular noise include theion channelsof excitablemembranes, synap-tictransmissionandnetworkinteractions.Despitethedominance ofK+currentsthecontributionofCa-activatedKcurrentstothe
resting potential of neurons is widely recognized, particularly in PV-expressing neuronsfiringrandomlyand in burst [14,28]. Large-conductance calcium-activated potassium channels (BK), small-conductance Ca2+-activated potassium channels (SK) and
Ca2+-activatednonselectivecationchannelsregulatespontaneous
firinginacomplementarymanner[29,30].ParvalbuminisaCa2+
buffer proteincharacterized by a slow-onset Ca2+ binding that
generallydoesnotaffecttheinitialamplitudeofCa2+transients,
butthenacceleratestheearlyphaseoftheintracellularCa2+
con-centration,thusaffectingshort-termplasticityandcontrollingthe intracellularCa2+availabletoSKchannels[30].LossofPVleadsto
enhancedsusceptibilitytoepilepticseizure[12]andmodifications ofthefiringpatternsatthethalamocorticallevel[13,15].The ques-tionisraisedwhetherfiringpatternsotherthantheregularfiring correspondtodistinctcellpopulations,maybelyingintheborder ofthenucleus,orwhethertheyaregeneratedbycellsthatareina differentfunctionalstate.
Threecelltypes,namelysmallandlargePV-positiveneurons aswellasPV-negativeones,werereportedinPV1-nucleus[6,4]. Despitethesmallnumbersofoursamplesthefewcells(n=4) char-acterizedbyactivityintheı-frequencyrangewereallrecordedin theposteriorpartofthenucleus.Theexperimentalmethodused heredoesnotallowtoidentifywhich celltype isassociated to whichfiringpattern,butthelargestobservedamplitudesofthe extracellularlyrecordedspikewaveformswerethoseofthe oscil-latorycells.Thespikeamplitudeisroughlyproportionaltothesum ofthecross-sectionalareasofthedendritesconnectedtothecell body[31].Thus,largerneuronsarelikelytogenerate extracellu-larspikeswithlargeramplitudesandthelargePVimmunoreactive neuronswerepreferentiallyreportedintheposteriorpartofthe nucleus[4].
Thefewoscillatorycellswereobservedwithfrequencies asso-ciated withdeep sleep. Interestingly,in thedendrites of other PV-positivecells (located in thethalamicreticularnucleus) the interplayofSKchannels,transientvoltage-gatedcalciumchannels (Tchannels),and sarcoendoplasmicreticulumcalciumtransport ATPasescomprises aspecializedCa2+ signalingtriad toregulate
oscillatorydynamicsrelatedtosleep[32].Thecurrentcontinuous recordingtimeforonecellwasatmost20min,wellbelowthe ultra-dianrhythmof1cycleper100min[33].Thepossibilitythatthe oscillatorycellsarenotpartofaseparatepopulation,butcellsin aparticularstateofsleep,cannotbediscardedapriori,inspiteof thefactthatnocellwasobservedswitchingbetweenregularand oscillatoryfiringmodes.
In Huntington’s disease [34] and Pick’s disease [35] selec-tive neuropathological changes were observed in the human LTN. Despite different etiology both diseases exhibit progres-sive impairementof speechproduction akinof speech apraxia accompaniedbyadecreaseincognitiveabilitiesleadingto demen-tia akin of frontotemporal dementia. No precise functions are known to be associated with the area of the PAG reachedby PV1-nucleus efferent projections. However, it is worth repor-tingthat lesionsof PAGaffectstates of consciousness[36] and thatPAGreceivesafferencesfromtheprefrontalcortex[37]and projectstointralaminarandmidlinethalamicnuclei[38]. More-over, PV is highly expressed in the thalamic reticular nucleus [13]whichplaysakeyrolein‘gating’consciousness[39].These observationstakentogetherwiththepresentfindingsmaysuggest thattheactivityofPV1-nucleusregulatespsychomotorfunctions in the framework of an extended reticular thalamic activating system.
5. Conclusions
Itispossibletospeculatethattheasynchronousactivity char-acteristicofthePV1neuronsisgeneratedintrinsically,subjectto modulationbysynapticinputs,intracellularCa2+concentrations,
and that the “network-driven” effect on their target may pro-ducevariousfiringpatternswithtransitionsinducedthroughsmall changesinPV1neuronalactivity.Thehypothesisisraisedthatthe firingpattern ofPV1-nucleusparticipatestofunctionalnetwork activitycontrollingdynamicinformationrelatedtocondition tran-sitionsassociatedwithawarenessandnon-consciousperception.
Acknowledgments
TheauthorthanksM.R.Celio,A.E.P.Villa,B.SchwallerandR. Kretzfortheirsuggestionsand M.Kaczorowski,C. MartiandS. Eichenbergerfortheirtechnicalassistance.
References
[1]J.C.Sipe,R.Y.Moore,Thelateralhypothalamicarea,CellTissueRes.179(1977)
177–196.
[2]C.Saper,L.Swanson,W.Cowan,Anautoradiographicstudyoftheefferent
con-nectionsofthelateralhypothalamicareaintherat,J.Comp.Neurol.183(1979)
689–706.
[3]M.R.Celio,CalbindinD-28kandParvalbuminintheratnervoussystem,
Neu-roscience35(1990)375–475.
[4]Z. Mészár, F. Girard, C.B. Saper, M.R. Celio, The lateral hypothalamic
parvalbumin-immunoreactive(PV1)nucleusinrodents,J.Comp.Neurol.520
(2012)798–815.
[5]M.R.Celio,A.Babalian,Q.H.Ha,S.Eichenberger,L.Clément,C.Marti,C.B.Saper,
Efferentconnectionsoftheparvalbumin-positive(PV1)nucleusinthelateral
hypothalamusofrodents,J.Comp.Neurol.521(2013)3133–3153.
[6]L.M.Geeraedts,R.Nieuwenhuys,J.G.Veening,Medialforebrainbundleofthe
rat:IV.Cytoarchitectureofthecaudal(lateralhypothalamic)partofthemedial
forebrainbundlebednucleus,J.Comp.Neurol.294(1990)537–568.
[7]R.Bleier,P.Cohn,I.R.Siggelkow,Acytoarchitectonicatlasofthehypothalamus
andhypothalamicthirdventricleoftherat,in:P.J.Morgane,J.Panksepp(Eds.),
HandbookoftheHypothalamus,AnatomyoftheHypothalamus,vol.1,Marcel
Dekker,Inc,NewYork,1979,pp.137–220.
[8]F.Girard,Z.Meszar,C.Marti,F.P.Davis,M.Celio,Geneexpressionanalysisinthe
parvalbumin-immunoreactivePV1nucleusofthemouselateralhypothalamus,
Eur.J.Neurosci.34(2011)1934–1943.
[9]C.G.Parsons,W.Danysz,W.Zieglgänsberger,Excitatoryaminoacid
neurotrans-mission,Handb.Exp.Pharmacol.169(2005)249–303.
[10]J.M.Tepper,C.J.Wilson,T.Koós,Feedforwardandfeedbackinhibitionin
neos-triatalgabaergicspinyneurons,BrainRes.Rev.58(2008)272–281.
[11]O.Caillard,H.Moreno,B.Schwaller,I.Llano,M.R.Celio,A.Marty,Roleofthe
calcium-bindingproteinparvalbumininshort-termsynapticplasticity,Proc.
Natl.Acad.Sci.U.S.A.97(2000)13372–13377.
[12]B.Schwaller,I.V.Tetko,P.Tandon,D.C.Silveira,M.Vreugdenhil,T.Henzi,M.C.
Potier,M.R.Celio,A.E.Villa,Parvalbumindeficiencyaffectsnetworkproperties
resultinginincreasedsusceptibilitytoepilepticseizures,Mol.Cell.Neurosci.
25(2004)650–663.
[13]L.Albéri,A.Lintas,R.Kretz,B.Schwaller,A.E.Villa,Thecalcium-bindingprotein
parvalbuminmodulatesthefiringpropertiesofthereticularthalamicnucleus
burstingneurons,J.Neurophysiol.109(2013)2827–2841.
[14]D.Orduz,D.P.Bischop,B.Schwaller,S.N.Schiffmann,D.Gall,Parvalbumin
tunesspike-timingandefferentshort-termplasticityinstriatalfastspiking
interneurons,J.Physiol.591(2013)3215–3232.
[15]A. Lintas, B. Schwaller, A.E.P. Villa, Visual thalamocortical circuits in
parvalbumin-deficientmice,BrainRes.1536(2013)107–118.
[16]Y.Asai,T.Aksenova,A.E.P.Villa,On-linereal-timeorientedapplicationfor
neu-ronalspikesortingwithunsupervisedlearning,Lect.NotesComput.Sci.3696
(2005)109–114.
[17]L.Sacerdote,A.E.Villa,C.Zucca,Ontheclassificationofexperimentaldata
modeledviaastochasticleakyintegrateandfiremodelthroughboundary
values,Bull.Math.Biol.68(2006)1257–1274.
[18]G.P.Moore,D.H.Perkel,J.P.Segundo,Statisticalanalysisandfunctional
inter-pretationofneuronalspikedata,Annu.Rev.Physiol.28(1966)493–522.
[19]Y.Yarom,J.Hounsgaard,Voltagefluctuationsinneurons:signalornoise?
Physiol.Rev.91(2011)917–929.
[20]A.A.Faisal,L.P.Selen,D.M.Wolpert,Noiseinthenervoussystem,Nat.Rev.
Neurosci.9(2008)292–303.
[21]S.Ostojic,Twotypesofasynchronousactivityinnetworksofexcitatoryand
inhibitoryspikingneurons,Nat.Neurosci.17(2014)594–600.
[22]R.R.Llinás,Theintrinsicelectrophysiologicalpropertiesofmammalian
neu-rons:insights into centralnervous system function, Science 242 (1988)
1654–1664.
[23]D.J. Amit, A. Treves, Associative memory neural network with low
temporal spiking rates, Proc. Natl. Acad. Sci. U.S.A. 86 (1989) 7871–
7875.
[24]M.Häusser,I.M.Raman,T.Otis,S.L.Smith,A.Nelson,S.duLac,Y.
Loewen-stein,S.Mahon,C.Pennartz,I.Cohen,Y.Yarom,Thebeatgoeson:spontaneous
firinginmammalianneuronalmicrocircuits,J.Neurosci.24(2004)9215–
9219.
[25]J.Iglesias,A.E.P.Villa,Effectofstimulus-drivenpruningonthedetectionof
spatiotemporalpatternsofactivityinlargeneuralnetworks,BioSystems89
(2007)287–293.
[26]J.P.Segundo,Whatcanneuronsdotoserveasintegratingdevices?J.Theor.
Neurobiol.5(1986)1–59.
[27]Y.Chen,H.Zhang,H.Wang,L.Yu,Y.Chen,Theroleofcoincidence-detector
neu-ronsinthereliabilityandprecisionofsubthresholdsignaldetectioninnoise,
PLoSONE8(2013)e56822.
[28]P.Coulon,D.Herr,T.Kanyshkova,P.Meuth,T.Budde,H.C.Pape,Burstdischarges
inneuronsofthethalamicreticularnucleusareshapedbycalcium-induced
calciumrelease,CellCalcium46(2009)333–346.
[29]J.A.Goldberg,C.J.Wilson,Controlofspontaneousfiringpatternsbytheselective
couplingofcalciumcurrentstocalcium-activatedpotassiumcurrentsinstriatal
cholinergicinterneurons,J.Neurosci.25(2005)10230–10238.
[30]B.Schwaller,Thecontinuingdisappearanceof“pure”Ca2+buffers,Cell.Mol.
LifeSci.66(2009)275–300.
[31]K.H.Pettersen,G.T.Einevoll,Amplitudevariabilityandextracellularlow-pass
filteringofneuronalspikes,Biophys.J.94(2008)784–802.
[32]L.Cueni,M.Canepari,R.Lujan,Y.Emmenegger,M.Watanabe,C.T.Bond,P.
Franken,J.P.Adelman,A.Luthi,T-typeCa2+channels,SK2channelsandSERCAs
gatesleep-relatedoscillationsinthalamicdendrites,Nat.Neurosci.11(2008)
683–692.
[33]K.Grass,H.Prast,A.Philippu,Ultradianrhythminthedeltaandthetafrequency
bandsoftheEEGintheposteriorhypothalamusoftherat,Neurosci.Lett.191
(1995)161–164.
[34]H.P.Kremer,R.A.Roos,G.M.Dingjan,G.T.Bots,G.W.Bruyn,M.A.Hofman,The
hypothalamiclateraltuberalnucleusandthecharacteristicsofneuronalloss
inHuntington’sdisease,Neurosci.Lett.132(1991)101–104.
[35]H.Braak,E.Braak,Pick’sdisease:cytoskeletalchangesinthehypothalamic
lateraltuberalnucleus,BrainRes.802(1998)119–124.
[36]E.E.Benarroch,Periaqueductalgray:aninterfaceforbehavioralcontrol,
Neu-rology78(2012)210–217.
[37]S.R.Sesack,A.Y.Deutch,R.H.Roth,B.S.Bunney,Topographicalorganizationof
theefferentprojectionsofthemedialprefrontalcortexintherat:an
antero-gradetract-tracingstudywithPhaseolusvulgarisleucoagglutinin,J.Comp.
Neurol.290(1989)213–242.
[38]A.A.Cameron,I.A.Khan,K.N.Westlund,K.D.Cliffer,W.D.Willis,Theefferent
projections ofthe periaqueductal gray in the rat: a Phaseolus
vulgaris-leucoagglutininstudy.I.Ascendingprojections,J.Comp.Neurol.351(1995)
568–584.
[39]F.Crick,Functionofthethalamicreticularcomplex:thesearchlighthypothesis,
Proc.Natl.Acad.Sci.U.S.A.81(1984)4586–4590.
