SLEEP AND AROUSAL: Thalamocortical Mechanisms

32 Pages·2006·0.3 MB·English

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December12,1996 2:34 AnnualReviews AR24-08 AR24-8
Annu.Rev.Neurosci.1997.20:185–215
Copyright(cid:13)c 1997byAnnualReviewsInc.Allrightsreserved
SLEEP AND AROUSAL:
Thalamocortical Mechanisms
g DavidA.McCormickandThierryBal1
or
ws. SectionofNeurobiology,YaleUniversitySchoolofMedicine,333CedarStreet,
vie NewHaven,Connecticut06510
e
nnualrnly. KEYWORDS: thalamus,cortex,spindlewaves,epilepsy,ascendingactivation
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wnl3/2 brane properties of these cells and their anatomical interconnections. Specific
Don 0 alterationsintheinteractionsbetweenthesecellscanresultinthegenerationof
5. y o paroxysmaleventsresemblingabsenceseizuresinchildren.Thereleaseofseveral
5-21ersit differentneurotransmittersfromthebrainstem,hypothalamus,basalforebrain,
997.20:18eller Univ arthentedirceucbelyarresbnurepauplrrcoeonssrstienaxgndrtheasenugleetsnnheinaranatcieoddnepeooxflcsailrteaiezbpaitlriihotyyntihonmfmtshaaannlyadmcpoorroctmiocraotiltcipnaylgraaanmsdtiadtthaealtlhcaeamltliiscs,
ci. 1ckef conducivetosensoryprocessingandcognition.
so
oR
Neurby
v. INTRODUCTION
e
R
u. Eventhefirstinvestigatortodirectlyrecordtheelectricalactivityinthemam-
n
An maliancerebralcortexnotedthatthepatternofcorticalactivitywasdependent
uponthestateoftheanimal(Caton1887). Sincethisremarkablebeginning,the
investigationofthecellularcorrelatesofsleepandarousalinthalamocortical
systemshasenjoyedseveralperiodsofrapiddevelopment. Theseincludethe
demonstrationofanascendingactivatingsysteminthebrainstemthatisessen-
tialforthegenerationofsleep-wakecycles(Bremer1938,Moruzzi&Magoun
1Presentaddress: InstitutAlfredFessard,CNRS,Ave. delaTerrasse,GifSurYvette,Cedex
91198,France.
185
0147-006X/97/0301-0185$08.00
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186 McCORMICK&BAL
1949,Jouvet1962),andtheproposalofhypothesesconcerningthegeneration
ofsleep-relatedthalamocorticalrhythms(reviewedinAndersen&Andersson
1968,Steriade&Descheˆnes1984,Steriadeetal1993c). Inthepast15years,
thisbaseofinformationhasbeencomplementedbyadramaticincreaseinour
knowledgeofthemechanismsoftheionic,cellular,andnetworkmechanisms
through which thalamocortical activity is generated during sleep and of how
thisactivityisdisruptedinthetransitiontothewakingstate. Inthisreview,we
examinethesemorerecentdevelopmentswithaspecificfocusonthethalamus,
a structure that is central to the generation of state-dependent activity in the
forebrain.
g
s.or During the periods of sleep that exhibit synchronization of the electroen-
w
e cephalogram (EEG-synchronized sleep), a number of rhythms are present.
vi
e Two distinct rhythms that are particularly prominent in thalamocortical sys-
nnualrnly. tems are delta waves and spindle waves (see Steriade & Descheˆnes 1984,
ao Niedermeyer 1993). Delta waves in the normal adult are 0.5- to 4-Hz os-
s.e
m arjournalpersonal us ctpoiolls3ae-tdsiopunepsroitonhdatshteoafroewthlaaexrrginrehgsytatdhnumdriswnoganfditnehegep7Es-ElteGoep1(,4sew-HehzFilioegsuscprielilna5dt,iloebnewsloatwvhea)st.aaRrpeepsseeuaaprrecarhsiem1rs--
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Downln 03/2 1968).
5. y o Extracellularandintracellularrecordingsfromthalamocorticalneuronsdur-
85-21versit icnegllsEEgeGn-esryantechrreopneitzietidveslbeeuprstindnisacthuararglleysstlheaetpirnidgeanoinmtaolpsroefveaalseldowtheartdthepesoe-
0:1Uni larizing potential (Figure 1) (Hirsch et al 1983, McCarley et al 1983). The
997.2eller transition from EEG-synchronized sleep to the waking or REM-sleep states
ci. 1ckef occurred with the progressive depolarization of thalamocortical cells and the
osRo abolitionoftheslowdepolarizingspikeanditsassociatedburstoffastaction
Neurby potentials(Figure1B).Thesealterationsinthefiringmodeofthalamicneurons
v. areassociatedwithdramaticchangesintheneurons’responsivenesstoperiph-
e
R eral stimuli. For example, during EEG-synchronized sleep, there is a marked
u.
n diminution of the responsiveness of LGNd thalamic neurons to activation of
n
A
their receptive fields (Livingstone & Hubel 1981), presumably owing to the
hyperpolarizedstateoftheseneurons, theinterruptingeffectsofspontaneous
thalamocorticalrhythms,andthefrequencylimitationsoftheburstfiringmode
(seeMcCormick&Feeser1990,Steriade&McCarley1990). Over-powerful
inhibitionalsomayaffectneuronalresponsivenessduringEEG-synchronized
sleep;thisinhibitionisspecificallyreducedbyactivationofascendingcholin-
ergicpathways(Ahlsenetal1984,Francesconietal1988,McCormick&Pape
1988,Curro´ Dossietal1992b,Pape&McCormick1995).
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THALAMOCORTICALACTIVITY 187
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wnl3/2 theEEGexhibitssynchronousslowwaves,andLGNdrelayneuronsdischargeinburstsofaction
Don 0 potentials(A).Incontrast,duringwakingorREMsleep,LGNdneuronsfireinthesinglespike
5. y o or tonic mode of action potential generation (A). Intracellular recordings in vivo during these
5-21ersit t(rBa)n.s(iPtiaorntsAinfrdoimcatMecthCaatrtlheeyyetarael1ac9c8o3m.PplairsthBedfrboymdHepiroslcahrizeattaioln19o8f3t.h)emembraneby10–20mV
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0:1Uni
997.2eller These results, coupled with the earlier observations on the importance of
ci. 1ckef thethalamusinthegenerationofsleeprhythms,suggestthattheinvestigation
osRo of thalamic neurons and neuronal circuits may be particularly fruitful in the
Neurby search to uncover the cellular mechanisms of sleep-wake alterations in the
v. forebrain.
e
R
u.
n
n THALAMICNEURONSEXHIBITTWOSTATES
A
OFACTIVITY
Early intracellular recordings of thalamocortical neurons in vivo revealed an
unusual rebound burst discharge following hyperpolarization; this discharge
could be generated by the intracellular injection of current or by the natural
occurrence of an inhibitory postsynaptic potential (reviewed in Andersen &
Andersson 1968, Descheˆnes et al 1984, Roy et al 1984). In vitro investiga-
tionsrevealedthatthereboundpotentialoccurringfollowinghyperpolarization
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188 McCORMICK&BAL
is generated by activation of a specialized Ca2C current, known as the low-
threshold,ortransient(I ),Ca2Ccurrent(Jahnsen&Llina´s1984a,b). Voltage-
T
clampanalysisconfirmedthepresenceofalargelow-thresholdCa2C current,
aswellashigh-thresholdCa2C currents,inthalamocorticalcells(Coulteretal
1989, Crunelli et al 1989, Hernandez-Crus & Pape 1989). These investiga-
tionsrevealedthatI showsbothactivationandinactivation. Activationoccurs
T
atmembranepotentialspositivetoapproximately−65mV,whileinactivation
becomescomplete,atsteadystate,atmembranepotentialspositivetoapproxi-
mately−65mV.ThekineticsofactivationofI areconsiderablyfasterthanare
T
g thekineticsofinactivation,similartotheNaCcurrentunderlyingthegeneration
s.or ofthemoretypicalfastactionpotential. Therefore,ifthemembranepotential
w
e isdepolarizedfromarelativelyhyperpolarizedmembranepotential(negative
vi
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s.ae o ontheorderof100–200ms,andinturnbringthemembranepotentialpositive
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5. y o potentials; however, they do not generate high-frequency bursts (Jahnsen &
5-21ersit Llina´s 1984a,b, McCormick & Feeser 1990). Thus, the properties of IT im-
8v parttwodistinctstatesofactionpotentialgenerationontothalamocorticalcells:
7.20:1er Uni (a)burstfiringuponremovalofahyperpolarizationthatsurpasses−65mVfora
99ell sufficientperiodoftimeand(b)tonicsingle-spikeactivityupondepolarization
ci. 1ckef positivetoapproximately−55mV.
so
oR
Neurby RhythmicBurstFiringandtheInteraction
v. ofTwoIonicCurrents
e
R DuringEEG-synchronizedsleep,thalamocorticalcellsgeneraterhythmicbursts
u.
n ofactionpotentialsinthefrequencyrangeof0.5–4Hz, evenduringthegen-
n
A
eration of spindle waves, which occur at frequencies of 7–14 Hz (McCarley
1983, Royetal1984, Amzica&Steriade1995a). Intracellularrecordingsin
slices of cat LGNd maintained in vitro revealed a similar pattern of activity.
Left unperturbed, a subpopulation of thalamocortical neurons generates low-
threshold Ca2C spikes in a rhythmic manner at a frequency of approximately
0.5–4Hz(Figure2)(McCormick&Pape1990a,Lerescheetal1991,Soltesz
etal1991). Thisrhythmicburstfiringresultsfromtheinteractionofthelow-
thresholdCa2Cspikeandahyperpolarization-activatedcationcurrentknownas
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THALAMOCORTICALACTIVITY 189
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ci. 1ckef Figure 2 Thalamocortical neurons generate two distinct patterns of action potentials via the
osRo interactionofioniccurrents.(A)ThiscatLGNdneurongeneratedrhythmicburstfiringatarateof
Neurby about2Hz.Depolarizationofthecellto−58mVwiththeintracellularinjectionofcurrent(depol.
v. currentinjection)haltedtherhythmicactivityandswitchedtheneurontothetonic,orsinglespike,
Re modeofactionpotentialgeneration,owingtotheinactivationofIT.Removalofthedepolarization
u. reinstated the oscillatory activity. (B) Expanded trace of oscillatory activity and the proposed
n
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depolarizationdeactivatestheportionofIh thatwasactiveimmediatelybeforetheCa2C spike.
RepolarizationofthemembraneduetoITinactivationisfollowedbyahyperpolarizingovershoot,
whichisduetothereduceddepolarizingeffectofIh.Thehyperpolarizationinturnde-inactivates
IT andactivatesIh, whichdepolarizesthemembranetowardthresholdforanotherCa2C spike.
(C)Expandedtraceofsingle-spikeactivity.(FromMcCormick&Pape1990a.)
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December12,1996 2:34 AnnualReviews AR24-08 AR24-8
190 McCORMICK&BAL
theh-current(I ). Hyperpolarizationofthalamocorticalneuronstomembrane
h
potentials negative to approximately −55 mV slowly activates a mixed NaC
andKC currentthatdepolarizestheneuronbacktowardthereversalpotential
ofthiscurrent(approximately−35mV).Consequently,thefallingphaseofa
low-thresholdCa2C spikeisassociatedwiththeactivationofI , andtheacti-
h
vation of I results in a slow depolarization. This pacemaker potential again
h
activatesI andthereforeanotherlow-thresholdCa2Cspike.
T
Thepreciseshapeofthelow-thresholdCa2Cspikemaybecontrolledbythe
activation of a variety of KC currents that have been characterized in thala-
mocortical neurons (see Huguenard & McCormick 1992, Soltesz et al 1991,
g
s.or McCormick&Huguenard1992). Theinteractionbetweenthevoltagedepen-
ew denceandthekineticsofthelow-thresholdCa2Ccurrentandthehyperpolariza-
vi
e tion-activatedcationcurrentresultintheintrinsicpropensityofthalamocortical
nnualrnly. neuronstogeneraterhythmicoscillationsinthefrequencyrangeof0.5–4Hz
ao (McCormick&Pape1990a,McCormick&Huguenard1992,Curro´Dossietal
s.e
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Downln 03/2 derlyingthecessationofspindlewavesandtotheneurotransmittercontrolof
5. y o synchronizedthalamocorticalrhythms(seebelow).
5-21ersit ThalamicReticularNeuronsalsoExhibitTwo
8v
0:1Uni StatesofActivity
997.2eller Surroundingthethalamusandinterposedbetweenthethalamusandthecerebral
ci. 1ckef cortexisacollectionofGABAergicneuronsknownasthethalamicreticularnu-
osRo cleus(reviewedinSteriade&Descheˆnes1984,Jones1985). Theperigeniculate
Neurby nucleusisconsideredpartofthethalamicreticularnucleusandisconnectedto
v. theLGNd. TheGABAergicneuronsofthethalamicreticularandperigeniculate
e
R nuclei are innervated by axon collaterals of thalamocortical and corticothala-
u.
n micneuronsandgiverisetoadenseinnervationofthalamocorticalcellsina
n
A
mannerthatoftenpreservesreciprocalinteractionsbetweenappropriatepoints
inthethalamus,thalamicreticularnucleus,andcerebralcortex(seeSteriade&
Descheˆnes1984,Jones1985,Shosakuetal1989,Uhlrichetal1991,Baletal
1995a,b,Pinaultetal1995a,b).
TheGABAergicneuronsofthethalamicreticularnucleuschangetheirfiring
modeinamannersimilartothatofthalamocorticalcells(Steriadeetal1986).
During periods of EEG-synchronized sleep, thalamic reticular cells generate
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THALAMOCORTICALACTIVITY 191
rhythmichigh-frequency(350–450Hz)burstsofactionpotentials,whiledur-
ingwakingandREMsleep,theseneuronsgeneratesequencesoftonicaction
potential activity. As in thalamocortical cells, these two activity states result
fromthe propertiesofthelow-thresholdCa2C current (Figure3)(Mulle et al
1986,Avanzinietal1989,Huguenard&Prince1992,Bal&McCormick1993,
Contrerasetal1993). However, theselow-thresholdCa2C spikesaredistinct
fromthoseofthalamocorticalneuronsinanimportantway: Theirvoltagede-
pendenceisshiftedtomorepositivemembranepotentials(Huguenard&Prince
1992,Destexheetal1996)suchthatthalamicreticularcellscangeneratelow-
threshold Ca2C spikes upon depolarization, even at membrane potentials of
g
s.or −65mV.Thisparticularpropertyisimportantforthegenerationofsynchro-
w
e nizedthalamocorticalrhythms,suchasspindlewaves,becausetheexcitationof
vi
e thalamicreticularneuronsbythalamocorticalandcorticothalamiccellsdrives
nnualrnly. theserhythms(seebelow).
ao A pronounced after-hyperpolarization follows the generation of each low-
s.e
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Downln 03/2 these cells may g1enerate rhythmic bursts of action poTtentialsK.CTahe kinetics
5. y o of IT and IKCa interact with the properties of thalamic reticular cells such
85-21versit tthhaetmrheymthbmraincefiprointegntoicacluorfstahtefcreeqllu(eAnvcaienszionfi0e.t5alto191829H, Bz,alde&peMndciCngormupiockn
0:1Uni 1993). Hyperpolarization of thalamic reticular neurons facilitates the occur-
997.2eller rence and intensity of low-threshold Ca2C spikes, but also reduces the fre-
ci. 1ckef quency with which these neurons intrinsically oscillate (Bal & McCormick
osRo 1993).
Neurby Rhythmicburstfiringinthalamicreticularneuronsisoftenfollowedbyapro-
ev. longed“tail”ofsingle-spikeactivityinvivoandinvitro(Figure3A1)(Domich
R et al 1986, Steriade et al 1986, Bal & McCormick 1993). This tonic tail of
nu. activityappearstobegeneratedthroughtheactivationofaCa2C-activatednon-
n
A
selectivecationcurrent(I ). Thus,thalamicreticularcellsareendowedwith
CAN
theintrinsicpropensitytogenerate(a)sequencesofactivitythattaketheform
of burst-burst-burst-burst-tonic firing at relatively hyperpolarized membrane
potentials(e.g. −65mVorso)and(b)tonic,alsoknownassingle-spike,activ-
ityfollowingdepolarizationtomembranepotentialspositivetoapproximately
−55mV(Figure3), astatethatcanbeimposeduponthesecellsthroughthe
actionsofavarietyofneuromodulatorytransmitters(seebelow).
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December12,1996 2:34 AnnualReviews AR24-08 AR24-8
192 McCORMICK&BAL
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v.
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nu. SYNAPTICINTERACTIONSBETWEEN
n
A
THALAMOCORTICAL,THALAMICRETICULAR,
ANDCORTICOTHALAMICCELLS
ThalamicReticulartoThalamocortical
Thalamocorticalandthalamicreticularcellsarehighlyinterconnectedinsitu
(Yenetal1985,Cucchiaroetal1991,Uhlrichetal1991,Liuetal1995,Pinault
et al 1995a,b). Activation of the thalamic reticular and/or perigeniculate nu-
clei,eitherartificiallyorspontaneouslythroughthegenerationofspindlewaves
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December12,1996 2:34 AnnualReviews AR24-08 AR24-8
THALAMOCORTICALACTIVITY 193
(seebelow),resultsinthegenerationofGABA receptor–mediatedinhibitory
A
postsynapticpotentials(IPSPs)inthalamocorticalneurons(Figure4A–C)(De-
scheˆnes et al 1984, Thomson 1988, Huguenard & Prince 1994, Warren et al
1994,Baletal1995a,b,Sanchez-Vivesetal1995). TheseIPSPscanbesuffi-
cientlylargeinamplitudeandlongindurationtoresultinthegenerationofa
reboundlow-thresholdCa2C spike,eveniftheyaregeneratedbyonlyasingle
perigeniculateneuron(Figure4C).
The activation of thalamic reticular neurons can also activate GABA re-
B
ceptorsinthalamocorticalcells(Huguenard&Prince1994,Baletal1995a,b,
Sanchez-Vives et al 1995). The activation of GABA receptors results, as it
g B
s.or doesinothercentralneurons,inthegenerationofslowinhibitorypostsynap-
ew tic potentials through the activation of a G protein and an increase in a KC
vi
e conductance(Crunellietal1988,McCormick1991,Soltesz&Crunelli1992).
annualronly. oTfheinlaocntgivdatuiroantioonf tohfeGlAowB-AthBrersehcoelpdtoCr–am2CedciuartreednIt;PSthPesrefafocrileittahteessethIePSrePmsocvaanl
s.e
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oaded fro0/06. For thhiaglhamraitce(rSetaincuchlaerz-oVripveersigeetnailc1u9la9t5e).cells must discharge simultaneously at a
wnl3/2 ThalamocorticaltoThalamicReticular
Don 0
5. y o Activationofthalamocorticalinputstothalamicreticularand/orperigeniculate
85-21versit ntheruoruognhstrheesualctstivinattihoengoefneexrcaittiaotnoroyfaemxciintoataocryidproesctespytnoarpst(iFcipgoutreen4tiDal–sF()E.PSSimPsi)-
0:1Uni larly,activationofcorticothalamicfiberstothalamicreticularneuronsalsore-
997.2eller sultsinpronouncedexcitation,owingtotheactivationofexcitatoryaminoacid
ci. 1ckef receptors,andthisexcitationoftenresultsinthegenerationofrhythmicburst
osRo firinginthesecells(DeCurtisetal1989,Bal&McCormick1993,Contreras
Neurby &Steriade1996).
v. Baletal(1995b)recentlyconfirmedthatthalamicreticularorperigeniculate
e
R neuronsformdisynapticloopswiththalamocorticalcellsintheferretLGNd.
u.
n Activation of a burst of action potentials with the intracellular injection of a
n
A
current pulse into a single perigeniculate neuron typically results in the gen-
eration of a return barrage of EPSPs at a latency of approximately 100–150
ms(Figure4GandH).ThesereturnEPSPsaregeneratedthroughtherebound
burst firing of thalamocortical neurons. Thus, the prolonged delay (100–150
ms) from the burst of action potentials in the perigeniculate cell and the re-
turn EPSPs is largely due to the duration of the GABA receptor–mediated
A
IPSPinthethalamocorticalneuron(80–130ms). Asecondcauseforthede-
lay is the time required for the generation of a Ca2C spike to result in the
P1:mbl
December12,1996 2:34 AnnualReviews AR24-08 AR24-8
194 McCORMICK&BAL
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