The thalamus serves as a gate that regulates the flow of

sensory inputs to the neocortex, and this gate is controlled

by neuromodulators from the brainstem reticular formation

that are released during arousal (Steriade et al. 1969, 1997;

Singer, 1977; Sherman & Koch, 1986; Castro-Alamancos,

2002a,b). Among others, cholinergic and noradrenergic

fibres project to the thalamus (Hallanger et al. 1990; Simpson

et al. 1997). Neurons from these neuromodulatory systems

discharge vigorously during behavioural arousal (Buzsaki

et al. 1988; Aston-Jones et al. 1991), and the transmitters

they release depolarize thalamocortical neurons and

enhance their firing rates (McCormick, 1992). Thus, during

aroused states of the brain, thalamocortical neurons display

significantly enhanced spontaneous firing rates. Synapses

are sensitive to activity and, in particular, thalamocortical

synapses display robust depression when stimulated at

high rates (Castro-Alamancos, 1997; Gil et al. 1997). These

properties suggest that differences in the tonic firing rates

of thalamocortical neurons between quiescent and aroused

states can change the gain of thalamocortical synapses and

significantly affect the mode of sensory transmission at the

thalamocortical connection.

A useful model sensory system to investigate these issues is

the rodent facial vibrissae (‘whisker’) system. Rats use their

whiskers to locate and identify objects (Guic-Robles et al.1989; Carvell & Simons, 1990; Brecht et al. 1997), and the

tactile skills of their whiskers are in some ways comparable

to primates using their fingertips (Carvell & Simons, 1990;

Simons, 1995). The ventroposterior medial thalamus

(VPM) receives sensory information about the whiskers

from the trigeminal nucleus via lemniscal fibres (Chiaia etal. 1991; Williams et al. 1994; Diamond, 1995). In turn,

VPM neurons send thalamocortical fibres to clusters of

neurons located in layer IV (called ‘barrels’), and these

fibres also leave collaterals in upper layer VI (Jensen &

Killackey, 1987). Each barrel correlates on a one-to-one basis

with the whiskers (Woolsey & Van der Loos, 1970). Despite

the anatomically modular and topographic arrangement,

the system displays extensive spatial and temporal

integration. For instance, neurons in a given barrel column

yield the strongest response to a single principal whisker

but also weaker responses to several surrounding whiskers

(Simons, 1978, 1985; Chapin, 1986; Armstrong-James &

Fox, 1987; Moore & Nelson, 1998; Ghazanfar et al. 2000;

Petersen & Diamond, 2000). Inhibition in the neocortex

has been implicated in the spatial contrast of principal vs.adjacent whiskers (Simons, 1995). Also, the temporal

properties of neural responses in the barrel cortex have been

shown to modulate the size of the whisker representations

(Sheth et al. 1998; Moore et al. 1999). In the rodent

somatosensory system, receptive field and representation

mapping have been carried out mainly in anaesthetized

preparations where the level of arousal is similar to slow-

wave sleep. However, during waking receptive fields and

pathways can change their properties at all levels of the

sensory axis from the brainstem to the neocortex (Chapin

& Woodward, 1981, 1982; Shin & Chapin, 1989, 1990;

Nicolelis et al. 1993; Fanselow & Nicolelis, 1999).

The present study investigates how the primary thalamo-

cortical pathway changes during aroused states. We show

that sensory responses evoked in the barrel cortex by

whisker stimulation are suppressed during aroused states.

Sensory suppression in the barrel cortex is mainly a

consequence of the activity-dependent depression of

Cortical sensory suppression during arousal is due to theactivity-dependent depression of thalamocortical synapsesManuel A. Castro-Alamancos and Elizabeth Oldford

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4

The thalamus serves as a gate that regulates the flow of sensory inputs to the neocortex, and this gate

is controlled by neuromodulators from the brainstem reticular formation that are released during

arousal. Here we show in rats that sensory-evoked responses were suppressed in the neocortex by

activating the brainstem reticular formation and during natural arousal. Sensory suppression

occurred at the thalamocortical connection and was a consequence of the activity-dependent

depression of thalamocortical synapses caused by increased thalamocortical tonic firing during

arousal. Thalamocortical suppression may serve as a mechanism to focus sensory inputs to their

appropriate representations in neocortex, which is helpful for the spatial processing of sensory

information.

(Resubmitted 12 January 2002; accepted 13 February 2002)

Corresponding author M. A. Castro-Alamancos: Department of Neurology and Neurosurgery, Room WB210, MontrealNeurological Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. Email: manuel_castro@bic.mni.mcgill.ca

Journal of Physiology (2002), 541.1, pp. 319–331 DOI: 10.1113/jphysiol.2002.016857

© The Physiological Society 2002 www.jphysiol.org

thalamocortical synapses caused by increased thalamo-

cortical tonic firing in VPM neurons during arousal.

Thalamocortical suppression during aroused states of the

brain may serve as a mechanism to focus sensory inputs to

their appropriate representations (barrels) in neocortex,

which is helpful for the spatial processing of sensory

information.

METHODSSurgical proceduresAdult Sprague-Dawley rats (300 g) were anaesthetized withurethane (1.5 g kg_1

I.P.) and placed in a stereotaxic frame.Lidocaine (2 %) was injected at incision sites and at points ofcontact of the skin with the frame. A unilateral craniotomyextended over a large area of the parietal cortex. Small incisionswere made in the dura as necessary and the cortical surface wascovered with artificial cerebrospinal fluid (ACSF) containing (mM):NaCl 126; KCl 3; NaH2PO4 1.25; NaHCO3 26; MgSO4.7H2O 1.3;dextrose 10; CaCl2.2H2O 2.5. Body temperature was automaticallymaintained constant with a heating pad. The level of anaesthesiawas monitored with field recordings and limb-withdrawal reflexesand kept constant at about stage III/3 using supplemental doses ofurethane (Friedberg et al. 1999). At the end of the experiments theanimals were killed with an overdose of sodium pentobarbitone(I.P.). The Animal Care Committee of McGill University, Canada,approved protocols for all experiments.

Electrophysiological proceduresExtracellular recordings were performed using electrodes(5–10 MV) filled with ACSF; single units and field potentials wererecorded simultaneously via the same electrodes located in theVPM thalamus and the primary somatosensory neocortex (barrelcortex). When field potentials were recorded alone the electrodewas placed at 800–1000 mm from the surface. Field potentialpolarity is displayed as negative down. Coordinates (in mm, frombregma and the dura; Paxinos & Watson, 1982) for the VPMthalamus recording electrode were anterior–posterior = _3.5,lateral = 3, depth = 5–6. Coordinates (mm) for stimulating thelaterodorsal tegmentum (brainstem reticular formation; 100 Hz,1 s) were posterior = 9, lateral = 0.7, depth = 5–6. The thalamicradiation was stimulated at approximately the following coordinates(mm): posterior = 3, lateral = 4, depth = 5. The medial lemniscuswas stimulated at approximately the following coordinates(mm): posterior = 5.5, lateral = 1.5, depth = 7.5. Electrical stimuliconsisted of 200 ms pulses of < 200 mA and were evoked using aconcentric stimulating electrode.

MicrodialysisTo apply drugs into the neocortex during recordings amicrodialysis probe (250 mm diameter, 2 mm long) was placed inthe neocortex 0.5–1 mm medial from the recording electrode, aspreviously described (Castro-Alamancos, 2000). ACSF wascontinuously infused through the probe at 2–4 ml min_1. Drugswere prepared fresh, and protected from light and from oxidation(40 mM ascorbic acid in the ACSF) as required. Scopolamine,hexamethodide, phentolamine and propanolol were applied at1–5 mM each, and CGP35348 (Novartis) was applied at 10 mM inACSF . To apply TTX (2 mM in ACSF) into the VPM thalamus amicrodialysis probe (250 mm diameter, 2 mm long) was insertedat the following coordinates (mm): posterior = 3, lateral = 2–3,depth = 4–6.

Sensory stimulationThe sensory stimulation consisted of deflecting large caudalwhiskers (one to four), which reliably discharged (> 80 % of trialsat 0.1 Hz) the neurons recorded in VPM and barrel neocortexwith short latencies (3–7 ms in VPM and 5–12 ms in neocortex).The selected whiskers were inserted into a glass micropipette(1 mm diameter) that was glued to the membrane of a miniaturespeaker. Application of a 1 ms square current pulse to the speakerdeflected the micropipette and the whiskers inside ~400 mm.Whisker stimulation was applied between 0.5 and 10 s after thereticular formation (RF) stimulation.

Current source–density analysisA 16-channel linear silicon probe (CNCT, University ofMichigan, USA) was inserted into the barrel cortex perpendicularto the pial surface. This required insertion of the silicon probe at a45 deg angle (in the coronal plane) at 5.5–6 mm lateral from themidline. Field potential recordings were obtained simultaneouslyfrom the 16 sites on the probe and from a VPM electrode thatserved to monitor multiunit activity. Band-pass filter settings wereselected for field potential (1 Hz to 3 kHz) or for multiunitrecordings (300 Hz to 3 kHz). A current source–density analysis(CSD) was derived from the 16-channel cortical recordings, aspreviously described (Castro-Alamancos, 2000).

Chronic recordingsAdult Sprague-Dawley rats (300 g) were anaesthetized with sodiumpentobarbitone (50 mg kg_1

I.P.) and placed in a stereotaxic frame.Lidocaine (2 %) was injected at incision sites and at points ofcontact of the skin with the frame. Recording electrodes wereplaced in the barrel cortex and stimulating electrodes were placedin the thalamic radiation. An insulated stainless-steel bipolarrecording electrode was placed in the whisker pad to record EMGsignals. All electrodes and connectors were held in place usingmini-screws and dental cement. During recovery from surgery theanimals were given Buprinorphine (0.02 mg kg_1

S.C.). Animalswere allowed 5_7 days before testing and were recorded forseveral days up to a maximum of 15 days after surgery. Duringrecovery after surgery, animals were closely monitored for anysign of distress or complications arising from the procedure.Electrophysiological recordings were performed as in anaesthetizedanimals, but JFET-operational amplifiers were attached to therecording electrodes at the animal’s head connector. During therecording sessions the animal was placed in an open fieldcontaining photobeams that detected movements performed bythe animal. The field potential activity in the neocortex and themotor activity detected with photobeams allowed us to differentiateperiods of active exploration from periods of slow-wave sleep. Forthe population analysis, peak amplitudes of 20 randomly selectedthalamic radiation-evoked responses were measured per animal(n = 10) and per condition (active vs. sleep). At the end of theexperiments the animals were killed with an overdose of sodiumpentobarbitone.

RESULTSThalamocortical suppression during activationSingle-unit recordings were obtained simultaneously from

thalamocortical neurons of the VPM and from neurons in

layers III–IV of the primary somatosensory barrel neocortex

(Fig. 1) of urethane-anaesthetized rats. Application of a train

of electrical stimulation (100 Hz, 1 s) to the brainstem

M. A. Castro-Alamancos and E. Oldford320 J. Physiol. 541.1

Thalamocortical suppressionJ. Physiol. 541.1 321

Figure 1. Activation induced by RF stimulation produces sensory suppression in neocortexA, field potential (FP) and single-unit recordings obtained in the barrel cortex through the same electrode,and a simultaneously recorded single unit in the VPM thalamus of a urethane-anaesthetized rat. RFstimulation was delivered for 1 s (100 Hz) and produced a robust activating effect consisting of lowamplitude irregular activity in the cortical field potential, reduced firing in the cortical unit and enhancedfiring in the VPM unit. B, raw traces and binned sum data from 14 trials of sensory responses evoked bywhisker stimulation before (Control) and after RF stimulation. The cortical field and unit responses aresuppressed by RF stimulation, while the thalamic unit response is enhanced. C, cortical single-unit recordingobtained in the same experiment shown in A and B. In contrast to cortical unit 1 shown in A and B, corticalunit 2 responds to RF stimulation by increasing its firing rate. However, like cortical unit 1 this unit alsosuppresses its response to whisker stimulation. Cortical unit 2 was recorded after cortical unit 1 in the samepenetration; the thalamic unit was the same for both cases.

reticular formation (RF stimulation) produced a strong

effect typical of aroused states (Fig. 1A) called activation,

which is characterized by an electrographic sign of low

amplitude fast activity (Moruzzi & Magoun, 1949). At the

single-neuron level, during activation the firing rate of all

VPM thalamocortical neurons recorded increased (n = 55

of 55; 100 %), while the firing rate of the neocortical

neurons recorded either decreased (n = 49 of 65; 75 %) or

increased (n = 16 of 65; 25 %). VPM neurons increased

their tonic firing after RF stimulation to 33 ± 4 Hz

(mean ± S.D.) for several seconds.

In urethane-anaesthetized rats, whisker displacements using

a mechanical stimulator produced successive sensory

responses in the VPM and barrel cortex (Fig. 1B). Single

units in VPM and in layer IV of barrel cortex responded

with short latency (3–7 and 5–12 ms, respectively) and

high fidelity (> 80 % probability of firing at short latency)

to whisker stimulation delivered at low frequencies (0.1 Hz).

When brain activation was induced by RF stimulation, the

probability of firing to whisker stimulation at short latency

(3–7 ms) in the VPM increased from 82 to 100 % (18 ± 3 %

increase; P < 0.0001, Student’s t test; n = 55 units). In

contrast, in the barrel cortex the probability of firing to

whisker stimulation at short latency (5–12 ms) decreased

from 82 to 19 % (Figs 1B and 3A) (63 ± 7 % reduction;

P < 0.0001, t test; n = 65 units). Cortical single units that

enhanced or reduced their spontaneous firing in response

to RF stimulation both showed a suppressed sensory-

evoked response during activation. Thus, cortical neurons

that enhanced their tonic firing as a consequence of RF

stimulation depressed their response to whisker stimulation

(Fig. 1C). The decrease in responsiveness to whisker

stimulation during activation was also reflected in the

suppression of the sensory-evoked field potential response

recorded in the cortex (57 ± 8 % reduction in amplitude;

P < 0.0001, t test; n = 15; Figs 1B and 3B). The field

potential response was recorded via the same electrode as

the single units and reflects the subthreshold synaptic

activity of a population of neurons surrounding the

electrode. It is noteworthy that the single-unit responses

evoked by whisker stimulation showed on average a

stronger suppression than the field potential responses

(Fig. 3A and B). This was a consequence of the fact that

some neurons such as the one in Fig. 1B almost entirely

stopped responding to the sensory stimulus. It is likely that

some of these neurons still produced a subthreshold

response but we would not have been able to detect these

responses using unit recordings. Other neurons may

simply not respond at all after RF stimulation because they

are only driven polysynaptically by the thalamic input and

thus are entirely dependent on the firing of other cortical

neurons, which may have been suppressed. This seems to

be the case because cortical neurons responding with very

short latency (5–8 ms) to whisker stimulation showed less

suppression than the whole population of cortical neurons.

Thus, the probability of firing to whisker stimulation for

these short latency neurons was 88 % during control

conditions and 40 % during activation induced by RF

stimulation (48 ± 3 % reduction; P < 0.0001, t test; n = 12

units). The 48 % reduction of very short latency cells is

significantly less than the 63 % reduction observed for the

whole population of cells that includes cells with longer

latencies. In summary, during activation induced by RF

stimulation the sensory response recorded in the barrel

cortex is suppressed, while the sensory response recorded

in the VPM thalamus is not suppressed.

Suppression occurs at the thalamocorticalconnectionThe barrel cortex is a complex structure that receives

afferents from the VPM thalamus in both layers IV and VI,

from where activity is distributed to other layers. To test

which parts of this thalamocortical network are being

suppressed by the RF stimulation we used a linear silicon

probe containing 16 recording sites at 100 mm intervals to

record voltage throughout the layers of neocortex (Fig. 2A)

and derive a CSD in response to whisker stimulation

(Bragin et al. 2000; Castro-Alamancos, 2000). The current

flow in the barrel cortex revealed by the CSD (Fig. 2B)

showed that the sensory-evoked response corresponded to

short latency current sinks in upper layer VI and layer IV,

which spread horizontally within those layers and

vertically to layer III. Application of RF stimulation

strongly depressed the sensory response in the barrel

cortex, but not the sensory response in the VPM (Fig. 2B).

Current flow in the neocortex was depressed beginning

with the earliest (monosynaptic) sinks in layers VI and IV.

As a consequence, the spread of activity within these layers

and to layer III was also strongly suppressed. On average

the peak amplitude of the short latency current sinks in

layers IV and VI and the longer latency sink in layer III

were significantly depressed by 51.6 ± 7, 59.8 ± 7 and

54.7 ± 8 %, respectively (n = 3 experiments; P < 0.0001, ttest; Fig. 3C). We also found that the response evoked in

the barrel cortex by stimulating thalamocortical fibres in

the thalamic radiation was suppressed by RF stimulation

(Figs 2C and 3B; see below). In contrast, the response

evoked in VPM by stimulating the primary sensory fibres

in the medial lemniscus was not suppressed by RF

stimulation. The thalamic response evoked by medial

lemniscus stimulation has been characterized previously

(Mishima, 1992). It consists of a very short latency and fast

component (arrow in Fig. 2C) that is blocked by glutamate

receptor antagonists (not shown) followed by a slower and

longer latency component (asterisk in Fig. 2C) which is the

recurrent corticothalamic response, as demonstrated by

inactivating the neocortex (Mishima, 1992). RF stimulation

did not significantly affect the initial fast response (Figs 2Cand 3B; n = 5 experiments; the peak amplitude of the medial

lemniscus-evoked response was 1.1 ± 0.08 mV before and

1.19 ± 0.1 mV after RF stimulation; not significant, t test),

M. A. Castro-Alamancos and E. Oldford322 J. Physiol. 541.1

Thalamocortical suppressionJ. Physiol. 541.1 323

Figure 2. Sensory suppression during activation occurs at the thalamocortical connectionA, schematic representation of the location of the 16-channel silicon probe placed at a 45 deg angle in thebarrel cortex, which was used to record field potential responses through the layers of barrel neocortex. Alsonote a single recording electrode placed in the VPM thalamus and a microdialysis probe located adjacent tothe recording electrode. The microdialysis probe was used to infuse TTX into the VPM as described in Fig. 5.B, current source–density analysis (CSD) of the sensory response evoked in the barrel cortex by whiskerstimulation before (Control) and after RF stimulation. The sink (red) and source (blue) distribution revealsthat the short latency responses in layers VI and IV are strongly depressed by RF stimulation. Also shownbelow is multiunit activity from the VPM thalamus and a field potential recording from one of the corticalsites (900 mm in depth). The multiunit traces are the average of five sensory responses. Notice the depressionof the cortical response, but not of the thalamic response, after RF stimulation. The field potentials used toderive the CSD are shown at the bottom. The scale range for the CSD is +3.5 to _3.5 mV mm_2. C, overlaidfield potential responses showing the effect of RF stimulation (red traces) on cortical responses evoked bywhisker stimulation (left), cortical responses evoked by thalamic radiation stimulation (middle) and onVPM responses evoked by medial lemniscus stimulation (right). The lemniscal response has twocomponents, marked by an arrow and an asterisk (see text for details). The responses are the average of tentraces.

but always abolished the long latency corticothalamic

response that followed. Taken together, the results

indicate that sensory suppression is occurring at the

interface between the thalamus and the neocortex, at the

thalamocortical connection.

Thalamocortical suppression occurs duringbehavioural arousalThe experiments presented thus far were performed in

anaesthetized animals, and activation was induced

artificially by RF stimulation. Although RF stimulation

triggers wakefulness in sleeping animals (Lucas, 1975)

and mimics many of the features of the aroused brain

(Moruzzi & Magoun, 1949), the question remains whether

suppression of the thalamocortical input actually occurs in

behaving animals during activated states. To test this

directly we chronically implanted recording and stimulating

electrodes in the barrel cortex and thalamic radiation,

respectively. The animals were placed in an open field

(43 cm w 43 cm) and motor activity was monitored using

photobeams and an EMG electrode in the whisker pad.

We found that indeed during behaviourally activated

states the thalamocortical response evoked by stimulating

the thalamic radiation was suppressed. Figure 4 shows

recordings from a rat during two distinct behavioural

states: sleep and waking. During slow-wave sleep, as

indicated by the enhanced fast Fourier transform (FFT)

power of the spontaneous cortical activity at low frequencies

(< 2 Hz; Fig. 4A), the thalamocortical-evoked response was

at its greatest level. As the animal awoke, the thalamo-

cortical-evoked response was strongly reduced, and was

maintained at this reduced level during the vigourously

active period of exploration that followed. During waking

the FFT power showed an enhancement at 4–5 Hz (Fig. 4A).

This is probably theta activity picked up by volume

conduction from the cortical electrode because the FFT

analysis of the spontaneous activity did not distinguish

between negative and positive components. Sensory

suppression occurred when waking occurred spontaneously

or was triggered in a sleeping rat by the investigator. Based

on recordings from several behaving animals (n = 10), the

amplitude of the field potential thalamocortical response

evoked by VPM stimulation was suppressed on average by

42 ± 7 % (P < 0.0001, t test; n = 10) between slow-wave

sleep and active exploration. In conclusion, similar to the

events that occur after RF stimulation, during behaviourally

activated states the thalamocortical response is suppressed

and therefore RF stimulation as used in the present study

mimics this aspect of natural arousal.

Mechanisms of thalamocortical suppressionHow does thalamocortical sensory suppression induced

by RF stimulation occur? Thalamocortical synapses are

sensitive to activity and display pronounced activity-

dependent depression at frequencies above 1 Hz (Castro-

Alamancos, 1997; Gil et al. 1997). Since RF stimulation

produces a strong activating effect in thalamocortical

neurons, which increases their firing rate, we reasoned that

increased thalamocortical activity caused by RF stimulation

could be depressing thalamocortical synapses and

reducing the efficacy of the thalamocortical connection. If

RF stimulation is depressing thalamocortical synapses by

increasing thalamocortical activity, then blocking thalamo-

cortical activity by inactivating the VPM thalamus should

eliminate the suppressive effect of RF stimulation. VPM

inactivation was produced with the sodium channel

blocker tetrodotoxin (TTX), and was confirmed when

whisker-evoked responses were completely absent in the

neocortex (Fig. 5A). To test the effect of RF stimulation on

the thalamocortical pathway before and after thalamic

inactivation we stimulated the thalamic radiation. When

the thalamus was intact, the response evoked in the barrel

cortex by stimulating the thalamic radiation was suppressed

M. A. Castro-Alamancos and E. Oldford324 J. Physiol. 541.1

Figure 3. Population data showing the percentagechanges induced by RF stimulation of VPM and cortexresponsesA, percentage changes induced by RF stimulation of VPM andcortex single-unit firing probability to whisker stimulation at shortlatency intervals (3–7 ms for VPM and 5–12 ms for cortex). n = 55and 65 units per group, respectively. *P < 0.0001, t test.B, percentage changes induced by RF stimulation of field potentialresponses evoked in cortex by whisker stimulation(Wkr å Cortex) or thalamic radiation stimulation (TR å Cortex)and of responses evoked in VPM by medial lemniscus stimulation(ML å VPM). n = 15, 6 and 5 experiments per group, respectively.*P < 0.0001, t test. C, percentage changes induced by RFstimulation of current sink amplitudes evoked by whiskerstimulation in layer IV, layer VI and layer III. n = 3 experimentsper group. *P < 0.0001, t test.

by RF stimulation (Fig. 5B). However, when the VPM

thalamus was inactivated with TTX, RF stimulation no

longer suppressed the thalamic radiation-evoked response

(Fig. 5B). This indicates that sensory suppression induced by

RF stimulation is a consequence of increased thalamo-

cortical firing in VPM. This experiment was performed

several times (n = 6 rats) with similar results. On average the

suppression of the thalamic radiation response was 55 ± 7 %

before (P < 0.0001, t test; n = 6) and 6 ± 4 % after (P > 0.1,

t test; n = 6) TTX application, i.e. there was a 90 % block of

the effect of RF stimulation with thalamic inactivation.

Thalamocortical synapses depress in response to activity

and also in response to application of certain neuro-

modulators in vitro (Gil et al. 1997; Hsieh et al. 2000) and

in vivo (Oldford et al. 2000). To distinguish between the

two possibilities, an activity-dependent depression of

thalamocortical synapses or a neuromodulator-mediated

depression of thalamocortical synapses, we tested whether

TTX application in the VPM thalamus was affecting the

cortical activating effects of RF stimulation. This was

accomplished by comparing the power spectrums of

cortical activity in the presence and absence of thalamic

Thalamocortical suppressionJ. Physiol. 541.1 325

Figure 4. Natural arousal produces thalamocortical suppressionA, fast Fourier transform (FFT) of the spontaneous field potential activity recorded from the barrel cortex ofa freely behaving rat. Blue indicates low power and red indicates high power for the frequency on the y-axis.B, top: amplitude of the thalamocortical response evoked in the barrel cortex by stimulating the thalamicradiation every 10 s (open circles). The running averages of three successive responses are shown by filledcircles. Middle, amplitude of the electromyographic activity (EMG; arbitrary units) recorded from thewhisker pad with subcutaneous electrodes. Bottom, locomotor activity (arbitrary units) recorded byphotobeam detectors in the cage. The x-axis time scale corresponds to all graphs. The animal is sleeping forthe initial 11 min (i.e. lying down in the cage with eyes closed) and the amplitude of the thalamocorticalresponse is large. After 11 min, the rat wakes up and moves actively about the cage for the remainder of theexperiment, and the thalamocortical response is suppressed. C, traces correspond to a thalamocorticalresponse evoked during slow-wave sleep and during the active exploratory state that follows. Each traceshown is 32.5 ms. The arrows mark the onset of the electrical stimulus to the thalamic radiation.

TTX (Fig. 5A). The results revealed that the activating

effects of RF stimulation in the barrel cortex were not

significantly different before and during thalamic TTX

application (n = 6; t test for the power between 0.5–15 Hz,

P > 0.1). This would be expected if the activating effect of

RF stimulation in neocortex was mainly mediated by the

basal forebrain (Jones, 1993). Since the modulation of

cortical neurons caused by RF stimulation was still present

during VPM inactivation with TTX, we reasoned that

RF stimulation is not depressing the thalamocortical

connection by releasing neuromodulator(s) in the cortex.

Thus, sensory suppression and cortical activation induced

by RF stimulation are independent processes. Conversely,

we propose that increased thalamocortical activity during

activated states produces the depression of thalamo-

cortical synapses and consequently suppresses sensory-

evoked responses in the neocortex. If this is the case,

activity in thalamocortical synapses should be able to

mimic the effect of RF stimulation. Indeed, similar to the

effects of RF stimulation, repetitive stimulation at 10 Hz

using sensory or thalamic radiation stimulation robustly

suppressed thalamocortical responses (Castro-Alamancos

& Connors, 1996) to a similar extent as RF stimulation

(Fig. 5C). To further test the potential for a cholinergic,

noradrenergic or GABAergic modulation of thalamocortical

synapses in the barrel neocortex, we applied simultaneously

cholinergic (scopolamine and hexamethodide), nor-

adrenergic (phentolamine and propanolol) and GABAB

(CGP35348) receptor antagonists via a microdialysis

probe in the barrel neocortex. Application of this drug

combination in the cortex via microdialysis (Fig. 6)

significantly enhanced the amplitude of the whisker-

evoked response and made the response broader (1.4 ±

0.2 mV before vs. 2 ± 0.3 mV after the drug combination;

n = 3 rats; P < 0.0001, t test). However, application of this

drug combination did not block the sensory suppression

induced by RF stimulation (Fig. 6; n = 3, suppression by

RF was 59 ± 6 % before and 75 ± 5 % after the drug

combination).

DISCUSSIONThe principal conclusion of the present study is that

during aroused states the transmission efficacy of the

thalamocortical connection is reduced leading to the

suppression of sensory responses in the neocortex. This is a

consequence of the activity-dependent depression of

thalamocortical synapses caused by increased tonic firing

of thalamic neurons. Importantly, this finding obtained

initially using brainstem RF stimulation was validated in

M. A. Castro-Alamancos and E. Oldford326 J. Physiol. 541.1

Figure 5. Sensory suppression induced by RFstimulation is abolished by thalamicinactivationA, cortical field potential responses to whiskerstimulation (left traces) and to stimulation of thethalamic radiation (right traces). The arrows markthe onset of the whisker stimulus (left) and thethalamic radiation electrical stimulus (right). Thenumbers on the traces mark the locations on the plotbelow. Infusion of TTX into the VPM thalamusabolishes the cortical response to whiskerstimulation, but not the cortical response tothalamic radiation stimulation. Also shown (right)is a power-spectrum of the field potential activityrecorded in the cortex before (Control) and after RFstimulation (RF stim) when the thalamus was intact(continuous line) or inactivated with TTX (dashedline). Thalamic inactivation does not significantlyaffect the cortical activating effect of RF stimulation.B, field potential responses to thalamic radiationstimulation are suppressed by RF stimulation whenthe thalamus is intact, but not when it is inactivatedwith TTX. C, the thalamocortical response evokedby stimulating the thalamic radiation is suppressedby activity. Repetitive stimulation of the thalamicradiation at 10 Hz sharply depresses thethalamocortical response (left), and this effect isequivalent to RF stimulation in an intact thalamus(right). The asterisk marks the small and longlatency response presumed to be due to intracorticalcollaterals of corticothalamic cells (see Discussionfor details).

behaving animals. This indicates that the RF stimulation

used in the present study mimics the cortical sensory

suppression that occurs during natural aroused states.

As a sensory input travels upward from the periphery it is

not depressed by RF stimulation until it reaches the

neocortex. In fact, at the level of the thalamus, sensory

responses are enhanced by RF stimulation (Steriade et al.1969; Singer, 1977; Castro-Alamancos, 2002a,b). CSD

revealed that the earliest current sinks in the thalamo-

cortical recipient layers (IV and VI) of neocortex are

suppressed by RF stimulation. The activity flow revealed

by the CSD closely agrees with morphological studies,

which have shown that thalamocortical fibres from VPM

project to layers IV–III leaving collaterals in layer VI of the

barrel neocortex (Bernardo & Woolsey, 1987; Jensen &

Killackey, 1987), and with electrophysiological studies

that mapped the laminar spread of whisker-evoked

activity within the neocortex using single-unit recordings

(Armstrong-James, 1995; Simons, 1995) and field potentials

(Di et al. 1990). The CSDs are also similar to those

obtained in primary somatosensory cortex using electrical

stimulation of the ventroposterior lateral thalamus (VPL)

(Castro-Alamancos & Connors, 1996; Kandel & Buzsaki,

1997). Since the thalamic output is enhanced and the earliest

current sinks in the thalamocortical recipient layers (IV

and VI) are suppressed, this indicates that sensory

suppression occurs at the thalamocortical connection.

This conclusion is supported by the observation that

cortical cells which enhanced or reduced their tonic firing

to RF stimulation both displayed a reduced sensory

response during arousal, indicating that a change in

cortical cell excitability cannot explain the suppression of

sensory responses. Taken together the results indicate that

cortical sensory suppression during arousal occurs at

thalamocortical synapses.

Previous work has shown that sensory responses are

reduced in the neocortex, thalamus and also brainstem

sensory nuclei during behaviourally aroused states and

movement in rodents, monkeys and humans (Chapin &

Woodward, 1981; Nelson, 1984; Cohen & Starr, 1987; Shin

& Chapin, 1989, 1990; Fanselow & Nicolelis, 1999). These

investigators have proposed that a central modulatory

process must account for sensory suppression since it

occurs away from the periphery and in the absence of

actual motor activity. The present study shows that one

mechanism which contributes to the suppression observed

at the cortical level is the significantly increased thalamo-

cortical unit firing during arousal, which leads to activity-

dependent depression of thalamocortical synapses.

However, it is important to note that other factors that are

not recruited by the RF stimulation used in the present

study may also contribute to the changes previously

detected at the level of the thalamus and brainstem sensory

nuclei. The present study focused only on the thalamo-

cortical pathway because this is what we found to be

modified by RF stimulation. Accordingly, our behavioural

experiments monitored only the thalamocortical sensory

pathway and not the sensory pathways to the thalamus or

brainstem. It is likely that additional modulatory systems,

which are activated during arousal or movement, produce

further effects at the thalamic and brainstem levels. It

seems also clear that the modulations that occur during the

waking state may be different depending on what the

animal is actually doing (Chapin & Woodward, 1981;

Fanselow & Nicolelis, 1999). Although this was not explored

in detail in the present study, there are indications in Fig. 4

that this is the case because the amount of thalamocortical

suppression varied during arousal. The present study

Thalamocortical suppressionJ. Physiol. 541.1 327

Figure 6. Blocking cholinergic, noradrenergic and GABAB

receptors in the neocortex does not abolish sensorysuppression induced by RF stimulationA, field potential responses evoked in the neocortex by whiskerstimulation. Under control conditions RF stimulation suppressesthe evoked response (upper traces). Simultaneous application ofscopolamine, hexamethodide, phentolamine, propanolol andCGP35348 enhances the whisker-evoked response, but under theseconditions RF stimulation also suppresses the sensory-evokedresponse (lower traces). Traces are the average of five responsesfrom a representative experiment. B, population data from threeexperiments in which the drugs mentioned in A were applied. Theaverage for each experiment was calculated from 10–15 controltraces and RF traces. RF significantly suppresses whisker-evokedresponses during control conditions and after application of thedrug combination (*P < 0.0001, t test). Also, application of thedrugs significantly enhances the evoked response as compared tocontrol (**P < 0.0001, t test).

emphasizes that during active behavioural states, such as

exploration, thalamocortical suppression is prevalent and

that RF stimulation simulates this effect in anaesthetized

animals.

The present study proposes that increased thalamocortical

unit firing produces activity-dependent depression of

thalamocortical synapses, which leads to sensory

suppression of neocortical responses. This conclusion is

based on several findings. First, thalamocortical synapses

depress with activity (Castro-Alamancos, 1997), and

neuronal tonic firing increases in thalamocortical neurons

during arousal. After RF stimulation the firing rate of

all thalamocortical neurons increased to ~33 Hz. This

discharge rate is characteristic of VPM neurons in awake

behaving rats (Nicolelis et al. 1993; Fanselow & Nicolelis,

1999). The analogous response of all VPM neurons to

RF stimulation was expected because thalamocortical

neurons represent a homogeneous population in their

response to neuromodulators (McCormick & Prince,

1987; McCormick, 1992). In addition, the differential effect

of RF stimulation on the firing of neocortical neurons was

also expected because in vitro studies have shown distinct

actions of neuromodulators depending on the cortical

neuronal type (McCormick & Prince, 1985; McCormick,

1992; Xiang et al. 1998).

Second, blocking the firing of thalamocortical neurons in

the VPM with TTX is sufficient to eliminate the thalamo-

cortical sensory suppression induced by RF stimulation by

about 90 %. A possible interpretation of this result is that it

resulted from the block by TTX of the cortical activation

mediated by the intralaminar nuclei of the thalamus

(Steriade et al. 1997) (e.g. by spread of TTX to the intra-

laminar nuclei). However, this is unlikely for two reasons.

(1) We found that cortical activation induced by RF

stimulation is not different when the VPM thalamus is

blocked with TTX. Thus, the cortical modulation induced

by RF stimulation is still present during application of

TTX in VPM, although the thalamocortical suppression

induced by RF stimulation is blocked. (2) It is unlikely that

the intralaminar nuclei were affected by the TTX because

the distance between the microdialysis probe and the

intralaminar nuclei is the same as that between the probe

and the thalamic radiation. If TTX was spreading this

distance the thalamic radiation-evoked responses should

have been affected, which was not the case. Another

important consideration with this experiment is that due

to the need to inactivate VPM using TTX we had to use

electrical stimulation of the thalamic radiation to stimulate

thalamocortical fibres. However, electrical stimulation of

the thalamic radiation also evokes corticothalamic responses

(Castro-Alamancos & Calcagnotto, 2001), which means that

layer VI corticothalamic neurons are being antidromically

activated. There are two consequences of this. (1) The

thalamus is recurrently stimulated by corticothalamic

synapses. However, this is not a problem because under these

same experimental conditions corticothalamic responses

to low frequency stimulation are very small and only

corticothalamic stimulation above 5 Hz produces a strong

thalamic response due to facilitation (Castro-Alamancos

& Calcagnotto, 2001). Moreover, the lack of involvement

of the corticothalamic connection in the cortical responses

evoked by thalamic radiation stimulation is demonstrated

by the fact that the amplitude of the cortical responses

to single stimuli of the thalamic radiation was not

significantly different before and after application of TTX

in VPM (Fig. 5). (2) The other consequence of the

antidromic activation of layer VI corticothalamic neurons

is that the cortex is recurrently stimulated via intracortical

collaterals from these neurons that reach the upper layers

(Zhang & Deschenes, 1997). Interestingly, these intracortical

collaterals behave much the same way as corticothalamic

synapses, producing strong facilitation (Stratford et al.1996) and long latency responses because these small

diameter fibres conduct much more slowly than the larger

thalamocortical fibres (Ferster & Lindstrom, 1985; Swadlow,

1989). Consequently, we expected to observe a long latency

response that could be attributed to these intracortical

fibres when we stimulated at high frequencies. Indeed, as

shown in Fig. 5C (asterisk), what we found was a very

small, long latency response that followed the initial

thalamocortical response. The amplitude of this facilitated

response to repetitive stimulation was about 5–10 % of the

amplitude of the response we measured to single stimuli,

and it was expected to be even smaller to single stimuli

because of the absence of facilitation. Thus, this leads to the

conclusion that an intracortical component originating

from axon collaterals of corticothalamic cells would not be

present in the single stimuli responses we measured or it

would be very small (< 5 % of the response) and have a

long latency. Therefore, the response we measure in the

cortex using single stimuli of the thalamic radiation is

mostly (> 90 %), if not entirely, due to stimulation of

thalamocortical fibres.

Finally, neuromodulators that may be released in the

neocortex by RF stimulation are known to affect

thalamocortical synapses when applied in vivo (Oldford etal. 2000) and in vitro (Gil et al. 1997; Hsieh et al. 2000).

However, we found that cholinergic, noradrenergic and

GABAB receptor antagonists applied together in the

neocortex did not reduce sensory suppression induced by

RF stimulation (in fact, they slightly enhanced the

suppression), which demonstrates that these major neuro-

transmitter systems do not contribute to thalamocortical

sensory suppression induced by RF stimulation.

Taken together, the results of the present study lead to the

conclusion that increased thalamocortical activity in the

M. A. Castro-Alamancos and E. Oldford328 J. Physiol. 541.1

VPM produces thalamocortical sensory suppression during

arousal. Our results do not rule out the effects of a potential

neuromodulator released in the neocortex by VPM

thalamocortical activity, which could depress thalamo-

cortical synapses. Alternatively, thalamocortical depression

may be a consequence of an activity-dependent depletion

of the synaptic machinery (Thomson, 2000). Both of these

mechanisms would be blocked by application of TTX in

the VPM thalamus. In vitro preparations are best suited to

investigate these issues.

Interestingly, a very recent study has reached similar

conclusions to ours (Swadlow & Gusev, 2001). They found

that the efficacy of the connection between thalamic and

cortical units was doubled immediately after silent periods

of thalamic firing. Thus, in agreement with our results,

thalamocortical efficacy is suppressed during periods of

enhanced thalamic firing. We also found in a recent study

that the corticothalamic connection is suppressed during

arousal under the same experimental conditions (Castro-

Alamancos & Calcagnotto, 2001). This was also manifest

in the present study by the RF-induced suppression of the

long latency component of the field potential response

evoked in the VPM by medial lemniscus stimulation, which

is a feedback corticothalamic response (Mishima, 1992).

This means that during arousal the thalamo-cortico-

thalamic recurrent loop is suppressed compared with

quiescent states. The enhanced loop during sleep may

serve to facilitate the propagation of slow oscillations,

which are prominent in the thalamocortical system during

that state. The suppressed loop during aroused states

may impede the flow of low frequency signals and

selectively allow the flow of high-frequency activity, as

shown for the corticothalamic pathway (Castro-Alamancos

& Calcagnotto, 2001).

What is the functional value of a suppressed thalamo-

cortical connection during arousal? Thalamocortical

suppression may be functionally useful as a gain regulator

of activity reaching the neocortex (Abbott et al. 1997;

Tsodyks & Markram, 1997). Increased thalamic tonic

firing during activation will reduce the strength of the

thalamocortical connection. By reducing the impact of

thalamocortical inputs sensory representations become

focused in the neocortex. This is important because in

studies of sensory representation mapping in anaesthetized

animals the area of neocortex that responds to a focal

peripheral stimulus is extremely large. For instance,

several barrels respond in the neocortex to deflection of a

single whisker in anaesthetized rodents (Simons, 1978;

Armstrong-James et al. 1992; Masino et al. 1993; Ghazanfar

& Nicolelis, 1999; Moore et al. 1999; Petersen & Diamond,

2000). In contrast, because of thalamocortical sensory

suppression during arousal, sensory inputs (i.e. whiskers)

may become significantly focused in the neocortex to their

appropriate representations (i.e. barrels). This could be

particularly helpful for spatial processing, such as stimulus

location, because the topographic arrangement at the

morphological level is maintained at the physiological

level.

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AcknowledgementsWe thank W. Sossin and B. Jones for comments on the manuscript,and Novartis for providing CGP35348. Multichannel siliconprobes were provided by the University of Michigan Center forNeural Communication Technology sponsored by NIH NCRR.The Medical Research Council of Canada, Natural Sciences andEngineering Council of Canada, Fonds de la Recherche en Santédu Quebec, Canadian Foundation for Innovation and SavoyFoundation supported this research.

Thalamocortical suppressionJ. Physiol. 541.1 331