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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: [email protected]
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