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VPM and PoM Nuclei of the RatSomatosensory Thalamus: IntrinsicNeuronal Properties and CorticothalamicFeedback

Carole E. Landisman and Barry W. Connors

Department of Neuroscience, Division of Biology and

Medicine, Brown University, Providence, RI 02912, USA

Sensory information originating in individual whisker follicles as-cends through focused projections to the brainstem, then to theventral posteromedial nucleus (VPM) of the thalamus, and finallyinto barrels of the primary somatosensory cortex (S1). By contrast,the posteromedial complex (PoM) of the thalamus receives morediffuse sensory projections from the brainstem and projects to theinterbarrel septa of S1. Both VPM and PoM receive abundant cor-ticothalamic projections from S1. Using a thalamocortical slicepreparation, we characterized differences in intrinsic neuronal prop-erties and in responses to corticothalamic feedback in neurons ofVPM and PoM. Due to the plane of the slice, the majority of ourobserved responses came from activation of layer VI because mostor all of the layer V axons terminating in PoM are cut.We found that VPM neurons exhibit higher firing rates than PoM

neurons when stimulated with injected current. Stimulation of cor-ticothalamic fibers evoked monosynaptic excitation, disynaptic inhi-bition, or a combination of the two in both nuclei. A few differencesin the feedback responses emerged: purely excitatory postsynapticpotentials (EPSPs) in VPM were smaller and facilitated more thanthose in PoM, and only the EPSPs in VPM had a strong NMDA com-ponent. For both nuclei, some of the feedback responses were purelydisynaptic inhibitory postsynaptic potentials (IPSPs) from the tha-lamic reticular nucleus (TRN). This was due to EPSP failures withinVPM and PoM combined with greater reliability of S1-originatingsynapses onto TRN. These findings suggest that despite theexclusively excitatory nature of corticothalamic fibers, activationof cortex can trigger excitation or inhibition in thalamic relayneurons.

Keywords: electrophysiology, excitation, higher order nucleus, inhibition,relay nucleus

Introduction

Sensory systems of the brain have hierarchical features, but

there are also parallel pathways of sensory information. Within

the parallel hierarchies of the forebrain lie enormous feedback

connections. That is, each area of primary sensory cortex sends

efferent fibers back to the relay area of thalamus from which it

receives feedforward input. These corticothalamic feedback con-

nections often greatly outnumber the thalamocortical feedfor-

ward connections, in some cases by 40 to 1 (Sherman and Koch

1990). Despite the dramatic scale of these anatomical findings,

the functional significance of corticothalamic connections is

poorly understood. Speculations about the function of cortico-

thalamic connections include sharpening and/or amplifying re-

ceptive field responses, focusing attention, and modulating

receptive field properties based on contextual information (Ster-

iade et al. 1993; Sherman andGuillery 2002; Sillito and Jones 2002).

Corticothalamic synapses are glutamatergic and can activate

a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid,N-methyl-

D-aspartate (NMDA), and metabotropic glutamate postsynaptic

receptors (Bromberg et al. 1981; De Biasi and Rustioni 1990;

Deschenes and Hu 1990; Scharfman et al. 1990; McCormick and

vonKrosigk 1992; Long et al. 2004; Landisman and Connors 2005).

Thus, the activation of corticothalamic fibers can cause a general

increase in excitability of thalamic relay neurons. Though both

feedforward and feedback fibers make glutamatergic synapses

onto thalamic neurons, only the feedback fibers contact the

metabotropic glutamate receptors (mGluRs; Martin et al. 1992;

Godwin et al. 1996; Liu et al. 1998; Vidnyanszky et al. 1996).

Activation of mGluRs can shift the state of thalamic neurons from

burst firing to single spiking mode (McCormick and von Krosigk

1992). These 2 neuronal states are often associated with sleep and

arousal, respectively (Steriade et al. 1993), although bursting may

occur duringwakefulness aswell (Ramcharan et al. 2000; Swadlow

and Gusev 2001).

In order to understand the functions of corticothalamic con-

nections more completely, it is important to consider aspects of

the anatomy as well as the physiological behavior of the local

circuitry. In the rat whisker barrel system, the cortical barrel

fields project onto several nuclei in somatosensory thalamus.

Neurons in 2 of these nuclei exhibit very different receptive field

sizes, and the projections they receive from primary somato-

sensory cortex (S1) differ in their source, number, and synapse

characteristics (Hoogland et al. 1987; Chiaia et al. 1991; Diamond,

Armstrong-James, Budway, and Ebner 1992; Diamond, Armstrong-

James, Ebner 1992; Lu and Lin 1993, though see Alloway et al.

2003). The ventroposteromedial nucleus (VPM) and the medial

portion of the posterior complex (PoM) are somatotopically

organized in a mirror image fashion about their common border

(Nothias et al. 1988). Under surgical levels of anesthesia, vibrissal

neurons in the PoM have an average receptive field size of 5

whiskers (Chiaia et al. 1991; Diamond, Armstrong-James, Ebner

et al. 1992).Neurons inVPM are clustered into discrete barreloids.

Each barreloid contains neurons most sensitive to one particular

whisker and receives input from (and sends output to) one

particular S1 barrel (Senft and Woolsey 1991; Diamond, Arm-

strong-James, Ebner et al. 1992; Agmon et al. 1995; Land et al.

1995). By contrast, the anatomy and connectivity of PoM is more

diffuse (Bourassa et al. 1995). Responses of PoM cells to whisker

movement can be largely suppressed by inactivation of cortical

inputs, whereas VPM neurons continue to respond briskly under

similar conditions (Diamond, Armstrong-James, Budway, Ebner

et al. 1992). The effects of silencing cortical input on PoM

responses are large, yet the synaptic mechanisms of feedback

onto PoM or VPM neurons are not known.

Dramatic differences in the anatomy of the corticofugal syn-

apses onto PoM and VPM neurons suggest that the 2 pathways

are functionally very different. The upper portion of layer VI of

S1 sends projections to VPM, and the lower portion of layer VI

Cerebral Cortex December 2007;17:2853--2865

doi:10.1093/cercor/bhm025

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sends themajority of its projections to PoM, though a small num-

ber of these neurons also send collaterals to VPM (Hoogland

et al. 1987; Bourassa et al. 1995; Killackey and Sherman 2003).

Furthermore, corticothalamic axons originating in layer V project

exclusively to PoM. All of the axons originating from layer VI

neurons are thin, and they terminate in small synaptic boutons

on thalamic relay neurons. By contrast, the layer V terminals

arise from large caliber axons and form large synaptic boutons.

As a general rule, large synaptic terminals have more active

zones, release transmitter more reliably, and are thus more ef-

ficacious (Pierce and Lewin 1994). It has been proposed that

the layer VI inputs play a more modulatory role, whereas the

layer V inputs serve as the primary ‘‘driver’’ of PoM cells

(Sherman and Koch 1990; Feig and Harting 1998; Sherman

and Guillery 1998; Reichova and Sherman 2004).

In this study, we first compare the intrinsic membrane prop-

erties of VPM and PoM neurons; differences in physiological

properties could help to explain the response properties of

these 2 neuronal groups in vivo. We then compare the con-

sequences of activating corticothalamic feedback fibers on VPM

and PoM neurons.

Materials and Methods

Slice PreparationSprague-Dawley rats aged P14--P21 were anesthetized using thiopental

sodium (50 mg/kg). The rats were then decapitated, and the brains

removed and quickly placed in ice-cold artificial cerebrospinal fluid

(ACSF) bubbled with 95% CO2/5% O2. The composition of the ACSF

was (in mM) 126 NaCl, 3 KCl, 2.0 MgSO4, 1.25 NaH2PO4, 26 NaHCO3,

2 CaCl2, and 10 dextrose. Thalamocortical slices were obtained as

described previously (Agmon and Connors 1991) using a Vibroslice

(Campden Instruments, Lafayette, IN). Three 400-lm sections (from

each hemisphere) containing the somatosensory thalamus and cortex

were prepared and placed either onto pieces of vinyl mesh in an

interface holding chamber or into a submersion chamber. The chambers

contained oxygenated ACSF, and slices were incubated for 1 h at 33 �Cand subsequently at room temperature. All experiments were carried

out in accordance with National Institutes of Health (NIH) guidelines.

Electrophysiological RecordingsAfter incubation in the holding chamber, an individual slice was trans-

ferred to either an interface recording chamber or a submersion chamber

held at 32--33 �C. Whole-cell patch recordings were made using glass

microelectrodes (5--7 MX) filled with internal solution (in mM: 138 K

gluconate, 4 KCl, 2 NaCl, 10 4-(2-hydroxyethyl)-1-piperazineethane-

sulfonic acid, 0.2 ethyleneglycol-bis(2-aminoethylether)-N,N,N 9,N 9-tet-

raacetic acid (EGTA), 4 ATP-Mg, 0.3 GTP--Tris, and 7

phosphocreatine--Tris; final pH 7.25). An Axoprobe--1A amplifier (Axon

Instruments, now Molecular Devices, Sunnyvale, CA) was used

in conjunction with a Labview A/D board and software (National

Instruments, Austin, TX) and a PC computer (Dell, Austin, TX) for data

acquisition. Data were digitized and collected at 20 kHz. A small

concentric bipolar stimulating electrode (FHC cat#CBBRC75; outer

diameter [OD] 200 lm, inner diameter [ID] 12.5 lm, Bowdoin, ME)

was placed either in deep layer VI or the internal capsule (IC)

containing fibers of passage from cortex to thalamus. Stimulation

currents ranging from3 to400lA,200lsecduration,wereused to evoke

synaptic responses. Train data consisted of 4 shocks at a frequency

of 40 Hz, unless otherwise noted. Individual illustrations of cell

responses to single-shock stimulation or train stimulation to the IC

are averaged traces (10--20 sweeps per trace). Latency analyses did

not take into consideration the many failures observed after the first

shock in a train of stimulation. Instead, all latencies were measured

for the first pulse that generated a postsynaptic potential (PSP). Spike

widths were measured at half height in milliseconds (see Table 1).

Data were analyzed using Labview and Origin (Microcal Software

produced by OriginLab, Inc., Northampton, MA) software. Where

indicated, drugs were bath applied via the ACSF that perfused the

slice at 2 ml/min. Drug doses (in lM) were 50 bicuculline

methiodide (BMI), 20 picrotoxin, 50 DL-2-amino-5-phosphonovaleric

acid (APV), 20 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 1 CGP-

62349 (a c-aminobutyric acid B [GABAB] blocker from Ciba-Geigy,

now Novartis International AG, Basle, Switzerland).

Anatomy and HistologyAnatomical tracer injections were made using dextran tetramethylrhod-

amine (10,000 MW), lysine fixable (Molecular Probes, now Invitrogen,

Carlsbad, CA). Dry tracer crystals were placed on the end of a broken

glass microelectrode, and the tip was lowered into the target region of

the slice (deep layer VI of S1 cortex). Slices were then left in the holding

chamber at room temperature for 8--12 h. After tracer incubation, slices

were placed in 4% paraformaldehyde with 20% sucrose overnight.

Finally, slices were resectioned on a freezing microtome into 80-lmsections, mounted on gelatinized slides, and fixed using a cover slip with

a solution made from 100 ml of 1 part 0.1 M phosphate-buffered saline, 3

parts glycerin, and 1 ml of saturated aqueous purpurogallin (a free

radical scavenger; recipe courtesy of Dr Stewart Hendry, Johns Hopkins

University).

Results

Anatomical Confirmation of the CorticothalamicPathway and Localization of Nuclei

To confirm that the corticothalamic fibers were intact in the

thalamocortical slice preparation, injections of the anterograde

tracer rhodamine--dextran were made into layer VI and in-

cubated for several hours (see Materials and Methods). Rhoda-

mine labeling (Fig. 1A,B) confirmed that individual cells in layer

VI sent axons to the thalamus via the internal capsule. In the

example shown, fibers can be seen both in the TRN as well as

the ventrobasal complex (VB) nuclei (Fig. 1B). However, trans-

port to PoM was not seen, probably because we were unable to

maintain the slice long enough to get full transport. This inter-

pretation is supported by our subsequent observation of mono-

synaptic excitation of the thalamic nuclei from stimulation of

corticothalamic fibers (see below).

To distinguish VPM from PoM cells, we first made sure we

could accurately localize each nucleus in living slices cut in the

thalamocortical plane (Agmon and Connors 1991). Under bright

field illumination in the recording chamber, the PoM appears as

a darker (in the interface chamber, lit from above) or lighter (in

the submersion chamber, transilluminated; see Fig. 1C), triangle-

shaped region medial to the arc-shaped band of VPM that, in

turn, is medial to the ventral posterolateral nucleus (VPL) and

the TRN. The clear distinction seen in the recording chamber

assured proper targeting of each nucleus. Cresyl violet staining

Table 1Intrinsic membrane properties of VPM and PoM neurons

VPM PoM

Resting membrane potential (mV) �59 ± 4 (n 5 40) �58 ± 5 (n 5 44)Input resistance (MX) 119 ± 35 (n 5 40) 112 ± 45 (n 5 44)Action potential half width (ms) 1.06 ± 0.29 (n 5 12) 1.19 ± 0.41 (n 5 15)Spikes per burst 5.3 ± 1.4 (n 5 41) 4.4 ± 1.8 (n 5 23)Firing frequency during a burst (Hz) 348.5 ± 81.3* (n 5 41) 231.7 ± 68.4* (n 5 23)Spike frequency adaptation ratiofrom burst firing

11.9 ± 5.7 (n 5 12) 16.8 ± 8.4 (n 5 7)

Spike frequency adaptation ratiofrom tonic firing

2.0 ± 0.9 (n 5 13) 2.8 ± 2.7 (n 5 10)

Note: All data are listed as mean ± SD. n 5 number of cells. All statistical values determined

using unpaired, 2-tailed t-tests.

*P � 0.0001.

2854 Cortical Feedback onto Somatosensory Thalamus d Landisman and Connors



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of resectioned slices confirmed the borders of VPM and PoM as

previously defined from unstained visualization of live slices

(data not shown).

Intrinsic Membrane Properties of VPM and PoMNeurons

We characterized the intrinsic membrane properties of indi-

vidual cells by applying depolarizing and hyperpolarizing current

steps. Both VPM cells and PoM cells exhibited intrinsic firing

properties typical of most thalamic neurons (Llinas and Jahnsen

1982). They fired intrinsic bursts when activated from relatively

hyperpolarized resting potentials (Vrest more negative than --58

to --60 mV) and tonic spikes when activated from more depo-

larized potentials (more positive than --58 mV) (Fig. 2A,C). Both

cell types fired only a single burst following a depolarizing step

from hyperpolarized holding potentials (see above). If a long

(several hundred milliseconds), strong depolarizing step was

delivered from a holding potential equal to or more hyper-

polarized than –60 mV, both cell types fired a fast burst of action

potentials followed by tonic spikes (Fig. 2B,D, right).

When stimulated with the same intensity current pulses from

Vrest, VPM cells fired at much higher frequencies than PoM cells

during tonic firing. Figure 2B,D show examples of responses to

current stimulation of a VPM neuron and a PoM neuron re-

corded from the same slice. Compared with PoM cells, cells

from VPM had lower spike thresholds and much higher firing

frequencies at every stimulus intensity tested (Fig. 2E). The

differences in tonic firing frequency were not due to differences

in Vrest or input resistance, which were nearly identical in the 2

cell types (Table 1). The average widths of individual action

potentials from the 2 nuclei were also indistinguishable, with

means of 1.06 ms for VPM cells and 1.19 ms for PoM cells.

Bothcell typesgenerated aburst of actionpotentials after sudden

release from hyperpolarization (Fig. 2B,D). The mean number of

spikes per rebound burst was indistinguishable for the 2 cell types

(Table 1). However, as was the case with tonic firing, VPM cells

fired much faster than PoM neurons during each burst (Table 1).

Both VPM and PoM cells showed spike frequency adaptation

during repetitive spiking. We calculated the adaptation rates as

Fi/Ff, where Fi is the initial firing frequency and Ff is the final

firing frequency for the minimum depolarizing step that elicited

a regular train of action potentials (Beierlein et al. 2003). Fi was

the inverse of the interval between the first 2 spikes in the train,

and Ff was the inverse of the interval between the last 2 spikes in

the train during a 600-ms depolarizing step. Because both VPM

and PoM cells adapt differently depending on whether they

are in bursting or tonic firing modes, we calculated the firing

frequencies and adaptation values from burst initiated as well as

tonic firing. The mean adaptation ratios for VPM cells were 11.9

from holding potentials that evoked bursts and 2.0 during

purely tonic firing (Table 1). Adaptation rates of PoM neurons

were 16.8 from bursting trials and 2.8 from tonic firing trials.

The small differences in adaptation rates between the 2 cell

types were not statistically significant.

Corticothalamic Response Heterogeneity of VPM andPoM Cells

Stimulation of the internal capsule evoked heterogeneous

synaptic responses in both VPM and PoM cells. These included

pure excitation (Fig. 3A), pure inhibition (Fig. 3B), and combi-

nations of excitation and inhibition (Fig. 3C). As these examples

also show, the strength and balance of EPSPs and IPSPs evoked

Figure 1. Anatomical layout of cortical feedback pathway in the thalamocortical slice.(A) Layer VI feedback fibers labeled with fluorescent dextrans mapped onto a cartoonof the thalamocortical slice to indicate the location of tracer injection and extent oflabeling. (B) Magnified view of labeled fibers from (A) showing continuous labelingfrom layer VI of S1 cortex to the TRN and the VB of the thalamus. (C) Bright fieldtransilluminated living slice photographed with stimulating and recording electrodes(stimulating: black horizontal arrow, top; recording: vertical arrows, sides). Darkand light regions delineate borders between the different nuclei of the thalamus. Scalebar 5 1.5 mm. Abbreviations: CPu, caudate putamine; IC, internal capsule; VPL,ventral posterolateral nucleus; VPM, ventral posteromedial nucleus; PoM, poster-omedial complex. Arrows indicate recording electrodes.

Cerebral Cortex December 2007, V 17 N 12 2855



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from a single stimulus location could also vary widely as the

stimulus intensity and number were varied. A comparison of the

excitatory responses in Figure 3A to the inhibitory responses in

Figure 3B shows that the amplitudes of both increased gradually

with changes in stimulus intensity and both response types

exhibited facilitation to 40 Hz train stimuli at low to moderate

current intensities (up to 4 times threshold, or 4T for Fig. 3B and

for all stimulus values for Fig. 3C). However, at higher stimulus

intensities, the IPSPs in Figure 3B also exhibit evidence of

depression.

Not surprisingly, responses that combined excitation and

inhibition were more complex than the purely excitatory or in-

hibitory ones. As seen in Figure 3C, IPSPs could dominate and even

completely obscure EPSPs. The source of these IPSPs is the

thalamic reticular nucleus (TRN), whose GABAergic neurons

directly contact both VPM and PoM neurons (see below). At low

stimulus intensities, evidence of small monosynaptic EPSPs from

corticothalamic sources can be seen in the responses of the PoM

cell in Figure 3C, but these EPSPs were overwhelmed by

concurrent IPSPs. In addition, the reliability of EPSPs in response

to the first stimulus was very low, and thus they were not even

evident following thefirst stimulus atmoderate stimulus strengths.

Only with very high stimulus intensities (>32T) or repetitive

activation (>4T) could the EPSPs generate detectable responses.

However, in all 3 categories large increases in stimulus

intensity make it harder to distinguish the synaptic origins of

the responses because mixed fiber recruitment is likely. For this

reason, characterizations of feedback responses throughout the

paper are based on stimulus intensities between T and 2T.

Responses consisting of IPSPs alone or weak EPSPs together

with strong, low-threshold IPSPs were common in both VPM and

PoM cells in response to corticothalamic stimulation (Fig. 3D).

In 60% of VPM cells (15 of 25) and 69% of PoM cells (9 of 13),

the response profiles were strongly dominated by IPSPs: that is,

Figure 2. Firing properties of VPM and PoM cells. (A) Transition from tonic firing to burst firing in a VPM neuron at different holding potentials (þ50 pA stimulation). (B) Example ofa typical VPM neuron response to intracellular depolarizing and hyperpolarizing pulses (�100, þ100, and þ300 pA stimuli). (C) Transition from tonic firing to burst firing in a PoMneuron at different holding potentials (þ50 pA stimulation). (D) Example of a typical PoM neuron response to intracellular depolarizing and hyperpolarizing pulses (�100,þ100, andþ300 pA stimuli). (E) Plot of firing rates (mean ± standard error) for VPM and PoM neurons to different positive current injections from Vrest. Values are the final steady-statefrequencies from tonic firing during 600 ms depolarizing current pulses. N 5 8 VPM cells, and 15 PoM cells. See Table 1 for Vrest values.




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the response of the neuron stayed negative to Vrest throughout

trials of 40-Hz stimulus trains delivered at low stimulus in-

tensities (<2T of the first detectable response—either EPSP or

IPSP). Only 31% of PoM responses (4 of 13) and 40% of VPM

responses (10 of 25) showed EPSPs alone. Because EPSPs tended

to be harder to detect than IPSPs, cells that appeared to have

purely inhibitory responses were further tested by increasing

stimulus intensity and by using train stimulation.

Latencies and Failures of EPSPs and IPSPs

Previous studies have shown that corticothalamic axons origi-

nating from layer VI are distinguished by ‘‘supernormal’’ con-

duction properties (Swadlow and Waxman 1975; Kelly et al.

2001; Beierlein and Connors 2002): for a time interval following

the propagation of a single action potential, and after its re-

fractory period, the conduction velocity of a second spike is

slightly increased compared with the first. Such a supernormal

shift in axonal conduction can also be expressed as a decrease in

the onset latency of an EPSP evoked during repetitive stimula-

tion. By contrast, feedforward thalamocortical responses show

no change in conduction velocity or slightly subnormal re-

sponses (Beierlein and Connors 2002). To test whether evoked

EPSPs recorded in VPM and PoM exhibited supernormal latency

shifts, we compared EPSP latencies of the first 2 responses

during the 40-Hz stimulus trains. The supernormal shift for VPM

neurons was, on average, 324 ls (7% of the total latency) and

350 ls (9%) for PoM cells, which were similar in magnitude to

the supernormal shifts described by Beierlein and Connors

(2002). Considering only responses showing supernormal shifts,

the absolute latencies of EPSPs in VPM ranged from 1.7 to 8 ms

(mean = 4.0 ± standard deviation [SD] 1.6 ms) and those of

EPSPs in PoM ranged from 3.7 to 16 ms (mean = 5.6 ± SD 3.1 ms;

Fig. 4A). Latencies of PoM responses were significantly longer

than those of VPM (P < 0.02, unpaired, 2-tailed t-test).

The determination of sources of IPSPs was also evaluated, but

supernormality could not be used because the responses were

disynaptic. During stimulation of the internal capsule, TRN cells

potentially can be activated either by input from collaterals of

axons originating in layer VI of S1 or by collaterals of thala-

mocortical axons originating in VPM. But they cannot be

activated antidromically because their axons do not leave the

thalamus.

We compared the latencies of all IPSPs recorded in VPM and

PoM neurons (Fig. 4B,C). IPSPs in PoM had a distinctly bimodal

distribution. A cluster of very short latencies (2--5 ms) is con-

sistent with antidromic activation of rapidly conducting thala-

mocortical (VPM) axons (Gil and Amitai 1996; Beierlein and

Connors 2002); IPSPs with much longer, more variable latencies

are consistent with orthodromic activation of the slower cor-

ticothalamic axons (Golshani et al. 2001). The distribution of

VPM latencies, however, was not obviously bimodal (Fig. 4C).

Because VPM is physically closer to the cortex and TRN (see

Fig. 1C), its disynaptic latencies should be shorter than those

seen in PoM (see Kao and Coulter 1996; Gentet and Ulrich,

2003). This assumption is supported by the greater average

EPSP latencies for PoM versus VPM neurons shown in Figure 4A.

Thus, we used the largest value from the faster latency cluster

in PoM (4.8 ms) to estimate the cutoff for corticothalamic-

generated IPSPs in both cell types. Our analysis of pure IPSP

responses and EPSP--IPSP combination responses in VPM

and PoM are based on this latency threshold. The mean

Figure 3. Response heterogeneity of VPM and PoM cells to intensity-dependent stim-ulation of internal capsule fibers. The multiple sweeps in each panel represent responsesto increasing stimulus intensity starting from the lowest detectable response (threshold).(A) Example of a VPM cell with EPSPs. (B) Example of a VPM cell with IPSPs. Stimulusintensities 5 25, 50, 100, 200, and 400 lA, for panels (A) and (B). (C) Responses ofa PoM cell that receives both excitation and inhibition. (Stimulus intensities5 10, 20, 40,80, 160, and 320 lA). Arrows highlight the EPSPs. All traces Vhold 5 �60 mV. (D) Plotof the response signatures over a population of VPM and PoM cells. The categories onthe x axis represent cells that exhibit EPSPs, IPSPs, or responses showing a combinationof excitation and inhibition (‘‘both’’). The y axis counts the percent of each type cell withthe given response signature. Cases with IPSPs potentially activated by antidromicspikes from VPM were not included in the graph (see Fig. 4B for threshold example).




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corticothalamic-generated IPSP latencies were 8.1 ms for VPM

cells and 11.9 ms for PoM cells.

As expected, corticothalamic EPSPs arrived faster than the

disynaptic IPSPs in all but one case (Fig. 5). But inhibition can

also precede and dominate excitation if the reliability of trans-

mitter release onto TRN cells and from its inhibitory synapses

exceeds that of the excitatory synapses onto relay cells. In

Figure 5A,B, the cells indicated by filled dots are cases where the

EPSPs consistently failed in response to single stimuli or to the

first stimulus in a train, effectively allowing IPSPs to arrive first.

Cases of this type were observed in both VPM (4 of 12 cells) and

PoM (4 of 14 cells), but only the 4 VPM responses to the right of

the dotted line are consistent with feedback excitation of both

pathways (because all responses to the left are probably IPSPs of

thalamocortical origin, as shown in Fig. 4). By comparison, EPSPs

evoked in TRN cells by single stimuli to the internal capsule

showed no failures (0 of 11 cells; data not shown). Thus, the

disynaptic pathway by which the corticothalamic circuit inhi-

bits relay cells, via TRN, appears to be more reliable than the

monosynaptic pathway by which it excites relay cells. More

detailed discussion of cortically generated EPSP responses in

TRN cells is provided below.

Corticothalamic Excitation of VPM and PoM Cells

To assess the strength of synaptic responses of thalamic neu-

rons to the activation of single corticothalamic axons, we used

minimal stimulation. Minimal EPSPs were measured by stimu-

lating the internal capsule with near-threshold intensities, such

that at least 50% of trials generated no response (Gil et al. 1999;

Fig. 6A). The minimal stimulus intensities ranged from 5 to 60 lA.Even under these weak stimulus conditions, inhibitory events

often obscured excitatory events, so inhibitionwas blocked phar-

macologically (picrotoxin was used to block GABAA receptors

and CGP-62349 to block GABAB receptors). The minimal EPSPs

generated by internal capsule stimulation ranged in amplitude

from 0.12 to 0.33 mV in VPM cells (mean = 0.24 ± SD 0.06 mV,

n = 11) and 0.15 to 0.64 in PoM cells (mean = 0.39 ± SD 0.2 mV,

n = 11). The PoM EPSPs were significantly larger than the

EPSPs from VPM (P < 0.03, unpaired, 2-tailed t-test; Fig. 6B).

When stimulated with brief trains at 40--60 Hz, cortico-

thalamic EPSPs onto both cell types showed facilitation that

was independent of stimulus intensity. On average, facilitation

was stronger in VPM cells than in PoM cells (Fig. 6C,D). Also,

a greater number of VPM cells than PoM cells showed

facilitation (92% in VPM versus 38% in PoM).

We tested whether slow NMDA receptor--mediated current

contributed to synaptic responses and facilitation by adding the

antagonist APV to the bath. APV strongly reduced facilitation of

responses from all VPM cells tested (5 of 5) but had no effect on

the facilitating short-term dynamics in PoM cells (3 of 3 cells)

(Fig. 6E,F). There was no significant reduction of the first EPSP

amplitude by APV for either cell type (control/APV = 0.82 ± 0.24for VPM and 1.02 ± 0.12 for PoM). NMDA receptor blockade had

a stronger effect on subsequent EPSPs in a train, particularly in

VPM; the second to fourth EPSP amplitudes were reduced by

36--45% by APV in VPM cells (P = 0.026--0.007, 1-tailed, paired

t-tests; significance increased with each successive pulse), com-

pared with reductions in PoM of only 1.7--5.2% (not significantly

different).

It should be noted that in both VPM and PoM, there were

4 cells (2 in VPM, 2 in PoM) that did not show supernormal

latency shifts to train stimulation (Fig. 7A). Because it is possible

that these responses are due to antidromic activation of feed-

forward fibers, we have eliminated them from all population

analyses. The 2 VPM cells had minimal EPSP amplitudes of 0.59

and 0.88 mV—well beyond the range of the cells with super-

normal responses. However, the absolute latencies of these 2

VPM responses were within the distribution of those of the

layer VI feedback responses (3.3 and 3.5 ms). One would expect

significantly shorter latencies for antidromic activation. Thus, it

is conceivable that these 2 responses are from unusually large

layer VI fibers.

Likewise, PoM had 2 cells with subnormal responses (vs.

supernormal). These responses were notable for their significantly

Figure 4. EPSP and IPSP response latencies. (A) Distribution of EPSP responselatencies in VPM versus PoM. (B) Response latencies for IPSPs seen in PoM cells. Grayline (also seen in panel C) marks the threshold for the beginning of latencies ofcorticothalamic origin in PoM (see Results for further discussion). (C) Responselatencies for IPSPs in VPM cells. Bin size 5 1 ms for all panels.




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larger minimal amplitude (Fig. 7B), but they too had absolute

latencies similar to the layer VI--generated EPSPs (5.1 and 5.9 ms;

Fig. 7C). Although these responses might also be either from

antidromic activation or from unusually large layer VI axons,

another possibility also exists for their origin. Layer V sends

feedback to PoM characterized by large-diameter axons termi-

nating in big proximal boutons. Previously, Li et al. (2003) have

shown that EPSPs from cortical layer V to thalamus do not

display supernormal responses. But in our preparation, these

layer V axons mostly traverse a pathway that is not conserved in

the slice. However, a small subset of these fibers does travel

ventrally with the layer VI fibers (Vienante et al. 2000).

Corticothalamic Axon--Mediated Inhibition of VPM andPoM Cells

As shown previously for VPM neurons, stimulation of the

corticothalamic pathway evokes both slow and fast inhibitory

responses (Kao and Coulter 1997). Similar responses can also be

seen in PoM neurons (Fig. 8). The timing of the 2 inhibitory

components as well as their different reversal potentials

suggests that these are GABAA and GABAB receptor--mediated

IPSPs (Crunelli and Leresche 1991; Ulrich and Huguenard,

1996). The first IPSP (Fig. 8A) had a faster rise time and reversed

near –71 mV, consistent with the predicted chloride reversal

potential for these cells. The second IPSP (Fig. 8A) had a slower

rise time and reversed near –85 mV, consistent with the more

negative reversal potential of potassium. Blockade with a GABAB

receptor--specific antagonist completely eliminated the second

IPSP (Fig. 8B) and left the faster GABAA component intact. We

used IPSP latency and the rate of rise as criteria to distinguish

GABAA from GABAB responses in VPM and PoM cells and/or

blockade of either component with the antagonists BMI (for

GABAA) or CGP-62349 (for GABAB). All PoM cells (20/20) and all

but one VPM cell (16/17) showing inhibition had a GABAA-like

component. The average GABAA-IPSP amplitudes from Vrest

were –3.1 mV for PoM cells and –2.4 mV for VPM cells. VPM cells

were much less likely than PoM cells to have a GABAB receptor--

like component as part of their inhibitory responses: 7 of 17

VPM cells and 20 of 22 PoM cells had IPSPs with a GABAB

component. The average amplitudes of the GABAB-IPSP com-

ponents for PoM and VPM cells were similar (–1.3 mV vs. –1.4

mV, respectively).

Corticothalamic Activation of the TRN

Our measurements of evoked IPSPs in VPM and PoM neurons

suggested that corticothalamic axons induce strong, reliable

excitation of TRN neurons, as described above. We recorded

directly from TRN cells to test this possibility. Figure 9A

illustrates an example of the response of a TRN neuron to

minimal corticothalamic stimulation. The test for supernormal-

ity was used to determine the origin of activation (see above),

and all data shown in Figure 9 were consistent with activation

by corticothalamic axons. The corticothalamic EPSPs in TRN

cells were relatively strong, and half of the cells studied showed

clear facilitation in response to 40 Hz train stimulation; EPSPs in

the other half were stable (n = 10 cells; Fig. 9A,B).

The minimal EPSPs from cortical feedback onto TRN cells

were of much larger amplitude than those onto VPM and PoM

cells (Fig. 9C). The average minimal EPSP for TRN cells was 1.41

mV compared with 0.24 and 0.39 mV for VPM and PoM, re-

spectively. There was almost no overlap among the EPSP ampli-

tudes of TRN responses and those of the other 2 thalamic nuclei.

These data suggest that corticothalamic feedback excites TRN

neurons much more strongly than it does VPM or PoM neurons.

Discussion

The VPM and PoM nuclei provide distinctly different spatial and

temporal features of somatosensory information to the neo-

cortex (Sosnik et al. 2001; Trageser and Keller 2004; Golomb

et al. 2006). Our measurements showed that the neurons in the

2 nuclei differ in their intrinsic membrane properties and

excitability and in the nature of the synaptic feedback they

receive from corticothalamic connections.

We initially characterized the axonal connectivity of our slice

preparation, which had previously been used primarily for

studies of thalamocortical pathways but only rarely for exam-

ining corticothalamic pathways. Jones et al. (1979) found that

focal injection of a cocktail of retrograde and anterograde tracer

Figure 5. Comparison of EPSP and IPSP latencies for individual VPM (A) and PoM (B)cells showing mixed responses (both excitation and inhibition). Each circle representsthe EPSP and IPSP latency from the response of a single cell. Black dots indicate cellresponses where the EPSP failed on the first shock during train stimulation but showedEPSPs to the second shock, which was used to calculate the EPSP latency. Diagonallines indicate the location for EPSPs and IPSPs with equal latencies. Thus, circles abovethe lines indicate IPSP latencies faster than EPSP latencies, and circles below the lineindicate IPSPs with longer latencies than EPSPs. Dotted vertical lines indicate theseparation of thalamocortical-evoked IPSPs (latencies\5.5 ms) from corticothalamic-evoked IPSPs (latencies[5.5 ms). N 5 12 VPM cells, and N 5 14 PoM cells.




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into sensorimotor cortex in vivo yielded superimposed labeled

cells in cortex and thalamus (i.e., feedforward and feedback

neurons). Our labeling study in slices showed that at least some

of the layer VI projections from primary somatosensory cortex

(S1) to thalamus are intact in the slice. Anatomical confirmation

of this pathway in the slice makes it very likely that the

responses we and others (Kao and Coulter 1997; Reichova and

Sherman 2004) recorded indeed had a corticothalamic origin.

Distinguishing the VPM and PoM nuclei in both the submersion

and interface chambers was clear and unambiguous due to

differences in their optical properties, as seen in Figure 1C, and

by comparison with nuclear positions in standard atlases

(Paxinos and Watson 1998).

Intrinsic Membrane Properties

The membrane properties of a neuron largely determine how it

transforms its synaptic inputs into output patterns of action

potentials. Relay neurons of the dorsal thalamus tend to have

certain electrophysiological characteristics in common, regard-

less of their nucleus of origin. Most notably, they display 2 modes

of spiking: when activated from a relatively negative resting po-

tential, they generate bursts of spikes driven by low-threshold

calcium currents and when activated from more depolarized

resting potentials, they generate tonic trains of spikes (Llinas

and Jahnsen 1982; Jahnsen and Llinas 1984).

We compared the intrinsic firing properties of VPM and PoM

neurons. Although their passive membrane properties were

Figure 6. Characterization of EPSPs. (A) Response of a VPM cell to single minimal shocks to the internal capsule (10 lA; 20 sweeps). (B) Plot of the distribution of minimal EPSPsfor the population of VPM and PoM neurons tested. Bin size5 0.1 mV, range5 0.1--0.7 mV. N5 11 VPM cells and 11 PoM cells. Comparison of VPM (C) and PoM (D) cell EPSPresponse amplitudes to train stimulation (40 Hz). The x axes plot the stimulus number, and y axes plot the EPSP response amplitude normalized to the first EPSP, plotted on a logscale. Each line represents the response of one cell. For pulse numbers 2--4, values[1 indicate facilitation and values\1 indicate depression. Solid gray lines at y value 1 indicatesthe location of unchanging EPSP amplitudes. Dotted lines in each graph show the population average for the given cell type. (E) and (F): Examples of a VPM cell (E) and a PoM cell (F)EPSP responses before and after application of the NMDA blocker APV. Black responses are before APV application, and gray superimposed responses are during APV application.All EPSPs for this were recorded in ACSF with full inhibitory blockade using BMI and CGP-62349 (see Materials and Methods).




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similar, when presented with similar suprathreshold stimuli the

VPM neurons had lower thresholds, were able to fire tonically at

higher frequencies, and generated higher frequency spike bursts

than PoM neurons. The relatively lower excitability of PoM

neurons may contribute to their sensory responsiveness in vivo.

In anesthetized rats, PoM neurons are generally more difficult to

excite with somatic sensory stimulation than are VPM neurons

(Hoogland et al. 1987; Chiaia et al. 1991; Diamond, Armstrong-

James, Ebner et al. 1992, b; Lu and Lin 1993; Sosnik et al. 2001).

In response to whisker inputs, PoM cells fire fewer spikes at

longer and more variable latencies than VPM cells.

Response Heterogeneity

The main goal of this paper was to characterize feedback effects

of S1 cortex onto the 2 thalamic nuclei, VPM and PoM. We ob-

served 3 different types of responses after stimulating the cor-

ticothalamic pathway: excitation alone, inhibition alone, or a

combination of excitation and inhibition. Despite the purely ex-

citatory nature of the feedback fibers themselves, the strength

and prevalence of inhibitory responses in both cell types was

significant (Fig. 3). Several previous studies have described

excitation and inhibition in multiple thalamic areas as a result

of activating cortical inputs (Pare et al. 1991; Warren et al. 1994,

1997; Kao and Coulter 1997; Bartlett and Smith 1999; Zhang and

Jones 2004).

Latencies of both excitatory and inhibitory events originating

from cortex had a much broader distribution than latencies

originating from thalamocortical activation (Figs. 4 and 5). These

findings are consistent with data from other studies that show

tight clustering of thalamocortical latencies (Gil and Amitai

Figure 8. Inhibitory responses show both early and late components. (A) Responsesof a PoM cell at different holding potentials to a single internal capsule shock in ACSF.First arrow indicates the onset of the early, fast inhibitory component. Second arrowindicates the onset of the slower, late inhibitory component. Reversal of the fast andslow inhibitory components can be seen near �71 mV and �85 mV, respectively. (B)The same cell in (A) after application of CGP-62349, which blocked the slow inhibitorycomponent. Responses to single shocks while the cell was held at different potentialsreveal a reversal of the fast inhibitory component near �75 mV. Stimulus 5 150 lA(A and B).

Figure 7. Distinction between layer V and layer VI inputs to PoM. (A) Responses topaired-pulse stimuli (50 Hz). Thin axons from layer VI can be identified by theirtendency to evoke shorter latencies from the second pulse compared with the first(supernormality). Larger diameter fibers exhibit either no change in latency or slightlylonger latencies to the second of 2 pulses (normality or subnormality). In the topexample (‘‘layer V’’), the second EPSP arrived 0.1 ms later than the first. In the bottomexample (‘‘layer VI’’), the second EPSP arrived 0.6 ms earlier than the first.(B) Corticothalamic responses of PoM cells sorted by change in latency and minimalamplitude (N 5 13 cells). (C) PoM responses of the same cells shown in panel B butplotted by absolute latency versus minimum EPSP amplitude. Filled circles representresponses from layer VI activation; open circles are from possible layer V activation.




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1996) and a broad range of corticothalamic latencies (Golshani

et al. 2001).

Excitatory Synaptic Responses

The direct effect of corticothalamic feedback on the VPM and

PoM is excitation. The amplitudes of minimal EPSPs from cortex

were significantly larger in PoM cells than in VPM cells. One of

the most important aspects of characterizing these EPSPs is

distinguishing their points of origin: whether the larger PSPs

seen in PoM come from layer V or from layer VI inputs.

Anatomically, the axons and terminals from layer V appear to

be much larger than those from layer VI. The distinction

between these 2 pathways is consistent with the idea that layer

V inputs serve as ‘‘drivers’’ to the PoM, and those from layer VI

provide a modulatory effect on activity both in VPM and PoM

(Sherman and Koch 1990; Feig and Harting 1998; Sherman and

Guillery 1998; Reichova and Sherman 2004). We think the dif-

ferences we have observed in EPSP magnitude in VPM versus

PoM largely arise from axons originating in layer VI, despite the

existence of the large layer V terminations in PoM. First, we saw

no bimodal distribution of PoM response amplitudes that would

indicate activation from layer V versus VI. This is not surprising

because the majority of layer V fibers traverse an anatomical

plane that is not preserved in the thalamocortical slice

(Veinante et al. 2000). Second, there is a large overlap in EPSP

response amplitudes (Fig. 6B), which is not consistent with

anatomical findings showing large synaptic boutons from layer

V (up to 5 lm in diameter) and very small ones from layer VI

( <1.5 lm; Bourassa et al. 1995; also see Vienante et al. 2000).

This difference in terminal size is more consistent with previous

studies of responses in higher order thalamic nuclei originating

from layer V versus VI (Li et al. 2003; Reichova and Sherman

2004). In both of those studies, the EPSPs from layer V axons

were reported to be 4--10 times the amplitude of those from

layer VI.

We did observe 2 PoM responses that may have had layer V as

their origin (Fig. 7). These 2 neurons had noticeably larger

minimal EPSP amplitudes and showed no evidence of latency

supernormality. However, their amplitudes were only modestly

larger than those observed by Li et al. (2003) and Reichova and

Sherman (2004). Another difference between our study and

that of Reichova and Sherman is that they observed no sig-

nificant difference in the amplitude of layer VI EPSPs in VPM

versus PoM. This could be due to different stimulation methods

because we used minimal stimulation and they reported am-

plitudes based on 1.5T stimulus intensities. This would also

explain why their observed EPSPs (presumably from layer VI)

were significantly larger than ours (~1.5 mV vs. ~0.2 mV).

Short-term facilitation of excitatory responses was present in

both cell types, but much stronger and more common for VPM

cells (Fig. 6C,D). In fact, the average PoM response showed no

facilitation because there were virtually equal numbers (and

equal amplitudes) of facilitating and depressing responses from

the 40-Hz train stimulation. The combination of larger EPSPs

and less facilitation suggests that layer VI terminations onto PoM

may be more reliable and thus have a stronger influence, than

those onto VPM cells.

In many cases, it was virtually impossible to elicit an EPSP

after one shock in both VPM and PoM cells (see Fig. 5A,B, filled

circles), suggesting a low probability of release from cortico-

thalamic synapses onto both cell types. This idea is supported by

the findings of Golshani et al. (2001) who have recorded pairs of

layer VI and VPM neurons. They reported a 68% failure rate of

VPM EPSPs in response to the first spike in a train from a cell in

layer VI. Our observations of such failures were slightly more

common in VPM than PoM neurons (33% vs. 20%, respectively),

further supporting our suggestion that layer VI terminations

onto PoM are more reliable than those onto VPM. We attribute

these differences to the fact that PoM cells receive input only

from lower layer VI, whereas VPM cells receive most of their

input from upper layer VI along with sparse input from lower VI

(Bourassa et al. 1995; Killackey and Sherman 2003). But it is

also possible that a single axon can have different effects on

Figure 9. Cortical feedback responses of TRN neurons to internal capsule stimulation.(A) Example response of a single TRN neuron to1.53 threshold stimulus train (40 Hz),showing strong facilitation. (B) Summary of the population of TRN responses to 40-Hztrain stimulation. All EPSP amplitudes are normalized to the response to the first pulse.The y axis is plotted on a log scale. Each line represents the responses of a singleneuron. Solid gray line indicates unchanging EPSP amplitude. Lines below solid grayshow response depression, and lines above solid gray show response facilitation.Dotted gray line indicates population average (N 5 10 cells). (C) Distribution ofminimal EPSP amplitudes for the 3 thalamic cells types: VPM, PoM, and TRN. Binsize 5 0.5 mV, range 5 0.5--4 mV. All EPSPs smaller than 0.5 mV are pooled in thefirst bin. (N 5 11 VPM, 11 PoM, and 10 TRN cells).




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separate postsynaptic targets, as seen in neocortex (Markram

et al. 1998).

Inhibitory Synaptic Responses

GABA released onto VPM and PoM neurons activated both

GABAA and GABAB responses, as determined by their time

courses (early and late), reversal potentials, and effects of

receptor-specific antagonists. Almost all cells of both nuclear

types had a GABAA component in their inhibitory responses.

However, many more PoM cells than VPM cells showed GABAB

responses (91% vs. 37%, respectively). As with the intrinsic

firing properties, the increased prevalence of GABAB-IPSPs may

contribute to the in vivo sluggishness of PoM neurons compared

with VPM neurons. That is, the GABAB responses may keep the

cells more hyperpolarized for longer periods of time during

a similar level of TRN activation (Roy et al. 1984; Bloomfield and

Sherman 1988; Salt and Eaton 1990; Crunelli and Leresche 1991;

Pare et al. 1991; Huguenard and Prince 1994; Kao and Coulter

1997; Kim et al. 1997; Warren et al. 1997; Kim and McCormick

1998; Bartlett and Smith 1999; Ziburkus et al. 2003). In fact,

strong inhibitory input from zona incerta (ZI) has been dem-

onstrated to robustly reduce PoM responses to whisker stimu-

lation in vivo (Trageser and Keller 2004). Furthermore, it has

recently been proposed that stronger GABAB-mediated inhibi-

tion in PoM compared with that in VPM may be a key factor in

the temporal coding of information in PoM (Golomb et al.

2006). More generally, the strength of IPSPs in both VPM and

PoM could also be due, in part, to strong electrical coupling of

clusters of TRN cells (Landisman et al. 2002; Long et al. 2004;

Landisman and Connors 2005).

Corticothalamic Activation of TRN

To substantiate our conclusions of strong inhibitory activation

in the corticothalamic pathway, we made direct recordings

from a population of TRN cells and characterized their re-

sponses to internal capsule stimulation (Fig. 9). As expected,

stimulation elicited responses consistent with both feedforward

and feedback activation, based on latency analysis. However, the

majority of responses (10 of 11) had properties consistent with

a cortical origin (i.e., exhibited supernormal response latencies).

This finding further supports our earlier attempt to differentiate

IPSPs in VPM and PoM based on latency threshold (Figs. 4 and

5). The presumptive feedback-activated EPSPs in TRN were

significantly larger in amplitude compared with those seen in

VPM and PoM (Fig. 9C; also see Golshani et al. 2001) and tended

to facilitate. The strength of these connections could be due to

a very large number of terminations of layer VI--originating

axons onto individual TRN cells (Cox et al. 1997; Liu and Jones

1999; Alexander et al. 2006).

It has been shown that the ZI as well as the anterior

pretectum (APT) exhibit strong inhibitory influence on the

PoM (ZI: Lavallee et al. 2005; APT: Bokor et al. 2005). Although

both of these nuclei are present in the thalamocortical slice, the

pathway from cortex via the internal capsule to the ZI (or APT)

to PoM does not appear to be intact. Along these lines, both ZI

and APT receive their cortical excitation from layer V. As

mentioned previously, the pathway from layer V to thalamus is

mostly or completely cut in our slice plane. In fact, the prep-

aration that preserves the pathway from APT to PoM is almost

perpendicular to the thalamocortical slice used here (horizontal

vs. 10� from vertical). Taken together with our data showing

direct activation of TRN, and with previous literature showing

connectivity between relay cells and TRN cells in this prepara-

tion (Bourassa et al. 1995; Kao and Coulter 1997; Gentet and

Ulrich 2003), we consider it likely that the inhibitory events we

observed in PoM were mediated by the TRN.

Implications for Thalamic Processing

Temereanca and Simons (2004) found that feedback from

cortex is somatotopically organized in the thalamus, probably

to enhance both excitatory centers of receptive fields as well as

their inhibitory surrounds. Our observation that corticothalamic

activation can evoke excitation alone, inhibition alone, or both

provides a mechanistic framework for these in vivo findings.

There are 3 possible ways to activate a predominantly inhibitory

response in VPM and PoM cells: 1) weaker activation of

corticothalamic synapses onto relay neurons compared with

TRN neurons and 2) faster activation of the disynaptic pathway:

cortex / TRN / VB compared with the monosynaptic

pathway: cortex / VB, or 3) an ‘‘open loop’’ anatomical

organization with feedback axons that activate only the

disynaptic inhibitory pathway and do not activate direct

excitation onto certain VPM and PoM neurons (Deschenes

et al. 1998; Pinault and Deschenes 1998a, 1998b). Our data

strongly support the first idea, but at least one case (Fig. 5B) also

supports the second possibility.

More specifically, we propose a model of how the feedback

circuit achieves these varied responses originating from a purely

excitatory set of corticothalamic synapses (Fig. 10). The third

possibility has been demonstrated anatomically and is also con-

sistent with our electrophysiological findings (see Fig. 3B,D). By

providing different strengths of activation to VPM, TRN, and

PoM, cortex can differentially modulate these areas over space

and time and thus change the balance of activity in each thala-

mic nucleus. In addition to varying the strength of activation,

indicated by EPSP amplitudes, cortical inputs to thalamus can

also vary in their reliability and speed. The disynaptic inhibitory

pathway from cortex, to TRN, to VPM or PoM may ‘‘win out’’

over direct monosynaptic excitation by gaining speed and reli-

ability at the second synapse.

Finally, differences in the balance of excitation and inhibition

to VPM and PoM suggest a mechanism for maintaining a rela-

tively quiet baseline in PoM compared with VPM in vivo. The

Figure 10. A model of the mono- and disynaptic feedback pathways from cortex layerVI to VPM, PoM, and TRN neurons in the thalamus. Line thickness is ranked by PSPamplitude and reliability, which is also consistent with the ranking of the anatomicalaxon arbor thickness: Thin lines indicate the slow-conducting fine fibers from layer VI,and thick lines indicate the fast-conducting larger fibers from the TRN to VPM andPoM.




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fact that a feedback inhibitory circuit from cortex may be

involved in quieting PoM suggests the possibility that feedfor-

ward modulation by PoM is triggered very selectively and

possibly very little during periods of high activity in cortex.

Thus, feedback from cortex can actually trigger net inhibitory

effects in both VPM and PoM cells of the thalamus—effectively

changing the sign of the strictly excitatory fibers from primary

cortex.

Notes

We thank Saundra Patrick for outstanding technical help and Michael

Beierlein for helpful comments on the manuscript. This research was

supported by the NIH (NS25983, NS40528, and DA125000), the Helen

Hay Whitney Foundation (C.E.L.), and the Shore Scholars in Medicine

Program (C.E.L.). Conflict of Interest : None declared.

Address correspondence to Carole E. Landisman, Center for Brain

Science, Harvard University, 16 Divinity Avenue, Biolabs 3038,

Cambridge, MA 02138, USA. Email: [email protected].

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