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1Department of Physiology, Faculty of Medicine, 15705 Santiago de Compostela, Spain; and 2Department of Medicine, University of La Coruña, 15006 La Coruña, Spain
Submitted 3 December 2002; accepted in final form 25 February 2003
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ABSTRACT |
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INTRODUCTION |
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). Corticofugal fibers primarily from motor area 4 and proprioceptive area 3a reach the ventrally located interneurons while the dorsal clustered cells receive corticofugal cutaneous input from area 3b (Cheema et al. 1983). These corticocuneate projections arise in layer V, course through the pyramidal tract (Chambers and Liu 1957; Martinez et al. 1995; Rustioni and Hayes 1981; Walberg 1957), and derive from collateral branches of corticospinal cells and from noncorticospinal cells (Bentivoglio and Rustioni 1986; Martinez et al. 1995; McComas and Wilson 1968; Rustioni and Hayes 1981).
The primary afferent and cortical inputs to the CN show a precise somatotopic topographic relationship (Amassian and De Vito 1957; Andersen et al. 1964a; Berkley et al. 1986; Cheema et al. 1983; Dykes et al. 1982; Gordon and Seed 1961; Martinez-Lorenzana et al. 2001; Rustioni and Weinberg 1989) and use glutamate as neurotransmitter (Conti et al. 1989; Kharazia et al. 1996). Both afferents can monosynaptically excite and/or disynaptically inhibit cuneo-lemniscal (CL) cells.
Histological studies in the rat indicate that the distribution of glutamate receptors in cuneate cells is such that non–N-methyl-D-aspartate (NMDA) receptors are localized at both CL cells and interneurons (Popratiloff et al. 1997), while NMDA receptors are also present (Watanabe 1994), but information about their cellular distribution is lacking. In vitro electrophysiological experiments (Deuchars et al. 2000; Núñez and Buño 2001) also support a role for both non-NMDA and NMDA receptors mediating evoked excitatory postsynaptic potentials (EPSPs).
In terms of inhibitory modulation, three interneuronal classes have been described in the rat dorsal column nuclei (DCN, cuneate, and gracilis): GABAergic, glycinergic, and interneurons colocalizing both neurotransmitters (Popratiloff et al. 1996). It has been shown that in this species, GABAergic cells synapse mainly on the proximal regions of CL cells (Lue et al. 1994) and also make axodendritic and axosomatic synaptic contact with other GABAergic and with glycinergic cells (Lue et al. 1994, 2001). Furthermore, glycinergic synaptic boutons, also in the rat, were found mainly on CL cells with a homogenous distribution all over the cellular surface (Lue et al. 2000), while glycinergic boutons on glycinergic cells appear to be scarce (Lue et al. 2001). To our knowledge, no systematic studies have been conducted to reveal glycinergic contacts on GABAergic cells. These results open a number of different combinations to explain the modulation of somatosensory processing at the CN.
The role of the corticocuneate feedback on the modulation of sensory ascendant processing has been a matter of major interest. Dawson (1958) reported that the mass response evoked in the CN of the rat by peripheral nerve stimulation was reduced by prior stimulation of the contralateral cortex, and Magni et al. (1959) showed that this reduction in the sensory response was mediated by descending activity in the pyramidal tract. Later work based on extracellular single unit firing demonstrated that electrical stimulation of the contralateral sensorimotor cortex could excite or block the activity of DCN cells (Andersen et al. 1964b; Gordon and Jukes 1964a,b; Jabbur and Towe 1961; Levitt et al. 1964; Towe and Jabbur 1961). Gordon and Jukes (1964b) and Andersen et al. (1962) postulated that there might be inhibitory interneurons within the DCN mediating the cortical inhibition.
Towe and Zimmerman (1962) reported that cutaneous stimulation produces a double discharge in the DCN, the first due to the ascending afferent volley and the second to a transcortical volley. Recent studies conducted in the rat (Malmierca and Núñez 1998) and the cat (Canedo 1997; Canedo and Aguilar 2000; Mariño et al. 2000; Palmeri et al. 1999) concluded that the cortico-DCN input provides positive feedback to physiologically matched neurons and a more widespread lateral inhibition to physiologically unmatched neurons. However, the cellular mechanisms underlying the cortico-DCN feedback are not well understood.
Accordingly, we sought to study the mechanisms mediating the somatosensory cortical influences on the middle CN. To this end, single unit extracellular recording was combined with iontophoretic ejection of agonists and antagonists of the main neurotransmitters present in the nucleus (glutamate, GABA, and glycine). It was found that the corticocuneate input produces complex interactions within the nucleus, activating (via non-NMDA and NMDA receptors), disinhibiting (via serial glycinergic-GABAergic interactions), and inhibiting (via GABAergic cells) the ascending cutaneous cuneo-lemniscal transmission.
Preliminary results have been reported in abstract form (Aguilar et al. 2001).
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METHODS |
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All procedures conformed to the Spanish Physiological Society, the International Council for Laboratory Animal Science, and the European Union (statute no. 86/809). Data were obtained from 22 cats weighing 2.5–3.5 kg that were anesthetized with 
-chloralose (60 mg/kg iv, n = 13) or sodium pentobarbital (35 mg/kg iv, n = 9) after induction with ketamine (10–20 mg/kg im). There was no evidence that choice of anesthetic affected the results obtained. The depth of anesthesia was evaluated by continuously monitoring heart rate (maintained around 120 beats/min) and electrocorticogram (ECoG; digitally filtered at a frequency band-pass of 1–50 to 100 Hz). High-amplitude and low-frequency electrocorticographic waves were taken as sign of adequate anesthesia. Changes in parameters that could indicate a decrease in the level of anesthesia were immediately corrected (Canedo and Aguilar 2000).
Tracheal and venous cannulae were inserted; the animal was positioned in a stereotaxic frame and artificially ventilated. Lidocaine hydrochloride (2%) was added to all insertion points. Muscular paralysis was induced with pavulon (1 mg/kg/h iv). Expired CO2 was maintained at 4 ± 0.5% by adjusting the respiratory rate and the inspired volume. A pH-balanced solution of 5% glucose in physiological saline was continuously infused (4 ml/h iv). The animal's temperature was maintained near 37.5°C by a thermostatically controlled electric blanket and an overhead radiant heat lamp.
The animals were suspended with clamps attached to the lumbar and thoracic vertebrae. The dorsal medulla was exposed to insert electrodes in the middle CN, running from the obex to a point 4 mm caudal from it (Fyffe et al. 1986). To minimize heart and respiratory associated movements, a bilateral pneumothorax was routinely performed. Warm agar (2% in physiological saline) was added to all the exposed areas to increase stability and avoid desiccation.
A small trephine hole made at Horsley-Clarke coordinates A2, L4.5, H-5 permitted the lowering of a bipolar stimulating electrode (0.5 mm intertip space, 40–50 µm diam and insulated except at the tip) into the medial lemniscus that served to identify antidromically CL cells (0.5–1.5 mA intensity, 1–5 Hz frequency, 0.05 ms pulse duration) according to standard criteria, including in all cases the collision test (Figs. 1 and 2, insets). Also, the pericruciate cortex was uncovered, and a set of four concentric bipolar stimulating electrodes, separated 3 mm from each other, was lowered 1–1.5 mm deep in the posterior gyrus sigmoideus to stimulate the somatosensory cortex (Fig. 1). These electrodes were fixed in position throughout the duration of the experiment.
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Extracellular recording and iontophoresis
Multi-barreled pipettes (3–5 barrels) attached to a mechanical microdrive were used for extracellular recording and iontophoretic ejection of drugs. The barrels were filled with 3 M NaCl, for recording, and a combination from the following drugs: D-2-amino-5-phosphonovaleric acid (APV; 50 mM, pH 8, NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX; 1 mM, pH 8, non-NMDA receptor antagonist), bicuculline methiodiode (20 mM, pH 4, GABAA receptor antagonist), GABA (1 M, pH 4), strychnine (10 mM, pH 5.5, glycine receptor antagonist), or glycine (1 M, pH 3.5). Ejecting DC currents (negative for APV and CNQX, positive for the others) were in the range of 30–120 nA for APV and CNQX, 5–20 nA for glycine, 20–35 nA for bicuculline (BiCu), and 40 – 80 nA for GABA and strychnine. The currents used for APV, CNQX, GABA, and glycine were established by observing their effects on the activation elicited by cortical stimulation; those for BiCu and strychnine were selected by measuring the current level necessary to reverse the effect of iontophoresed GABA and glycine, respectively. When not in use, each drug barrel was subjected to a retaining 25-nA DC current of opposite polarity to prevent unwanted diffusion from the pipette. A balance barrel with physiological saline was used in a first series of experiments to evaluate whether ejection of current affected the cellular activity. These controls did not produce side effects, and the balance barrel was discarded since an extra barrel increases the tip thickness and the pressure exerted on the tissue, thus depressing cellular activity.
After a cell was well isolated from the background, the ML was stimulated, and the cells responding antidromically were classified as CL neurons. The cutaneous excitatory receptive field was determined by brushing and light touching of the skin, and a bipolar needle stimulating electrode (9-mm intertip separation) thrust into the region of the skin activating the cuneate cell under study with minimal threshold and latency. Rectangular pulses of 0.05- to 0.1-ms duration at 0.5–1 Hz were applied through each of the four pairs of electrodes placed in the cortex. The current intensity was gradually increased up to a maximum of 2 mA, and when a cuneate cell was activated from one of the electrodes, the other sites were also tested. The electrode that evoked an excitatory response with minimal threshold and latency was chosen as the testing (best) electrode and was used for stimulation for the rest of the protocol. The effect of cortical stimulation was averaged for 25–70 trials in control conditions, again during ejection of selected drugs, and finally after recovery. Stability was ascertained by comparing responses collected during the first and the last set of trials, and only cells that showed recovery of responses above 80% of control values were included in the study. Poststimulus histograms (1 Hz, 1-ms bin) were constructed from the accumulated number of spikes for the total number of sweeps.
Intracellular recording
In five animals, sharp micropipettes filled with 2.5 M K+-acetate (20–50 M
resistance measured in the neural tissue) were used to record intracellularly from cuneate cells activated from the somatosensory cortex while varying the membrane potential by current injection through the recording pipette. The resistance of the micropipette was continuously checked by observing the change in voltage produced by current pulses using an intracellular amplifier in the bridge mode. The bridge was balanced and the capacitance neutralization adjusted to give the fastest step response to a current pulse. In these experiments, no ejection of drugs were made.
Recordings were stored in magnetic tape, and off-line analysis of each session was performed to assess the integrity of the cell during the recording period. The recording electrode was considered to be within the CN when cellular responses were obtained to gentle taping and brushing of the ipsilateral forearm. Postmortem histology confirmed that all recordings were obtained from the middle cuneate nucleus.
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RESULTS |
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Corticocuneate input excites CL and nCL cells through NMDA and non-NMDA receptors
The excitatory response evoked by cortical stimulation on CL and nCL cells was reduced by iontophoretic ejection of CNQX and/or APV. Ejection of CNQX alone gradually decreased the cortical-induced activation of the 25 CL and 12 nCL (5 nCL1, 7 nCL2, see following text) cells tested, by an average of 72 ± 28% (Fig. 2A1; antidromic identification shown in the left inset) and 73 ± 27%, respectively. Ejection of APV alone decreased the cortical-induced activity of these same cells by 52 ± 12% (CL neurons) and 63 ± 21% (nCL neurons). Concurrent APV and CNQX ejection decreased the cortical-induced excitation by 97 ± 3% (CL cells, Fig. 2A2) and 98 ± 2% (nCL cells, Fig. 2B). These data are summarized diagrammatically in Fig. 2C.
In the control condition, CL and nCL cells tended to generate trains of action potentials, usually with spikes grouped in doublets when the current intensity applied to the cortical best point was 
500 µA (Figs. 2, 3, 4, 5A). The number of spikes per train as well as train duration were invariably reduced by high-intensity cortical stimulation and by APV ejection.
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The NMDA ligand receptors have the now well-known property of voltage dependence, and with depolarization-induced relief from the Mg2+ block, they become more active during membrane depolarization. Accordingly, a total of 15 cells recorded intracellularly (11 CL) were depolarized to different membrane potentials by DC current injection through the recording electrode while stimulating the best point in the somatosensory cortex. All these cells showed a double excitatory response; the early component decreasing and the late component increasing in amplitude with membrane depolarization (Fig. 3). Thus the late component can be considered to be an NMDA-mediated response, thereby substantiating the extracellular/microiontophoretic data.
In short, the somatosensory corticocuneate excitation of CL and nCL neurons is produced through both non-NMDA and NMDA receptors.
Two classes of cortically activated nCL neurons: glycinergic and GABAergic
From a total of 30 nCL cells sampled at depths where the CL cells were encountered, two different subpopulations could be distinguished according to their sensitivity to iontophoretically applied GABA and glycine. Representative examples are illustrated in Fig. 4, A and B, for three different nCL1 neurons representing the first population (n = 13). Electrical stimulation of the contralateral somatosensory cortex at the region representing the forearm evoked excitatory responses in the nCL1 cells of Fig. 4A, peaking at 11 (Fig. 4A1, control) and 15 ms (Fig. 4A2, control). Glycine ejection drastically reduced the cortically evoked excitation (Fig. 4A) as well as the spontaneous activity (Fig. 4B). Subsequent ejection of strychnine not only reversed the effect of glycine but also incremented the cortical excitation, thus demonstrating the specificity of the glycine effect (Fig. 4A). Note that a cortical stimulating intensity of 2 mA was necessary to fire these two nCL1 cells through the best electrode and that the cells did not show bursting activity (Fig. 4A1, control and recovery; Fig. 4A2). Strychnine ejection uncovered the bursting discharges, masked by 2 mA stimulation, in four of six of these nCL1 cells and also greatly reduced the latency of the cortical-induced excitation (Fig. 4A1: strychnine; glycine + strychnine). The corticalinduced activation of these 13 cells was depressed by 81 ± 20% of control after glycine, while subsequent ejection of strychnine reversed the effect of glycine and further increased the cortical-induced excitation by 66.5 ± 44%. We have labeled this group the nCL1 neurons.
The cortical-induced activation of the second interneuronal subpopulation (nCL2 neurons, n = 17) was not affected by glycine nor by strychnine (Fig. 4C). Increasing the ejecting current 120nA and/or increasing the ejection time 15 min did not affect the cortical-induced activation of these nCL2 cells. Furthermore, they were recorded in the same electrode tracks as the nCL1 cells and therefore the lack of effect cannot be ascribed to a deficient ejection of drugs or to other technical problems. These results, together with the action of glycinestrychnine ejection on CL cells (see following text), lead us to suggest as the most plausible interpretation of the results that the nCL2 cells, insensitive to glycine and strychnine, are glycinergic interneurons, while the nCL1 cells, sensitive to glycine and strychnine, are GABAergic interneurons. These two groups of interneurons were equally affected by GABA, which silenced the spontaneous activity (when present) as well as the cortical-induced activity, after application periods of 5–6 min.
Corticocuneo-lemniscal transmission is depressed through nCL1 (GABAergic) neurons and disinhibited through serial glycinergic-GABAergic local interactions
GABA and glycine were tested on the cortical-induced excitation in a total of 16 CL cells. The examples shown in Fig. 5 for two different CL neurons (Fig. 5, A and B) illustrate the characteristic effect of GABA/BiCu and glycine/strychnine. GABA consistently suppressed the cortical-induced activation, an effect that was reversed by simultaneous ejection of BiCu (Fig. 5, A and B, bottom). The ejection of BiCu reversed the inhibition induced by GABA, increased the cortical-induced excitation by 85 ± 31.2% (Fig. 5C), uncovered the bursting discharges masked by high-intensity (2 mA) cortical stimulation, and decreased the latency of the cortical response (Fig. 5B, bicuculline).
The ejection of glycine produced an unexpected finding since it consistently increased the cortical-evoked excitation in all 16 CL cells tested (35 ± 10.8% of control; Fig. 5B, glycine). Strychnine ejection decreased the cortical-induced activation (56.4 ± 16.9% of control; Fig. 5, B and C), demonstrating the specificity of the glycine effect. Strychnine also decreased the spontaneous [Fig. 6(1)] and the cutaneously evoked [Fig. 6(3)] activity of 6 CL cells tested, an effect that was reversed by simultaneous ejection of BiCu [Fig. 6(2)].
These data, taken together with the results obtained from the CL cells, point to the suggestion that the nCL1 neurons (presumed GABAergic) are inhibited through nCL2 cells (presumed glycinergic).
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DISCUSSION |
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This study describes the cellular mechanisms mediating the corticofugal influence over cutaneous ascendant transmission through the cuneate nucleus. Three main findings are reported as follows: 1) the excitatory corticocuneate input exerts a bimodal effect on CL and nCL cells via non-NMDA and NMDA receptors, 2) two different classes of cuneate interneurons can be distinguished according to their sensitivity to strychnine, and 3) the cortical-induced activation of CL cells is enhanced by glycine and BiCu and depressed by strychnine and GABA.
The CL cells are probably cuneothalamic neurons since those projecting to the pretectum and tectum are located outside the region sampled in this study (Berkley et al. 1980, 1986; Bull and Berkley 1984). It is, however, possible that some cuneate neurons project to other different sites of the ML, such as the cerebellum or the spinal cord, but the great majority of these cells are also located outside the middle cuneate nucleus (Berkley et al. 1980, 1986; Bull and Berkley 1984; Cheek et al. 1975; Enevoldson and Gordon 1984; Mantle-St John and Tracey 1987; Wiberg and Blomqvist 1984), indicating that the nCL cells of this study probably represent interneurons.
Corticocuneate activation of CL and nCL cells
The descending cortical fibers reach the cuneate nucleus via the pyramidal tract (Jabbur and Towe 1961; Mariño et al. 2000; Valverde 1966; Walberg 1957), contact mainly distal dendrites (Lue et al. 1997; Rustioni and Sotelo 1974; Walberg 1966), and release glutamate as neurotransmitter (Broman 1994; Kharazia et al. 1996). Sensorimotor cortical stimulation induces EPSPs on CL cells that often are complex and of long duration, having several peaks (Canedo et al. 2000; Mariño et al. 2000; Schwartzkroin et al. 1974; see also Fig. 3). NMDA and non-NMDA receptors are present in the dorsal column nuclei (Popratiloff et al. 1997; Watanabe et al. 1994). Non-NMDA receptors participated in fast synaptic transmission, while NMDA receptors were related to slower processes such as long-term-potentiation (Collingridge et al. 1983; Cotman and Iversen 1987), but also play a role in sensory transmission (Kemp and Sillito 1982; Kwon et al. 1991; Salt 1987; Sillito et al. 1990). We show here that corticocuneate fibers induce a bimodal excitation on CL and nCL cells (Figs. 2 and 3); the first component decreased and the second increased in amplitude with membrane depolarization (Fig. 3), which suggests that the second component is probably NMDA-dependent (Dingledine et al. 1999). This, together with the finding that ejection of any of the blockers (CNQX or APV) reduced the corticocuneate-evoked responses, points to a role for both classes of glutamate receptors in the cortical-induced response as a whole.
The NMDA component allows two important functions: 1) it increases the amplitude and duration of the excitatory response, and 2) it introduces Ca2+ to the cell. A larger amplitude and response duration increases the firing probability of the neurons, facilitates summation with other inputs, increases the electrotonic transmission to the soma, and augments the duration of the repetitive firing (see Fig. 2, A2 and B). Finally, calcium entry via NMDA channels may trigger different forms of synaptic plasticity (Núñez and Buño 2001).
Corticoneate inhibition and disinhibition of CL cells
GABA ejection suppressed the cortical-induced activity of all CL cells tested, an effect that was reversed by the GABAA antagonist BiCu, thus indicating that the cortical-induced lateral inhibition produced on the cuneolemniscal transmission is mostly, if not solely, due to the activation of GABAergic interneurons. Our data do not allow us to completely differentiate between GABA receptor subtypes; however, previous data indicate a predominant presence of postsynaptic GABAA receptors in the dorsal column nuclei (Núñez and Buño 2001), whereas GABAB receptors seem to be restricted to the presynaptic primary afferent terminals (Deuchars et al. 2000). The reported effects of GABA were probably induced through GABAA receptors since GABAB receptors produce slower and longer-lasting responses by coupling to Ca2+ and K+ channels via G proteins and second messenger systems, and more importantly, they are activated by baclofen and are BiCu-resistant (Hill and Bowery 1981). Direct cortical-induced presynaptic inhibition of primary afferents is unlikely since the corticocuneate fibers do not make axoaxonic contacts with primary afferent terminals (Cheema et al. 1984). Furthermore, presynaptic inhibition exerted through the corticocuneate terminals is also unlikely since there are no data reporting GABAergic boutons on these terminals.
In addition, BiCu ejection uncovered high-frequency doublets of spikes masked by high-intensity (2 mA) cortical stimulation (Fig. 5Bg). This can be explained since 2-mA stimulation not only activated somatosensory cortical cells in topographic alignment, but also cells not topographically aligned with the CL neuron under study, and that the unaligned corticocuneate feedback abolished burst firing through lateral inhibition (see Fig. 7, route III). However, BiCu may block Ca2+-activated potassium currents that underlie postspike and postbursting hyperpolarization, thus increasing neuronal excitability as is known to occur in the thalamic reticular nucleus (Debarbieux et al. 1998) and midbrain (Seutin et al. 1997). Notwithstanding these nonspecific effects, several reasons point to a GABAA-mediated action of BiCu in the cuneate nucleus: 1) the bursting activity obliterated by high-intensity cortical stimulation was not only uncovered by ejecting BiCu (Fig. 5Bg) but also by ejecting glycine (Fig. 5Bb), which has no known side effects on potassium currents and is consistent with glycinergic-GABAergic disinhibition of CL cells (Fig. 7, route III), 2) the ejection of BiCu was adjusted to reverse the effect of applied GABA, 3) with the currents used, the ejection of BiCu did not induce spontaneous bursting [Fig. 6(2)], and 4) the recurrent-induced bursting of CL cells is blocked by strychnine, and when masked by high-intensity lemniscal stimulation, uncovered by BiCu (Aguilar et al. 2002), again pointing to a specific action of BiCu on GABAA receptors and to a serial glycinergic-GABAergic interaction.
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Strychnine is the best substance to distinguish between responses to GABA and glycine (Hill et al. 1976). We show that the nCL neurons can be separated in two groups based on their sensitivity to glycine and strychnine (Fig. 4). Our results would suggest that the nCL2 cells have no glycine receptors. Indeed, it has been shown that glycinergic cells in the rat cuneate nucleus receive a minority of synaptic inputs from other glycinergic cells (Lue et al. 2001). It is therefore rational to expect to find a reduced number of glycine receptors in these neurons. Although the cellular distribution of glycine receptors is unknown, they could be located in the distal dendrites and thus not affected by glycine/strychnine released near the soma. The finding that glycine increases and strychnine depresses the cortically induced excitation (Fig. 5B) indicates that the strychnine-dependent effect of glycine is indirectly produced on CL cells. This would suggest that the CL cells do not possess glycine receptors (Kelly and Renaud 1973). These authors were unable to reverse the afferent-evoked inhibition of CL neurons by iontophoretic ejection of strychnine. Furthermore, the glycinergic receptors of CL cells appear to be located in the distal dendrites (Lue et al. 2000; Popratiloff et al. 1996), and are unlikely to be affected by antagonist iontophoresed near the soma or, else, the effect of strychnine could not be detectable on spiking activity.
A reasonable explanation of our results is that glycinergic cells disinhibit CL neurons through GABAergic cells (Fig. 7, route II). Blocking the glycine receptors allows the GABAergic cells to inhibit cuneolemniscal transmission, thus explaining the suppression of the cortically induced excitation by strychnine. In addition, the glycine released by corticocuneate activation is not limited to participation in disinhibitory transmission and may also facilitate excitatory responses by allosteric binding at NMDA receptors.
The present results can be explained even accepting that some interneurons colocalize GABA and glycine (Popratiloff et al. 1996). The colocalizing interneurons may serve other roles, for example, modulate primary afferent input through an independent circuit or via the different distribution of receptors (GABA proximal, glycine distal). Moreover, a species difference may exist since colocalizing interneurons are unknown in the cat.
The nCL cells are probably interneurons intermingled between the CL cells and not ventrally located since they were recorded at the same depths as the CL cells and were activated by somatosensory cortical stimulation. This may be of functional importance since the interneurons located between the CL clustered cells receive mainly cutaneous and somatosensory corticofugal signals (from area 3b) (Cheema et al. 1983) and thus may specifically serve to modulate the cutaneous cuneolemniscal transmission. In contrast, the interneurons located more ventrally receive mainly proprioceptive signals (Berkley et al. 1986; Cheema et al. 1983; Rustioni and Weinberg 1989) and corticofugal input from the primary motor cortex (Cheema et al. 1985), and therefore, may be more implicated in the modulation of movement-related and/or posture-related signals (Berkley et al. 1986).
Functional significance
Previous work demonstrated that the corticocuneate feedback restricts receptive field sizes by reinforcing a central core of activated CL cells and by potentiating the inhibition produced by the receptive field surround, thus enhancing the surround antagonism of a center response (Canedo and Aguilar 2000). The present work further demonstrates that the cortex enhances the center response by activating non-NMDA and NMDA receptors and by blocking (disinhibiting) the lateral inhibition exerted on the center through serial glycinergic-GABAergic interactions. Moreover, the cortex also potentiates the inhibitory surround via GABAergic interneurons. The circuit design of Fig. 7 is shared by the cortical input and by cuneolemniscal recurrent collaterals re-entering the cuneate nucleus (Aguilar et al. 2002). In this way, a group of CL cells activated from the skin are potentiated through recurrent collaterals and transcortically, via topographically aligned cortical somatosensory cells. Both mechanisms enhance the centersurround contrast, increasing spatial resolution and potentiating weak signals. The NMDA component of the cortico-cuneate excitatory response also increases the temporal resolution of impulses from the receptive field by maintaining the depolarization of CL and nCL cells, thus augmenting their frequency-following capability to ensure a potentiated center over the inhibitory surround during high-frequency stimulation.
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ACKNOWLEDGMENTS |
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This work was supported by grants from the Comisión Interministerial de Ciencia y Tecnologia (PM99-0024) and the Xunta de Galicia.
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FOOTNOTES |
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Address for reprint requests: A. Canedo, Dept. of Physiology, Faculty of Medicine, 15705 Santiago de Compostela, Spain (E-mail: fsancala{at}usc.es).
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