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MS 1218 Received 8 June 2000; accepted after revision 7 September 2000.
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ABSTRACT |
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INTRODUCTION |
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A fundamental property of the spinal cord is the generation of the locomotor programme through an intrinsic network driven by a local circuit termed the central pattern generator (CPG) (Sherrington, 1898; Pearson & Rossignol, 1991). Such a programme requires finely tuned coordination of limb muscle contractions which rely on alternation of motor signals from left and right homosegmental ventral roots (VR), as well as heterosegmental alternation of motor outputs to flexor and extensor muscles on the same side. Simplified preparations like the in vitro spinal cord of neonatal rat (for review see Kiehn et al. 1997) generate rhythmic motor outputs with characteristic phase alternation (termed fictive locomotion) and are therefore useful models for studying the cellular mechanisms involved in locomotor pattern generation and maintenance.
In this preparation rhythmic locomotor-like patterns can be elicited by bath-applied excitatory substances like NMDA (Kudo & Yamada, 1987), serotonin (Cazalets et al. 1992; Beato et al. 1997) or a high level of potassium (Bracci et al. 1998). Although this approach has yielded important insights into the mode of operation of the fictive locomotor network, persistent bath application of these excitatory substances to the entire spinal tissue represents a non-physiological condition. One functionally important issue is whether descending inputs from the locomotor region of the brainstem or sensory signals ascending from the periphery would have the ability to trigger the activation of the locomotor CGP. Whereas fictive swimming is induced by activating certain sensory inputs to the spinal cord of the tadpole (Soffe, 1991) or lamprey (McClellan, 1984), comparable observations on rat spinal cord in vitro are sparse. While electrical stimulation of the descending ventrolateral funiculus can induce fictive locomotor patterns (Magnuson et al. 1995; Magnuson & Trinder, 1997), there is only a preliminary report (Smith et al. 1988) that stimuli applied to a skin flap still attached to the rat isolated spinal cord can produce similar effects.
In the present study on the neonatal rat spinal cord in vitro we describe the occurrence and the basic properties of an alternating locomotor-like pattern triggered by stimulating dorsal root (DR) fibres.
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METHODS |
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Experiments were performed on spinal cord preparations (comprising a region from mid-thoracic level to conus medullaris) isolated from neonatal Wistar rats (0-4 days old) under urethane anaesthesia (0.2 ml I.P. of a 10% w/v solution) as previously described (Bracci et al. 1997, 1998). This procedure is in accordance with the regulations of the Italian Animal Welfare Act and is approved by the local authority veterinary service.
The spinal cord was firmly fixed to the bottom of the recording chamber and superfused (7.5 ml min-1) with Krebs solution of the following composition (mM): NaCl, 113; KCl, 4.5; MgCl2.7H2O, 1; CaCl2, 2; NaH2PO4, 1; NaHCO3, 25; glucose, 11; bubbled with 95% O2-5% CO2; pH 7.4 at room temperature. All agents were bath applied via the superfusing solution at the concentrations mentioned in the text.
DC ventral root recordings (usually from pairs of L2 and L5 VRs; Kjaerulff & Kiehn, 1996) were obtained with glass suction microelectrodes containing an Ag-AgCl pellet and filled with Krebs solution. DC-coupled VR recordings were amplified, displayed on-line on a chart recorder, and digitally stored on DAT tape (acquisition rate 11 kHz) or on computer hard disk. Period (T) was defined as the time between the onset of two cycles of locomotor-like activity. When period values were averaged for a pool of preparations, data from each spinal cord were calculated as the mean of the first five to ten cycles. Phase between two roots was defined as the latency for the onset of a cycle in one root during the cycle of the other root, divided by the period and expressed in angular degrees whereby 180 deg represents complete phase alternation and 0 or 360 deg full phase coincidence (Kjaerulff & Kiehn, 1996).
DR electrical stimuli were delivered via miniature bipolar suction electrodes. Stimulus intensity (range, 1-20 V; duration, 0.1 ms) was usually calculated in terms of threshold (Th), which was defined as the minimum intensity to elicit a detectable response in the homolateral VR (on average Th = 1.8 ± 0.9 V, n = 25). Afferent DR volleys (evoked by stimulation of the distal end of an L5 DR) were recorded with a 3 M NaCl-filled recording microelectrode located at the site of entry of the DR into the cord. In accordance with Fitzgerald (1988), two negative-polarity peaks were detected with conduction velocities of 1.0 ± 0.6 and 0.34 ± 0.07 m s-1 (n = 5). The second, slower peak appeared with stimuli of about 1.6×Th intensity. Maximal volley amplitude was observed with 10×Th stimuli. No fatigue of volley peaks was observed with stimuli up to 10×Th at 10-20 Hz for 120 s.
Data were quantified as means ± S.D.; statistical significance was assessed using Student's t test or ANOVA followed by Tukey's test. In either case the accepted level of significance was P = 0.05. The strength of coupling between left/right and L2/L5 VRs was analysed with circular statistics (Kjaerulff & Kiehn, 1996) in which R is the concentration of phase values around the mean ± its angular deviation. The Rayleigh test with the small-sample modification (Drew & Doucet, 1991) was used to establish the statistical significance of these values. Serotonin and strychnine were purchased from Sigma; NMDA was purchased from Tocris.
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RESULTS |
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VR oscillations induced by DR stimuli
Figure 1A shows an example of activity induced by applying a 12.5 s train of 2 Hz stimuli (2×Th) to the left L5 DR. During the stimulation train a gradual baseline depolarization developed, upon which oscillatory activity (with action potential firing on top of each oscillation) emerged. The period (T) of this pattern was 1.0 ± 0.2 s measured for nine cycles. This oscillatory activity outlasted the stimulus train and presented typical alternation between contralateral VRs and intersegmental VRs (for example left L2 was in antiphase with left L5). In order to quantify the pattern alternation, the phase of this activity was expressed in polar plots as shown in Fig. 2 for 18 preparations. Individual data points refer to single preparations stimulated within the 0.5-10 Hz and (1.3-10)×Th range. In each panel data (from left/right VRs or from cranial/caudal homolateral VRs) were grouped around 180 deg indicating that they occurred in antiphase. In particular, mean values were 186 ± 17 deg (left/right L2), 180 ± 20 deg (left L2/L5), 182 ± 21 deg (right L2/L5), and 182 ± 19 deg (left/right L5). The Rayleigh test showed that for each one of these root pairs the coupling strength (expressed as R values; see Methods) was significant (R = 0.92 ± 0.28 for left/right L2; R = 0.91 ± 0.30 for left L2/L5; R = 0.89 ± 0.30 for right L2/L5; R = 0.92 ± 0.28 for left/right L5; P < 0.005 for each pair; number of cycles from each preparation was 5-15).
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Each panel shows DC records of responses from pairs of VRs (left (l) or right (r) of L2 and L5 segments) in the same preparation. Oscillations are in alternation between contralateral VRs and between intersegmental VRs of the same side; they are not time-locked with the stimuli (applied at constant intensity of 2×Th; stimulus artifacts are shown as large deflections) and persist when the train is over. A, record from the L5 DR stimulated with a 2 Hz train (25 pulses); T, 1.0 ± 0.2 s. B, stimulation of the left L2 DR with a 2 Hz train; T, 1.25 ± 0.3 s. C, stimulation of the left L5 DR with a 10 Hz train; T, 1.25 ± 0.3 s. D, stimulation of the left L2 DR with a 10 Hz train; T, 1.25 ± 0.3 s. Baseline traces are shown for left VR L2 and right VR L5 only. | ||
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Distribution of oscillatory phase values (expressed in degrees; see Methods) recorded for pairs of VRs following DR stimuli (0.5-10 Hz and (1.3-10)×Th). Each data point represents the mean result (averaged from 5-15 cycles) from a single spinal cord preparation. Grouping of data around 180 deg indicates phase lock between responses from each pair of VRs. | ||
Figure 1B shows that, in the same preparation shown in Fig. 1A, a similar pattern of oscillatory activity (T, 1.25 ± 0.3 s; 7 cycles) was observed when the stimulus train (2 Hz) was applied to left L2 DR. In the same preparation it was also possible to evoke an oscillatory pattern when stimulating left L5 or left L2 DRs at higher frequency (10 Hz; same intensity; T, 1.25 ± 0.3 s, 5 cycles in either case) as shown in Fig. 1C and D. The pattern of activity illustrated in Fig. 1 was elicited in 42/54 preparations. DR stimuli were ineffective in eliciting oscillatory activity from twelve spinal cord preparations, eight of which generated fictive locomotor patterns with bath application of NMDA (4-6 µM) and serotonin (5-8 µM) (see also Kjaerulff & Kiehn, 1996; Beato et al. 1997) while the remaining four were insensitive to these chemical agents as well. Since DR stimuli evoked alternating patterns in the large majority of preparations, the electrophysiological characteristics of this effect were further explored.
Characteristics of DR stimuli used to induce alternating patterns
We first tested how the oscillatory pattern might have changed with varying intensities of DR stimulation. As indicated by the histograms of Fig. 3A, period (calculated for the first 5-10 cycles; 0.5-4 Hz stimulus rate) weakly depended upon stimulus intensity because a significant (one way ANOVA followed by Tukey's test; P < 0.05) decrease was found only when strong (
10×Th) pulses were applied (compared with the 1.3, 1.8 and 5×Th groups; n = 12). We next explored the relation between oscillatory period and stimulation frequency when the stimulus intensity was 10×Th. The histogram in Fig. 3B shows that there was no significant change in oscillation period when stimulating with low frequency (0.5-4 Hz) trains (T, 1.55 ± 0.05 s), high frequency (10-50 Hz) trains (T, 1.6 ± 0.2 s), or even single stimuli (T, 1.56 ± 0.15 s). Note that in only 3/12 preparations was a single, high voltage ( 10×Th) stimulus able to elicit oscillations (lasting on average 14 ± 3 s). The histogram in Fig. 3B also indicates that the rhythmic activity induced by the combined application of NMDA (4 µM) plus serotonin (5 µM; Beato & Nistri, 1999) had a similar period of oscillation (T, 1.39 ± 0.21 s; n = 5).
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A, relation of oscillation period to stimulation intensity (n = 12 preparations): there is a significant (*P < 0.02) reduction in the period of oscillations only for high intensity (10×Th) stimuli. Period values (usually 5-10 episodes) corresponding to each histogram are: 1.3×Th, T = 2.08 ± 0.07 s; 1.8×Th, T = 2.30 ± 0.18; 5×Th, T = 1.80 ± 0.15 s; 10×Th, T = 1.55 ± 0.01 s. B, period values for oscillations induced by different types of stimuli (intensity (2-5)×Th) remain the same with low (0.5-4 Hz; T = 1.72 ± 0.15 s) or high (10-50 Hz; T = 1.6 ± 0.2 s) frequency trains (n = 12), a single stimulus (1.56 ± 0.15 s, n = 3) or patterns (n = 5) induced by NMDA (4 µM) plus serotonin (5-HT, 5 µM; T = 1.39 ± 0.21). C, records showing gradual lengthening of period of L2 VR oscillations during a train at 1 Hz (1.7×Th intensity). Sharp deflections are stimulus artifacts. | ||
While our average period data were collected during the first five to ten cycles of an oscillatory episode, it was clear that the oscillatory pattern usually varied during the train as shown in Fig. 3C. Oscillations did not have a stereotypic onset and abrupt termination as the rhythm started simultaneously in left and right L2 (stimulus train applied to L5 DR; 1 Hz), built up to the fastest (2 s) cycles and became progressively longer. In the example of Fig. 3C rhythmic oscillations lasted 55 s (on average 50 ± 20 s, n = 25 spinal cords) after which they failed despite continuing stimulation.
Duration of fictive locomotor patterns
Experiments were carried out to investigate why the alternating pattern slowed down despite continuous stimulation. First, we quantified this phenomenon. In twelve preparations (stimulated at 0.5-4 Hz, 2-5×Th intensity) the cycle period (normalized to that of the first cycle in each episode for each spinal cord) grew to 174 ± 15% after only the first ten cycles with a slope of 6.1 ± 0.4% increment/cycle over the subsequent 11 cycles (r = 0.98 ± 0.21). The mechanism responsible for this delayed slowing down of oscillations was investigated in tests like those depicted in Fig. 4. In this example, repetitive, weak (1.3×Th) stimuli applied to the right L5 DR (to activate only low threshold afferent fibres) evoked oscillations (T, 1.7 s) which lasted about 15 s and then waned even though the polarization level of the VRs remained steady. Could this have been caused by generalized depression of synaptic activity in the spinal cord? This possibility seemed unlikely since pattern loss was not associated with depression of VR reflex responses (see Fig. 4, bottom row) as indicated by the average reflex area (3.2 vs. 2.9 mV ms) recorded from left L2 VR during and after rhythmic oscillations (see corresponding records for the times indicated by open horizontal bars). Note that VR reflexes were averaged after the 4th response in the train, i.e. when they reached steady-state amplitude after the very early depression of monosynaptic transmission (Lev-Tov & Pinco, 1991). In the experiment shown in Fig. 4, when the intensity of the stimulus was raised (3.8×Th) presumably to recruit higher-threshold fibres, the oscillatory pattern (T × 2.0 s) returned for 15 s after which it failed again. Even if the VR reflex was smaller than the one observed with the weaker stimuli, it remained unchanged (1.1 vs. 1.2 mV ms) throughout the stimulation at 3.8×Th (see sample traces indicated by open bars). Baseline activity was also enhanced by irregular spontaneous firing. Thus, the secondary loss of alternating activity was not associated with generalized, intense synaptic fatigue in the spinal network. Further increase in stimulus intensity (8.8×Th) was unable to re-establish the alternating pattern. Similar results were obtained from eight preparations. Despite using a wide range of stimulus intensity (1-10×Th) or frequency (0.5-50 Hz) it was not possible to elicit persistent alternating patterns.
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Long train of stimuli delivered to the right L5 DR (2 Hz) at different intensities (1.3, 3.8 or 8.8×Th) elicits responses recorded from two contralateral VRs (lL2 and rL1): a stimulus just above threshold for activating the faster conducting fibres induces an alternating pattern (T, 1.7 s) that is lost after about 15 s; the pattern is recovered (T, 2.0 s) when stimulus intensity is raised above the voltage threshold for slower conducting fibres. When the pattern is lost again after about 15 s, further increase in stimulus intensity cannot re-establish the pattern. The traces in the bottom row show time-locked lL2 VR reflexes (averages of 30, 28, 28 and 22 sweeps, respectively) recorded during the time indicated by the open bars: loss of locomotor-like activity is not associated with depression of VR reflex. Smaller amplitude reflexes during stronger stimuli indicate partial development of synaptic fatigue. Stimulus artifacts are fast deflections of varying amplitude owing to sampling rate. | ||
When the stimulus intensity strength was relatively large (2.5×Th) so as to activate both classes of afferent fibres from the outset, patterns emerged with a gradual slowing down in period value until failure (not shown; n = 8). Further increasing the stimulus intensity could not reinstate oscillations.
In five preparations we next explored whether loss of patterned activity was selective for the stimulated input or whether stimulation of the contralateral root could re-establish the rhythm. Thus, the pattern recorded from L2 VRs was evoked by left DR L5 stimulation (2 Hz) first at low intensity (1.4×Th) until it disappeared and was then elicited with stronger (2.5×Th) impulses. In the latter case it lasted 12 ± 4 s and then disappeared again. At this stage right DR L5 (or L4) was stimulated at low intensity (1.4×Th) and generated the pattern which also lasted 12 ± 4 s (period value was 121 ± 30% of the previous one). As usual, loss of rhythmicity occurred against a background of intense irregular firing and could not be reversed by low or high threshold stimuli applied to left or right DR L5. A period of rest (circa 10 min) was, however, sufficient to re-instate DR stimulation-induced rhythmic activity.
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DISCUSSION |
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The principal finding of the present study is the observation that in the neonatal rat spinal cord in vitro locomotor-like patterns of activity can be reliably evoked by trains of DR stimuli. This is a novel result as DR stimulation has only been reported to reset (Iizuka et al. 1997) or partially entrain (Sqalli-Houssaini et al. 1993) the locomotor rhythm induced by bath application of chemical substances. The present data thus suggest that stimulation of sensory afferent fibres can induce fictive locomotor-like patterns in the neonatal rat spinal cord.
General characteristics of rhythmic activity induced by DR stimuli
A variety of stimulation protocols was used to induce patterns of rhythmic activity which were recorded from two pairs of contralateral VRs (usually L2 or L3 and L5). Such a rhythmic activity showed not only phase alternation between pairs of contralateral VRs, but also intersegmental phase alternation between VRs innervating mainly flexor and extensor muscles (L2/3 and L5, respectively). Oscillations had a period ranging from 1 to 2 s and thus were not time-locked with DR stimuli. These period properties are consistent with those of fictive locomotion induced in the neonatal spinal cord in vitro by bath application of agents such as NMDA (T, 0.24-6.25 s, Kudo & Yamada, 1987), serotonin (T, 1-4 s, Cazalets et al. 1992; T, 1.8-2.5 s, Beato et al. 1997), or high potassium (T, 0.8-2.3 s, Bracci et al. 1998) and confirmed in the present study with application of NMDA plus serotonin (T, 1.39 ± 0.21 s). Furthermore, the oscillatory activity induced by DR stimulation presented the typical phase alternation at segmental and intersegmental level which is a hallmark of fictive locomotion evoked by chemical substances (Kiehn et al. 1997). It is widely accepted that these substances activate the mammalian spinal CPG responsible for driving the rhythmic firing of motoneurones (reviewed by Kiehn et al. 1997). Also in our case, the oscillatory activity of motoneurones was likely to be driven by the CPG and could be regarded as a locomotor-like pattern turned on by the activation of dorsal afferents which are known to project to the CPG itself (Hultborn et al. 1998).
Even relatively weak DR stimuli (1.3×Th) were very effective for inducing locomotor-like patterns. Electrical pulses below 1.6×Th activated fast conducting, low threshold afferents while stronger stimuli also recruited high threshold DR fibres. Since low and high threshold afferents are expected to carry distinct sensory information, the possibility of activating the locomotor CPG even with rather low stimuli suggests that discrete inputs carried by a restricted class of sensory axons are sufficient to trigger the operation of the CPG. This condition might thus prove to be a useful model for investigating how physiological stimuli activate and interact with the CPG. It seems that such a model would also be experimentally advantageous over the indiscriminate activation of the vast majority of spinal neurons by bath-applied substances.
How long can fictive locomotor-like patterns last?
Unlike the persistent and stable fictive locomotor pattern elicited by chemicals (Kiehn et al. 1997), the DR-induced pattern was usually transient. With a long stimulus train the oscillatory pattern waned despite persistent motoneuronal depolarization, unimpaired firing and unhindered polysynaptic reflex. When the stimulus applied to a heterosegmental root was initially weak so as to activate primarily low threshold DR fibres, it was possible to reinstate the pattern by recruiting an additional class of higher threshold fibres within the same root. Even in the latter case the pattern faded but it could be transiently rescued by weakly stimulating the contralateral DR.
The cause for the disappearance of the rhythmic pattern remains uncertain. Lack of depression of DR volleys (with stimulation protocols comparable to those used to elicit locomotor-like patterns) indicated that afferent stimuli probably continued to reach the spinal tissue. The persistence of VR reflexes equally suggests that the motoneuronal output remained operative. Synaptic fatigue, if it had played any significant role in this phenomenon, should thus have been confined to interneurones impinging upon the CPG or to CPG interneurones themselves.
CPG interneurones of the rat spinal cord can generate long episodes of locomotor-like rhythmic activity and are thus not particularly prone to fatigue (Kiehn et al. 1997). If their fatigue had been due to any excessively strong activation by afferent stimuli, it should have been possible, through fine tuning of the stimulus characteristics, to obtain a condition of stable DR-induced rhythm. This goal could not be attained by the present study despite extensive tests. This observation suggests that loss of rhythmicity was due to either fatigue in the pathway upstream of the CPG (as indeed observed with afferent impulses in the presence of strychnine and bicuculline; Bracci et al. 1997) or stimulus-patterned release of some transmitters which inhibited the CPG operation. The first possibility seems more likely as recruitment of additional pathways either homolaterally (by increasing the stimulus strength) or contralaterally was temporarily sufficient to restore the oscillatory activity. Models to simulate rhythmic oscillations generated by chick embryo spinal neurones have very recently been proposed to account for the episodic nature of cyclic oscillations which is thought to be due to either activation of a slow process (for example, gradual turning on of a persistent conductance or some metabolic process) or to build-up of synaptic fatigue (Tabak et al. 2000). It will be interesting to apply these models to the fictive locomotor-like patterns induced by DR stimuli in the rat spinal cord.
Generation of locomotor-like patterns by DR stimuli
One hypothesis is that DR stimuli induced an increase in extracellular K+ concentration ([K+]o) during a locomotor-like rhythm since, in the neonatal spinal cord, single and repetitive stimuli elicit K+ transients (Walton & Chesler, 1988) large enough to influence neuronal excitability. Moreover, phasic variations in [K+]o have been reported to occur during fictive swimming recorded from the lamprey spinal cord in vitro (Wallen et al. 1984). Finally, application of high [K+]o, within a certain range of concentrations, is known to induce fictive locomotion in the rat spinal cord (Bracci et al. 1998). Future experiments are necessary to test this hypothesis by measuring [K+]o variations with K+-sensitive electrodes inserted within the ventral horn where the CPG is supposed to be located (Kjaerulff & Kiehn, 1996). This approach may, however, be complicated by the condition that, in an intact spinal cord preparation, final placement of the K+-sensitive electrode would be blind, a fact that would make it very difficult to identify any response as due to the activity of CPG neurones which are thought to be present in various laminae (Kjaerulff et al. 1994). Notwithstanding the precise mechanism underlying the generation of fictive locomotor-like patterns by DR stimuli, it seems likely that rhythmogenesis was caused by enhanced release of excitatory transmitters from spinal neurones activated by DR fibre stimulation. If this electrical activation was temporally restricted, as in the case of single pulses which were rarely sufficient to trigger fictive locomotion, no oscillatory activity resulted. Repetitive stimulation presumably caused persistent neuronal depolarization which in turn (through membrane depolarization and facilitation of transmitter release) recruited a larger population of cells up to threshold for locomotor-like electrical behaviour. The weak dependence of locomotor-like oscillations on stimulus intensity and their lack of dependence on stimulus frequency indicate that there is strong non-linearity of the input/output operation of the CPG network.
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REFERENCES |
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This work was supported by grants from Istituto Nazionale di Fisica della Materia and from Ministero dell'Universita' e della Ricerca Scientifica e Tecnologica (MURST cofinanziamento) to A.N.
Corresponding author
C. Marchetti: Biophysics Sector and Istituto Nazionale di Fisica della Materia Unit, International School for Advanced Studies (SISSA), 34014 Trieste, Italy.
Email: marche{at}sissa.it
Author's present address
M. Beato: Department of Pharmacology, The School of Pharmacy, London WC1N 1AX, UK.
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A. Rozzo, L. Ballerini, G. Abbate, and A. Nistri Experimental and Modeling Studies of Novel Bursts Induced by Blocking Na+ Pump and Synaptic Inhibition in the Rat Spinal Cord J Neurophysiol, August 1, 2002; 88(2): 676 - 691. [Abstract] [Full Text] [PDF]
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H. Gabbay, I. Delvolve, and A. Lev-Tov Pattern Generation in Caudal-Lumbar and Sacrococcygeal Segments of the Neonatal Rat Spinal Cord J Neurophysiol, August 1, 2002; 88(2): 732 - 739. [Abstract] [Full Text] [PDF]
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 D. Morin and D. Viala Coordinations of Locomotor and Respiratory Rhythms In Vitro Are Critically Dependent on Hindlimb Sensory Inputs J. Neurosci., June 1, 2002; 22(11): 4756 - 4765. [Abstract] [Full Text] [PDF]
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C. Marchetti and A. Nistri Neuronal Bursting Induced by NK3 Receptor Activation in the Neonatal Rat Spinal Cord In Vitro J Neurophysiol, December 1, 2001; 86(6): 2939 - 2950. [Abstract] [Full Text] [PDF]
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