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1 CNRS UMR 5543, Université de Bordeaux II, Zone nord Bat 2, 2e étage, 146, rue Léo Saigna, 33076 Bordeaux cedex France
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Abstract |
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(Received 21 March 2005;
accepted after revision 3 August 2005;
first published online 4 August 2005)
Corresponding author J.-R. Cazalets: CNRS UMR 5543, Université de Bordeaux II, Zone nord Bat 2, 2e étage, 146, rue Léo Saigna, 33076 Bordeaux cedex France. Email: jean-rene.cazalets{at}umr5543.u-bordeaux2.fr
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Introduction |
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Muscles of quadruped forelimbs and hindlimbs are activated by neuronal networks that are located in the cervical (Jovanovic et al. 1998; Ballion et al. 2001) and lumbar cord enlargements (Rossignol, 1996; Cazalets & Bertrand, 2000b). Between these two regions (and also merging with them), are networks that drive motoneurones innervating trunk muscles along the axis of the body. Rhythmic activation of trunk muscles coordinated with appendicular locomotor activity has been observed in man (Thorstensson et al. 1982), rat (Gramsbergen et al. 1999) and cat (Zomlefer et al. 1984), where it was proposed that such activity has a central nervous origin (Koehler et al. 1984). Although coordination between these subsets of neuronal networks must occur during expression of meaningful locomotor behaviour, to date little data are available on the ‘metanetwork’ functioning of the spinal cord during ongoing locomotion.
The present study was therefore undertaken to address the functioning of the spinal cord, studying it as a whole, rather than as separate elements, and to see how its various regions might interact to coordinate motor activity. To this end, simultaneous multisite extracellular recordings were performed at the thoracic, lumbar and sacral levels in an isolated spinal cord preparation of newborn rat. Based on a method initially used by others (Bracci et al. 1996b), a pharmacological approach involving bath application of inhibitory synaptic blockers strychnine and bicuculline was employed for several reasons: (1) powerful and stereotyped bursts of action potentials are spontaneously produced; (2) the sharp onset of the bursts allows accurate determination of their timing; (3) the suppression of inhibitory connections within the spinal cord reveals underlying connectivity. It was therefore postulated that motor output recorded under these restrictive conditions might reveal coupling and other hard-wired properties of the system. Our results show that motor activity propagates along the spinal cord with a specific temporal pattern and that there is an asymmetry in the propagating characteristics from rostral to caudal versus caudal to rostral directions. Moreover, it was found that intersegmental coupling relies on a combination of local circuit connectivity as well as long projection fibres. This preparation offers a simplified model for studying network interactions in the mammalian nervous system.
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Methods |
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All drugs were from Sigma. Strychine (Stry) and bicuculline (Bic) were freshly prepared and dissolved in the saline at the appropriate concentration. The mixture of Stry–Bic was bath-perfused throughout the experiment. Spontaneous activity, which generally started within 15 min following superfusion onset, was recorded continuously in sequences lasting 30 min. In some experiments, synaptic activity was suppressed using a modified saline from which Ca2+ was removed and 2 mM MnCl was added (phosphate was also removed from the saline to avoid precipitation).
Compartmentalization of the spinal cord was achieved by building walls of Vaseline, which was deposited across the bath and the cord with a fine syringe needle (0.5 mm). The water-tightness of walls was checked by over-filling one compartment on either side of a wall. If no change in the saline level occurred after several minutes, the walls were taken to be watertight. Mechanical cord lesions were performed using sharp MC-52 scissors (Moria, Paris).
Data acquisition was performed at 1 kHz on 16 channels using a Digidata 1322A interface driven by Axograph software (Axon Instruments). Up to 16 ventral roots were recorded simultaneously (Fig. 2), using stainless-steel pin electrodes (200 µm diameter) insulated from the bath with Vaseline (in all figures, the location of the extracellular electrodes has been indicated with dots). Signals, amplified 5000 x using laboratory-made amplifiers, were treated and analysed using Axograph analysis plug-ins. The signal was rectified without any smoothing or filtering. Each burst of activity was detected using a threshold value that was defined at 20% of the maximum amplitude for each trace and a minimum period value (according to the mean period in the measured sequence) was used in order that each burst could not be detected twice. Each time a burst was detected in this reference trace, it was sampled with all other associated recorded traces. Individual cycles were superimposed and then averaged (see Fig. 5). This process allowed the switch from a continuous mode of recording to an episodic one. The aim was to increase the signal-to-noise ratio in order to obtain a more accurate detection of burst onsets. Subsequent measurements were automatically performed on the averaged trace using a method based on onset detection (onset at 5% of maximum peak amplitude). Only the initial onset of burst activity was considered. Lag graphs were plotted using Igor-Pro software (Wavemetrics, OR, USA). Electrical stimulations were also performed with bipolar stainless-steel pin electrodes insulated with Vaseline.
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Results |
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Bath application of strychinine and bicuculline at standard concentrations of 10–6 M and 2 x 10–5 M, respectively (Bracci et al. 1996b), induced repetitive bursts of action potentials, as shown in Fig. 1A. The mean period of 76 ± 11 s (n = 13 preparations) was in the same time range as that reported in previous work using the same protocol (Bracci et al. 1996a,b; Ballerini et al. 1997). A burst was identified by an abrupt onset of spiking activity as shown in the insets in Fig. 1A, which present two burst examples on a faster time base. Comparable effects were observed at concentrations ranging from 4 x 10–6 to 4 x 10–5 M bicuculline and 10–6 to 10–5 M strychnine, although with a longer interburst interval at the lowest bicuculline concentrations. To assess whether burst occurrence followed a specific temporal organization, burst distribution with time was analysed during sequences that lasted 100 min. Correlation analysis showed that there were no significant changes (P = 0.95) of the motor period with time, and a linear regression was performed (period duration versus recording time, slope 0.06) to fit the data (Fig. 1B). The number of burst occurrences during intervals of 1 min was also measured in sequences ranging from 60 to 120 min. The distribution of this burst occurrence was significantly (P < 0.05) fitted by a Poisson distribution as seen in the case experiment of Fig. 1C where the black line traces the theoretical distribution and the grey bars the actual distribution of motor burst period (Fig. 1C). The same significant result was observed in all 12 preparations examined (with a mean of 44 counted periods in each experiment). This therefore indicates that despite repetitive burst production, this activity occurred randomly under the experimental conditions.
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The occurrence of an intersegmental delay was observed in all preparations (n = 19) in which spontaneous activity was expressed under bath application of Stry–Bic. Surprisingly, however, the locus at which a burst first occurred varied from one cycle to another as seen in Fig. 3, following analysis of the entire sequence monitored at a slow time scale in Fig. 3A. Figure 3B presents expanded views of three cycles (numbered from 1 to 3) extracted from the sequence. In all examples, the dashed line indicates the onset of the first motor burst. Cycle 1 (Fig. 3B1) started at the high thoracic level, cycle 2 (Fig. 3B2) was initiated at the lumbar level and cycle 3 started at the Co1 level. Moreover, during a given sequence, cycle initiation switched randomly from one site to another. In a further analysis of 386 cycles from nine preparations (Fig. 3C), the occurrence of cycle-initiating bursts was assigned to one of seven arbitrarily defined regions of the cord (x axis in Fig. 3C). The probability for initial burst occurrence was highest in three main cord regions (highlighted in grey in the spinal cord schema of Fig. 3C); namely the coccygeo-sacral area, the rostral lumbar/distal thoracic area and the rostral thoracic area. Thus, although the ‘leading segment’ could vary from one cycle to another, there were preferential areas in which bursting initiation occurred.
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Two hypotheses could explain the propagation of motor activity described above. First, long ascending/descending fibres-distributing collaterals at each segmental level could sequentially activate the motor groups distributed along the spinal cord. Second, the propagation could derive from locally interacting segmental networks that segmentally activate each other.
To assess these possibilities, the rostral (T1) and caudal (Co2) parts of the spinal cord were stimulated electrically to test the potential implication of long spinal tracts and to measure the propagation velocities of any such direct pathway. To be sure that the activated pathways directly reached a given segment, without intervening synaptic relay, stimulations were performed under synaptic blockade (superfusion of 0 Ca2+ saline containing Mn+, see Methods) in a compartmentalized spinal cord (Fig. 7A; n = 4 preparations). Electrodes for stimulation were placed at the rostral (T1) and caudal (Co2) ends of the spinal cord and ventral roots at lumbar and sacral levels were recorded (see dots in Fig. 7A). Under control conditions (note in the absence of Stry–Bic), stimulation at T1 elicited segmental bursts of action potentials with an increasing rostro-caudal delay (dashed lines, Fig. 7B1). Similarly, a caudo-rostral burst delay was observed from the S2 to L2 level when stimulating in Co2 (Fig. 7C1). Under bath application of 0 Ca2+–Mn+ saline in the thoraco-lumbar compartment (including L2 rectangle; see Fig. 7A), stimulation at T1 no longer elicited a burst in the L2 ventral root (Fig. 7B2), indicating that the synaptic pathways to this caudal spinal region were blocked. However, a volley of action potentials was still recorded in the more caudal S1 and S2 unblocked ventral roots with an unchanged latency. In a corollary experiment, synaptic activity was blocked in the caudal part of the spinal cord with the rostral compartment now placed under control saline (Fig. 7C2). Under these conditions, no activity was recorded in the sacral ventral roots in response to Co2 stimulation while activity was evident higher up the cord in the L2 ventral root (Fig. 7C2).
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In addition to the spontaneous expression and propagation of activity under Stry–Bic conditions (Figs 2–6), motor burst propagation was also examined when stimulating the spinal cord in the presence of strychnine and bicuculline. If electrical stimulation directly activates long fibres that distribute to each segmental level (see Fig. 7), it could be expected that such activity is propagated faster than that occurring spontaneously. In fact, if segmental activation involves long spinal fibres that distribute to each segmental level, it will be faster since it requires only the time for spike propagation along the fibres, as well as synaptic delay. According to the estimated conduction velocity in this preparation (around 1.1 m s–1) and 2–3 ms for synaptic delay, the minimum time required for end-to-end propagation is about 30 ms which does not at all correspond to the propagation time (80–150 ms) recorded during spontaneous bursting (Fig. 6B). To test this possibility, stimulations were performed at three sites: T1 segment, L5 dorsal root and the Co2 segment. Figure 8 presents the corresponding lag plots obtained from the pooled data of six such experiments. The total time required for propagation was similar for ascending (triangles, 51 ± 5 s, n = 6) and descending (circles, 50 ± 9 s, n = 6) waves, and as predicted was much shorter than the propagation time observed during spontaneous activity (compare with Fig. 6B). The data values were compared for the total propagation time during spontaneous and stimulated conditions using a one-way ANOVA considering the four conditions, i.e. spontaneous rostro-caudal and caudo-rostral propagation, and rostro-caudal and caudo-rostral propagation during stimulation. It showed that the total time for propagation was not different during stimulation in the rostro-caudal or caudo-rostral propagation directions, and that during stimulation the propagation was significantly faster than during spontaneous activity (P < 0.005). However, although the total propagation time was reduced, the lag plots established under electrical stimulation exhibited some similarities with spontaneous activity, with a change in the slope again seen from T2–T13 versus T13–Co1. In Fig. 8B, the slopes calculated from the lag diagrams of Figs 6B and 8A were plotted to compare lag changes during spontaneous and stimulation-induced propagation. As evident in Fig. 8B (left panel), slope values which were negative for descending and positive for ascending propagation, were always smaller during spontaneous propagation. Surprisingly, when stimulating the L5 dorsal root (line with filled squares in Fig. 8A), the ascending and descending waves emerging from mid-lumbar segments had a lower slope (Fig. 8B, right panel). Slope comparisons indicated that there was a significant difference (P < 0.0001) when considering the propagation in the T2–T13 segments (filled bars) to the propagation in the T13–Co1 segments (open bars). Altogether this suggests that dorsal root stimulation did not provoke the direct involvement of long fibre tracts but rather activated local networks via sensory input pathways, which in turn propagated the information up and down the cord with longer intersegmental delays.
Although the above data indicate that during spontaneous activity, local segmental interactions mediate motor burst propagation, Fig. 9 shows that long intersegmental pathways might also contribute to spontaneous burst propagation. In these experiments (n = 3), the spinal cord was separated into three compartments (see Fig. 9A1 and B1). Under control conditions, i.e. with Stry–Bic saline in all three compartments (Fig. 9A1), spontaneous motor bursts were observed in all recorded ventral roots. When the middle compartment (spanning 10 segments from T8 to L4) was bathed with a 0 Ca2+–Mn+ saline, burst activity disappeared in the T13 ventral root. However, an absolute coordination persisted (all bursts crossed the 10 medial segments), between the segments above and below the intervening compartment, although the motor bursts were now weaker. Thus, this indicates that intersegmental coupling is indeed mediated in part by long projecting pathways which continue to propagate axial bursts in the absence of local interactions that were suppressed by the blockade of synaptic activity.
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Discussion |
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The bath application of strychnine and biculline has been extensively used to study motor rhythms in vitro (Ballerini et al. 1995, 1997; Bracci et al. 1996a,b, 1997, 1998). The idea is that such disinhibited motor networks express spontaneous burst patterns under these conditions. However, the disinhibition-induced bursting results not only from the specific activation of locomotor networks by removal of inhibition; both strychnine (Shapiro et al. 1974; Dale, 1995) and bicuculline (Debarbieux et al. 1998) block several types of K+ and Ca2+ voltage-gated channels. Therefore, as shown in thalamic neurones (Debarbieux et al. 1998), it is likely that bursting induced by bicuculline and strychnine may result also from a synergistic action of both blockade of inhibition and of K+ channels on various neuronal classes. The motor burst period values recorded here (mean 76 ± 11 s) were longer than those reported by Bracci et al. 1996b). This may be attributable to differences in extracellular K+ concentration (3 mM in these experiments) which plays an important role in setting motor output (Sqalli-Houssaini et al. 1993; Bracci et al. 1998). It is unlikely that these motor rhythms are directly related to locomotion, and thus, inferences about bursting mechanisms under physiological conditions cannot be made. However, it is also clear that this method does allow inferences about some of the underlying wiring properties of the spinal networks in the absence of inhibition. The temporal analysis of motor bursting sequences also indicated that, under our experimental conditions, bursts were randomly emitted along the spinal cord, with their occurrence following a Poisson distribution (Fig. 1). Whatever the mechanisms for initial burst onset in a given cycle, which is presumably triggered by a summation of spontaneous excitatory synaptic activity, the multiple electrode recording method used here allowed disclosure of three zones of hyperexcitability in which burst initiation occurred preferentially (grey zones Fig. 3C2). First, the sacral area has recently been highlighted as having important rhythmogenic capabilities (Cazalets & Bertrand, 2000a; Lev-Tov et al. 2000), being implicated in tail movements (Gabbay et al. 2002). Second, it has been demonstrated that the low thoracic/high lumbar segments contain key rhythmogenic components for generating locomotor activity (Cazalets et al. 1995; see review by Cazalets, 2000). Finally, the third zone corresponds to the caudal end of the network driving forelimb movements (Ballion et al. 2001). These experiments therefore provide indirect confirmation of the heterogenous nature of spinal cord in terms of the longitudinal distribution of its rhythmogenic capacity.
Coupling mechanisms
Metachronal motor activity (one part being active after another) is a characteristic of all systems involving segmentally repeated muscles or appendages. This includes the locomotor systems of undulating animals such as fish (Cohen, 1987; Matsushima & Grillner, 1992; Miller & Sigvardt, 2000), tadpoles (Tunstall et al. 2002), snakes (Gasc et al. 1989), newt (Delvolve et al. 1997), leech swimming (Masino & Calabrese, 2002) as well as crayfish swimmeret beating (Skinner & Mulloney, 1998b). Metachronal activation allows the production of appropriately timed forces against the substrate to produce body displacement. Two main hypotheses have been raised to explain how these systems may work. On one hand long intersegmental neuronal tracts could be involved in coupling mechanisms while on the other hand, local interactions between adjacent segmental oscillators could explain the lag between segments (for review see Skinner, 1998a).
In one of the best studied systems, the lamprey spinal circuitry for locomotion, which is comprised of about 100 segments that are sequentially activated, the phase lag between consecutive segments remains close to 1% of the cycle, leading to approximately one wavelength of body curvature. In a recent study (Miller & Sigvardt, 2000; see also McClellan & Hagevik, 1999), the respective and complementary roles of the two mechanisms have been analysed. When blocking synaptic activity in a middle section of lamprey spinal cord preparation, segments rostral and caudal to the synaptically inactivated area remained coordinated, although the long coupling fibres were not able to maintain a correct phase lag across the blocked area. However, within these rostral and caudal sections of spinal cord, adequate local intersegmental phase lags were not changed by the loss of distant coupling inputs. Interestingly, comparable mechanisms may be operating in the rat spinal cord. This study has found that long projecting fibres also have access to distant segments (Fig. 7) since coordination persists when local connectivity is blocked (Fig. 9). On the other hand, if only long-distance coordinating fibres were involved, the total time for propagation would remain close to that encountered during direct stimulation of the ascending and descending pathways (i.e. 50 ms, open symbols in Fig. 8A) while the propagation time is in fact much longer during spontaneous (Fig. 6) or sensory-elicited motor burst activation (filled squares in Fig. 8A).
When partial sectioning of the lateral white matter was performed (Fig. 10B), the remaining pieces of the spinal cord above and below the lesion had different burst periods although relative coupling was maintained. These differences in motor period may be attributable to differences in the excitability of the segments. In the lamprey spinal cord, it has been suggested that the motor period in distant segments may also be modulated by the relative complement between available shorter and longer coupling fibres (Miller & Sigvardt, 2000). Here, the changes in motor period seen after sectioning of the lateral spinal cord (Fig. 10) suggest that long fibres are necessary for maintaining appropriate timing of the overall network.
Despite similarities between rat spinal circuitry and the motor networks of invertebrate and lower vertebrate models, complete analogy does not occur. First, in the newborn rat spinal cord, the metachronal wave exhibits clear temporal discontinuities in that activity propagates faster in the rostral segments than in caudal ones (Fig. 6). It is unlikely that these region-specific changes in propagation rate are due to differences in conduction velocity or synaptic latency of long fibres, since activity propagates at the same speed in both directions during direct spinal cord stimulation (Fig. 8A). One explanation could be that in the rostral part of the cord, coordination relies more on long fibres coupling mechanisms while in the caudal section segmental interactions predominate. Alternatively, since the lumbar segments are intimately involved in hindlimb control, it could be that more complex local circuit interactions slow propagation through this region.
Besides propagation non-linearity, another striking characteristic of the newborn rat cord is the difference between spontaneous rostro-caudal and caudo-rostral propagation (Fig. 6), suggesting that there is a directional asymmetry in the functioning of the underlying circuitry. One possibility is that it could reflect the involvement of different neuronal networks in rostro-caudal or caudo-rostral directions of propagation. Again, in other models such as the lamprey, this is not observed under normal functioning of this system, although propagation in both directions may be observed when a middle segment is overexcited, relative to adjacent rostral and caudal ones (Matsushima & Grillner, 1992). In addition, differences in excitability between various zones found under our experimental conditions (Fig. 3C) have also been observed in the leech swimming system where the segmental oscillators are not uniform in their ability to generate rhythmic motor output (Hocker et al. 2000).
Although it is difficult to evaluate the respective contributions of local interactions versus long coupling pathways running along the spinal cord in the coordination process, it is likely that they may act simultaneously.
Functional relevance of intersegmental coupling
Locomotion as well as postural adjustments implicate the activation of motoneuronal pools along the body which subserve different functions. In this way, the task assigned to metachronal segmental activation in mammals does not fulfil the same function as in undulating animals. In the latter, the aim is to produce bending of the body that ensures adequate forces against the surrounding substrate. Although such a mode of coordination is not spontaneously exhibited in quadrupeds and man, it has been reported that there is metachronal activation of the axial musculature in man (Prince et al. 1994; J. R. Cazalets, unpublished observations). In mammals, trunk muscles have been shown to play a major role in postural maintenance since anticipatory postural adjustments are needed for a correct execution of movement. Besides this postural role, there is also a phasic activation of trunk muscles in synchrony with limb muscle activity during locomotion in various species including the cat (Carlson et al. 1979; Koehler et al. 1984; Zomlefer et al. 1984), rat (Gramsbergen et al. 1999) and man (Thorstensson et al. 1982). It is therefore likely that in mammals, a longitudinal coupling system may be involved in the axial and limb musculature.
In conclusion, the present data obtained in the presence of synaptic inhibitory blockers revealed that the newborn rat spinal cord possesses the intrinsic ability for the metachronal propagation of motor activity. Furthermore, these experiments highlight specific zones in the spinal cord with specific excitability and integration properties. It is proposed that the ‘meta-network’ which emerges under these conditions, may be at work in coordinating the various spinal regions during normal motor functioning associated with either postural or propulsive behaviours. It is now, however, necessary to perform further studies to see if normal network operation behaves in the same way. In any case the system described here may be used as a simple mammalian model for studying neuronal network coupling.
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), coccygeal area (Co2, 
, or L5 dorsal roots (
). B, plots of lag slope during Stry–Bic-induced bursting (leading burst in either the coccygeal area (coc) or the thoracic area (thor)), during electrical stimulation of spinal cord (at Co2 or Thor1) and L5 dorsal root. The key panel above the histogram indicates the portion of curve on which the corresponding slope was calculated. The slope value expressed in m s–1 assumes that the length of each segment is 1 mm.
