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. 2000 Aug 1;526(Pt 3):639–652. doi: 10.1111/j.1469-7793.2000.00639.x

Depression of group Ia monosynaptic EPSPs in cat hindlimb motoneurones during fictive locomotion

S Gosgnach 1, J Quevedo 1, B Fedirchuk 1, D A McCrea 1
PMCID: PMC2270044  PMID: 10922014

Abstract

  1. The effects of fictive locomotion on monosynaptic EPSPs recorded in motoneurones and extracellular field potentials recorded in the ventral horn were examined during brainstem-evoked fictive locomotion in decerebrate cats. Composite homonymous and heteronymous EPSPs and field potentials were evoked by group I intensity (< = 2T) stimulation of ipsilateral hindlimb muscle nerves. Ninety-one of the 98 monosynaptic EPSPs were reduced in amplitude during locomotion (mean depression of the 91 was to 66 % of control values); seven increased in amplitude (to a mean of 121 % of control). Twenty-one of the 22 field potentials were depressed during locomotion (mean depression to 72 % of control).

  2. All but 14 Ia EPSPs were smaller during both the flexion and extension phases of locomotion than during control. In 35 % of the cases there was < 5 % difference between the amplitudes of the EPSPs evoked during the flexion and extension phases. In 27 % of the cases EPSPs evoked during flexion were larger than those evoked during extension. The remaining 38 % of EPSPs were larger during extension. There was no relation between either the magnitude of EPSP depression or the locomotor phase in which maximum EPSP depression occurred and whether an EPSP was recorded in a flexor or extensor motoneurone.

  3. The mean recovery time of both EPSP and field potential amplitudes following the end of a bout of locomotion was approximately 2 min (range, < 10 to > 300 s).

  4. Motoneurone membrane resistance decreased during fictive locomotion (to a mean of 61 % of control, n = 22). Because these decreases were only weakly correlated to EPSP depression (r2= 0.31) they are unlikely to fully account for this depression.

  5. The depression of monosynaptic EPSPs and group I field potentials during locomotion is consistent with the hypothesis that during fictive locomotion there is a tonic presynaptic regulation of synaptic transmission from group Ia afferents to motoneurones and interneurones. Such a reduction in neurotransmitter release would decrease group Ia monosynaptic reflex excitation during locomotion. This reduction may contribute to the tonic depression of stretch reflexes occurring in the decerebrate cat during locomotion.

The monosynaptic excitation of homonymous and synergistic hindlimb motoneurones following activation of group Ia muscle spindle afferents (e.g. Eccles et al. 1957) is considered to be a fundamental component of postural regulation. Accordingly, muscle stretch during movements such as locomotion activates group Ia afferents which, by monosynaptically exciting motoneurones, produces muscle contraction to counter muscle lengthening (see Lundberg, 1969). The gain of this simple reflex depends upon both motoneurone excitability and the strength of synaptic transmission between afferents and motoneurones. Phasic changes in the amplitude of monosynaptic reflexes during locomotion have been reported in a number of studies in man and cat (see Brooke et al. 1997). Since motoneurones are subject to a rhythmic depolarization during locomotion, it is not surprising that monosynaptic reflexes are larger in the locomotor phase in which the motoneurones are actively depolarized (Akazawa et al. 1982). However, in addition to a phasic reflex modulation between the locomotor phases, the gain of the monosynaptic reflex during locomotion is tonically reduced compared to non-locomotor conditions in cat (Bennett et al. 1996) and in man (Capaday & Stein, 1986; Faist et al. 1996; Andersen & Sinkjaer, 1999). There is no evidence for the emergence of an inhibitory postsynaptic component of the monosynaptic EPSP that might account for the decrease in reflex gain during locomotion. On the contrary, intracellular recordings reveal an additional disynaptic excitatory component of the monosynaptic EPSP and a reduction in group I-evoked inhibition during fictive locomotion (see McCrea et al. 1995; Angel et al. 1996; Quevedo et al. 2000).

Three lines of evidence suggest that there is a presynaptic reduction of transmitter release from terminals of group Ia afferent fibres during locomotion that contributes to a depression of the monosynaptic reflex. First, the rhythmic changes in the excitability of group Ia afferents during fictive locomotion (Duenas & Rudomin, 1988) suggest a primary afferent depolarization (PAD) and reduction in transmitter release (see Rudomin & Schmidt, 1999). Second, intra-axonal recordings directly demonstrate a rhythmic PAD of group Ia afferents (Gossard et al. 1991; Gossard, 1996). Third, there is a rhythmic modulation of some monosynaptic group I field potentials recorded in the intermediate laminae of the lumbro-sacral spinal cord during fictive locomotion (Perreault et al. 1999). Since field potentials reflect transmembrane currents resulting from synaptic transmission between afferents and their target neurones, field potential depression indicates a presynaptic inhibition of transmission from Ia afferents to interneurones in these regions during locomotion. In addition to rhythmic reductions in presynaptic transmitter release, there is strong evidence for a tonic presynaptic inhibition of synaptic transmission during locomotion. There is both a tonic increase in Ia fibre excitability (Duenas & Rudomin, 1988) and a tonic decrease in group I field potential amplitude (Perreault et al. 1999) during fictive locomotion. Such phenomena would be expected to produce an overall reduction in the gain of the monosynaptic reflex during locomotion and some phasic reflex modulation between the flexion and extension phases.

Intracellular recordings from motoneurones, however, provide no evidence for either a tonic depression of Ia EPSPs or the rhythmic fluctuations of EPSP amplitude expected during locomotion. Although only a few unitary monosynaptic Ia EPSPs were examined, Gossard (1996) found Ia EPSPs were depressed only in the locomotor phase in which the motoneurone was hyperpolarized. The amplitudes of the two composite Ia EPSPs illustrated by Shefchyk et al. (1984) are similar in control and locomotor conditions with only a slight phasic modulation during locomotion.

The present study sought to investigate further the discrepancy between the evidence for a tonic presynaptic reduction in synaptic transmission and the absence of a tonic reduction in Ia EPSP amplitude in motoneurones during fictive locomotion. Our interest in this topic arose during an analysis of the emergence of locomotor-related disynaptic excitation of flexor and bifunctional motoneurones (Quevedo et al. 2000) when it became apparent that monosynaptic Ia EPSPs were depressed tonically during fictive locomotion. Here we present the effects of fictive locomotion on composite monosynaptic EPSPs and ventral horn extracellular field potentials evoked by electrical stimulation of hindlimb peripheral nerves. The results show that both monosynaptic group Ia EPSPs and field potentials are substantially decreased during locomotion and that there is a delayed recovery of both field potentials and EPSPs following cessation of locomotion. Preliminary results have been presented (Gosgnach et al. 1998, 1999).

METHODS

Preparation

Experiments were performed on 23 cats of either sex weighing 2.1-4.5 kg. All surgical and experimental protocols were in compliance with the guidelines set out by the Canadian Council for Animal Care and the University of Manitoba. For the surgery, anaesthesia was induced and maintained with halothane (5 % and 1-2 %, respectively) delivered in a mixture of 30 % oxygen and 70 % nitrous oxide. A surgical plane of anaesthesia was verified throughout the surgery by monitoring arterial blood pressure and by repeatedly testing for the lack of withdrawal reflexes and muscle tone. Two veins were cannulated to administer drugs and fluids, and blood pressure was monitored from the carotid artery. A tracheotomy was performed. Atropine (0.05 mg kg−1s.c.) and dexamethasone (2 mg kg−1i.v.) were given at the beginning of the surgery and a 5 % glucose and bicarbonate solution was delivered intravenously throughout the experiment at a rate of 5 ml h−1. Supplemental saline and dextran infusions were given as required to maintain blood pressure. Selected left hindlimb nerves were dissected and cut in preparation for electrical stimulation and monitoring locomotion. The dissected nerves included the left semimembranosus and anterior biceps (taken together as SmAB), posterior biceps (PB), semitendinosus (St), sartorius (Sart), lateral gastrocnemius and soleus (LGS), tibialis anterior (TA), extensor digitorum brevis (EDB) and extensor digitorum longus (EDL). The Sart nerve was placed in a bipolar cuff electrode for stimulation and recording. In the right hindlimb, the AB or SmAB nerve was dissected to monitor contralateral electroneurogram (ENG) activity. Other femoral, sciatic and obturator nerve branches, as well as tendons around the hip, were cut bilaterally. Following an L4-L7 laminectomy, the cat was placed in a rigid frame. A mechanical precollicular-postmammillary decerebration was performed with removal of both corticies and all tissue rostral to the transection. This rendered the animal totally insentient allowing the anaesthetic to be discontinued. Gallamine triethiodide (Flaxedil, 2-3 mg kg−1 h−1) was administered and the cat artificially ventilated. Mineral oil pools over the spinal cord and both hindlimbs were warmed by radiant heat. Dissected nerves were placed on bipolar electrodes for stimulation and recording. A lethal injection of pentobarbital anaesthetic was administered at the end of the experiment. Some of the present results were obtained in the same preparations used to examine disynaptic excitation of flexor and bifunctional motoneurones during fictive locomotion (Quevedo et al. 2000).

Stimulation and recording

Glass microelectrodes filled with 100 mM QX-314 (Alamone Laboratories, Israel) in 2 M potassium citrate (tip diameter, 1.8-2.5 μm; resistance, 2-3 MΩ) were used for intracellular recording from antidromically identified hindlimb motoneurones. Intracellular diffusion of QX-314 was used to block motoneurone action potentials and permit better assessment of the afferent-evoked EPSPs. Extracellular field potential recordings were made using either the same electrode or glass microelectrodes filled with 2 M sodium citrate. Fictive locomotion was evoked by unilateral or bilateral stimulation of the mesencephalic locomotor region (MLR) (80-200 μA, 1 ms pulses at 12-18 Hz; see Guertin et al. 1995). In one experiment three EPSP measurements were made following intravenous clonidine (200 μg kg−1) and naloxone (100 μg kg−1) administration to aid in the initiation of MLR-evoked fictive locomotion.

Selected peripheral nerves were electrically stimulated using strengths expressed in multiples of threshold current. Threshold current (T) was defined as the smallest current producing a detectable extracellular compound action potential volley at the cord dorsum recording electrode. The peripheral nerve stimulation strength (≤ 2T, 100 μs constant current pulses delivered at 3-5 Hz) was adjusted to evoke a large monosynaptic EPSP in the motoneurones without orthodromic or antidromic action potentials. Thus, particularly in the case of homonymous EPSPs, the stimulation strength chosen may not have produced maximum EPSP amplitude. In most cases field potentials were measured with the same electrodes used for intracellular recording and often immediately after moving the electrode from an intracellular location to one nearby. All field potentials were recorded in the ventral horn. When recording field potentials, stimulation intensity was adjusted to reduce antidromic activation as much as possible and the extracellular recording electrode was positioned to avoid obvious antidromic spikes. The protocol for collection and analysis of intracellular data was as follows. Motoneurones were impaled and antidromically identified prior to the effects of QX-314 on the action potential. Motoneurones were classified as flexor, extensor or bifunctional motoneurones. Motoneurones exhibiting depolarization during both phases of fictive locomotion (some EDB, PB, St motoneurones) were considered to be bifunctional motoneurones. EPSPs were collected for 10-20 s before the onset of MLR stimulation (control) and then for 1-2 min after the initiation of rhythmic alternating activity in flexor and extensor nerves (i.e. during fictive locomotion). EPSPs recorded between the onset of brainstem stimulation and the initiation of fictive locomotion were analysed separately. MLR stimulation was turned off and nerve stimulation continued at the same rate (recovery period). Although EPSP recovery was often examined for only 10-30 s, in some cases EPSP averages were made at 30 s intervals for up to 5 min after the end of MLR stimulation. Extracellular field potential recordings in the ventral horn were made using the same protocol.

Data analysis

EPSPs were considered to be monosynaptic if they had a central latency of < 1 ms (measured as the time between arrival of the peak of the earliest positive component of the afferent volley in the cord dorsum and the onset of the earliest upward deflection of the EPSP). In order to avoid contamination by the locomotor-dependent disynaptic component of the EPSP (Schomburg & Behrends, 1978; McCrea et al. 1995; Angel et al. 1996; Degtyarenko et al. 1998; Quevedo et al. 2000) amplitude measurements were made on the rising phase of the EPSP, at a fixed latency just before the peak (see Fig. 1) that would exclude any disynaptic component. The emergence of disynaptic excitation during locomotion also prevented a meaningful comparison of the decay phase of the monosynaptic EPSPs during control and locomotor conditions. Field potential measurements were made just before the peak of the negative deflection on field potentials with latencies of 0.6-0.9 ms. All measurements were made from averages of monosynaptic EPSPs or field potentials. Activity in a rectified, integrated ENG was used to divide the step cycle into flexion and extension phases. EPSPs evoked during flexion and extension were sorted and separate averages were calculated.

Figure 1.

Figure 1

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EPSP amplitude is depressed at the onset of locomotion

The two vertically oriented waveforms are rectified, integrated ENGs from St and Sart peripheral nerves. Their rhythmic activity, which begins shortly after the commencement of MLR stimulation (filled bar), indicates the onset of fictive locomotion. The traces to the right are high-gain intracellular records from a LGS motoneurone showing the monosynaptic EPSPs evoked by LGS nerve stimulation (1.2T, 4 Hz; every fifth EPSP is shown). On the far right are averages of the EPSPs evoked before (control) and soon after the onset of fictive locomotion. The average locomotor EPSP is depressed to 74 % of control. The arrival of the afferent volley at the cord dorsum is indicated by the filled arrow, and the point at which the EPSP measurement was made by the open arrow.

In order to determine motoneurone membrane resistance, short-duration depolarizing or hyperpolarizing constant current pulses (0.5 ms, 15-40 nA) were delivered to the motoneurone throughout the control, locomotor and recovery periods. Typically these pulses preceded peripheral nerve stimulation by 10-30 ms. The area of the resulting voltage transient was divided by the area of the current pulse to give resistance in ohms. The primary aim was to examine the changes in resistance and EPSP amplitude recorded at the same time. Some resistance measurements may have been obtained in motoneurones with a leak conductance (i.e. poor impalement) larger than that desired for absolute membrane resistance determination (see Hochman & McCrea, 1994).

Data capture and analysis were performed using software developed within the Winnipeg Spinal Cord Research Centre (a Pentium PC running QNX for data capture and QNX or Linux for analysis).

Statistical analysis

Following data analysis, means and standard deviations were calculated for EPSP amplitude, field potential amplitude and membrane resistance obtained during control and locomotor conditions. Results are expressed as means ±s.d. unless otherwise noted.

RESULTS

The amplitudes of 98 monosynaptic Ia EPSPs recorded in 69 α-motoneurones (22 flexors, 32 extensors and 15 bifunctionals) and 22 extracellular field potentials recorded in the ventral horn were compared during control and fictive locomotor conditions. EPSPs and field potentials were evoked by electrical stimulation of peripheral nerves at strengths ranging from 1.2 to 2T in the L4 to L7 segments of the spinal cord. Changes in membrane resistance were measured in 22 motoneurones with simultaneous recording of 29 EPSPs during control and fictive locomotion periods.

Group Ia monosynaptic EPSPs are depressed during fictive locomotion

Figure 1 shows 30 s of a 2 min period of data collection from a LGS motoneurone in which the LGS nerve was stimulated (1.2T) at 4 Hz. In this and all motoneurones, action potentials were blocked by intracellular diffusion of QX-314. The rhythmic alternating activity in the rectified integrated St (active during extension) and Sart (flexor) ENGs shows fictive locomotion beginning shortly after the onset of continuous MLR stimulation (indicated by the filled bar). The horizontal series of traces immediately to the right of the ENG records are homonymous Ia EPSPs recorded in this LGS motoneurone. For clarity, only every fifth EPSP that was evoked is shown. The two traces to the far right are the averages of the 58 EPSPs occurring before MLR stimulation (control) and of the 58 EPSPs occurring after locomotion began. The EPSP amplitude was reduced from the onset of and throughout fictive locomotion. The averaged control EPSP (3.8 mV) was significantly larger (P < 0.005, Student's t test) than the locomotor EPSP (2.9 mV).

To better appreciate the time course of EPSP depression, Fig. 2 shows records from the entire 120 s of data collection (480 EPSPs evoked) of the LGS motoneurone illustrated in Fig. 1. The top two traces in Fig. 2A are rectified and integrated ENGs from flexor (Sart) and extensor (SmAB) nerves. They show rhythmic activity beginning in the flexor (Sart) nerve at 17 s, shortly after the onset of MLR stimulation (represented by the filled bar). The third trace shows the DC-coupled intracellular recording from the LGS motoneurone. The expanded records in Fig. 2Aa and Ab show development of alternating activity of the flexor and extensor ENG bursts (note the rhythmic locomotor drive potential, LDP, in the motoneurone). The averaged control EPSP (n = 58) is overlaid on the average calculated throughout the entire 83 s locomotor period (n = 348) in Fig. 2B and shows a significant (P < 0.005, Student's t test) depression of the latter to 74 % of the control amplitude. For illustration purposes the amplitude of the monosynaptic EPSP is plotted as a five-point moving average immediately below the ENG and intracellular traces in Fig. 2A. As locomotor activity begins (shortly after the onset of MLR stimulation), EPSP amplitude decreases sharply from the control amplitude of 3.8 mV to an average of 2.9 mV. With the development of robust rhythmic activity in both flexor and extensor nerves (approximately 60 s into the run), EPSP amplitude falls further to 2.7 mV.

Figure 2.

Figure 2

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Group Ia monosynaptic EPSPs are depressed throughout and following periods of fictive locomotion

A, top two waveforms are rectified, integrated ipsilateral ENGs from flexor (Sart) and extensor (SmAB) peripheral nerves and the third is a DC-coupled low-gain intracellular record from the LGS motoneurone (Mn) illustrated in Fig. 1. The membrane potential is plotted as a relative voltage scale. The EPSP amplitude evoked by LGS stimulation (1.2T, 4 Hz) and measured from high-gain AC-coupled traces is plotted as a five-point moving average before (control, open bar), during (MLR on, filled bar) and after (recovery, open bar) MLR stimulation. Portions of the upper records are expanded in a and b. EPSP amplitude decreases with the onset of fictive locomotion which at first is characterized by weak extensor nerve activity (see expanded time scale in a). As rhythmic locomotor activity improves (see b) about 60 s into the data collection period, EPSP amplitude is further decreased. B, the averaged monosynaptic EPSP recorded during the control period (n = 58, 0-17 s period in A) is superimposed on that obtained during fictive locomotion (n = 348, 17-100 s). Control EPSP amplitude (3.8 mV) is 26 % larger than that during locomotion (2.8 mV). C, the small phasic modulation of the EPSP within the locomotor cycle is indicated by the similar amplitudes of EPSPs occurring during the flexion and extension phases. Lower traces in B and C are the cord dorsum recordings.

Ninety-one of the 98 (93 %) Ia monosynaptic EPSPs recorded in 69 motoneurones decreased in amplitude during locomotion. Seven EPSPs (recorded in 1 PB, 1 EDB, 2 EDL and 1 unidentified flexor motoneurone) increased in amplitude during locomotion (mean, 121 ± 17 % of control). Taking all of the observations together the amplitude of the 98 monosynaptic EPSPs investigated was significantly decreased (P < 0.001, Student's t test) from an average of 2.53 mV during the control period to 1.65 mV during locomotion. The mean of the percentage change during locomotion of each of the individual 98 EPSPs was to 70 % of control. Of the 91 depressed EPSPs the mean depression was to 66 % of control. The depression of EPSPs recorded in flexor (to 75 % of control), extensor (to 66 %) and bifunctional (to 71 %) motoneurones was similar (P = 0.34, one-way ANOVA on ranks). The case illustrated in Figs 1 and 2 was selected because the depression (to 74 %) was representative of the other 97 EPSPs examined.

Figure 3 illustrates the finding that there was no clear relationship between locomotor EPSP depression and control EPSP amplitude. Both small and large EPSPs were decreased in amplitude during locomotion. Five of the seven EPSPs that increased in amplitude during locomotion, however, had control amplitudes of less than 2 mV. After removing these seven EPSPs, control EPSP amplitudes were divided into three groups (< 2 mV, 2-4 mV, > 4 mV) and the average EPSP depression during locomotion was calculated. The largest EPSPs (> 4 mV) were depressed more (to 58 % of control) than the smallest EPSPs (depressed to 73 %, P < 0.05, one-way ANOVA on ranks and pairwise comparison, Dunn's test). The depression of those EPSPs with control amplitudes between 2 and 4 mV (to 65 %) was not significantly different from those of the neighbouring groups.

Figure 3.

Figure 3

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Relationship of control EPSP amplitude to that recorded during locomotion

EPSP amplitude recorded during locomotion (relative scale) is plotted against control EPSP amplitude (mV). Points plotted above and below the 100 % line indicate EPSPs facilitated and depressed, respectively, during locomotion.

There can be a delay between the onset of MLR stimulation and the onset of fictive locomotion. Perreault et al. (1999) have shown that extracellular field potentials recorded in the intermediate and dorsal laminae may show a depression during this period of MLR stimulation that usually becomes more pronounced as locomotion commences. In nine cases in the present study there was a substantial delay (at least 10 s) between the onset of MLR stimulation and the onset of locomotion. In only one case was EPSP amplitude decreased (to 77 % of control) with MLR stimulation before the onset of locomotion. The lack of depression before the onset of locomotion in eight out of the nine cases suggests that the depression of the monosynaptic EPSPs recorded in motoneurones is not a result of MLR stimulation per se but is inherent to the locomotor process (see Discussion).

Phasic modulation of Ia EPSPs

The phasic modulation of Ia EPSPs within the step cycle was examined by creating separate averages for EPSPs during flexion and extension. In the example in Fig. 2C, EPSP amplitudes during the flexor phase and extensor phase were similar and the EPSPs were almost superimposable. To further examine phasic EPSP depression during fictive locomotion, the ratio of EPSP amplitude recorded during the extension phase and flexion phase (extensor amplitude∖flexor amplitude) was plotted in Fig. 4 for 44 EPSPs recorded in 32 extensor motoneurones (•), 35 EPSPs recorded in 22 flexor motoneurones (○) and 19 EPSPs recorded in 15 bifunctional motoneurones (▴).

Figure 4.

Figure 4

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Phasic modulation of EPSPs during locomotion

Average amplitudes of EPSPs recorded during extension (E) and flexion (F) were calculated separately and expressed as a ratio (amplitude during extension∖amplitude during flexion). A ratio of 1.0 indicates that EPSP amplitude was equal in the two locomotor phases. This ratio is plotted against averaged control EPSP amplitude.

Of the 98 EPSPs represented in Fig. 4, 27 were larger during flexion, 37 were larger during extension and 34 were close to equal (within 5 % of each other) in the two phases. In the 35 EPSPs recorded from flexor motoneurones EPSP amplitude was larger during flexion in four cases, larger during extension in 18 cases and similar (± 5 %) for the two phases in 13 measurements with a mean ratio (±s.e.m.) of 1.17 ± 0.04. In both extensor motoneurones (13 larger during flexion, 13 larger during extension and 18 similar in the two phases; mean ratio ±s.e.m., 1.01 ± 0.05) and bifunctional motoneurones (5 larger during flexion, 5 larger during extension and 9 similar in the two phases; mean ratio ±s.e.m., 1.04 ± 0.05) EPSP amplitude depression was not consistently greater in one phase or the other. Thus, although motoneurones are subject to an active and rhythmic depolarization and hyperpolarization during fictive locomotion (Jordan, 1983), there was no simple relationship between EPSP amplitude and motoneurone depolarization.

Figure 5 shows the effects of fictive locomotion on the sample of 98 EPSPs. Data are plotted in ascending order with squares indicating the mean EPSP amplitude occurring throughout fictive locomotion. The vertical lines show EPSP amplitude modulation within the step cycle without indicating the phase in which maximum effect occurred. This figure shows that many depressed EPSPs were without phasic modulation (see also the points on unity line of Fig. 4). In most cases in which there was a phasic modulation, there was a depression in both phases (i.e. both ends of the vertical line fall below 100 %). The seven EPSPs which were facilitated during locomotion are plotted on the right (squares above 100 %).

Figure 5.

Figure 5

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Most EPSPs are reduced below control amplitude in both locomotor phases

Effects of fictive locomotion on the amplitudes of 98 EPSPs plotted from most depressed (left) to facilitated (right; points above the 100 % line). Vertical bars indicate EPSP amplitude modulation between the flexion and extension phases.

The only other comparison of Ia EPSP amplitude before and during fictive locomotion of which we are aware is a sample of unitary EPSPs recorded in four TA and two extensor motoneurones (Gossard, 1996). Unitary monosynaptic EPSPs evoked during the phase in which the motoneurone was depolarized were larger than control EPSPs which were in turn larger than EPSPs evoked when the motoneurone was hyperpolarized (Gossard, 1996). In the present study we found that eight of the nine composite EPSPs recorded in five TA motoneurones (evoked by homonymous and heteronymous nerve stimulation) were depressed during locomotion. Of these eight EPSPs, four were larger during extension (mean, 12 ± 4 %), one was larger during flexion (17 %) and three were similar (within 5 %) in the two phases. In no case was the EPSP recorded in a TA motoneurone larger during one of the phases of locomotion than in control. As shown in Fig. 5 EPSP amplitude facilitation (above control) in any phase of the step cycle occurred in only 12 out of 98 cases. These results on composite EPSPs thus differ from those for unitary EPSPs (Gossard, 1996).

Recovery of EPSP amplitude following locomotion is delayed

As illustrated in Fig. 2A, EPSP depression did not recover immediately following locomotion. In the short recovery period (10-20 s) examined in the majority of recordings, recovery to control EPSP amplitude was usually incomplete. Therefore to better estimate the time course of monosynaptic EPSP amplitude recovery, recordings of 11 EPSPs in nine motoneurones were made for up to 5 min after locomotion. An example is illustrated in Fig. 6. As in previous figures, the upper two traces are ENG records from flexor (Sart) and extensor (LGS) peripheral nerves. The graph shows the averaged amplitude of an EPSP in a LGS motoneurone evoked by medial gastrocnemius (MG) nerve stimulation over a 4 min period. EPSP amplitude decreased slightly at the onset of locomotion and this depression became greater as extensor activity was established. The membrane potential of this motoneurone returned to the pre-locomotor control value immediately following locomotion (not illustrated). Full recovery of the EPSP did not occur until 2 min after the cessation of locomotion. This example is similar to the observations summarized in the first row of Table 1. The mean recovery time of the 11 EPSPs examined was 114 s. By 3 min, only six out of the 11 EPSPs had recovered to within 5 % of the pre-locomotor (control) amplitude (Table 1). Even after 5 min, three EPSPs had not fully recovered (i.e. remained depressed by more than 5 % of their control amplitude). The fastest recovery time of these 11 EPSPs was within 10 s after the end of locomotion.

Figure 6.

Figure 6

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Prolonged recovery of monosynaptic Ia EPSP amplitude after locomotion

Averaged amplitude (± s.e.) of a Ia EPSP recorded in a LGS motoneurone and evoked by 1.4T stimulation of the MG nerve (4 Hz) before (control), during (MLR on) and after (recovery) MLR stimulation. MLR stimulation produces fictive locomotor activity in ipsilateral flexor (Sart) and extensor (LGS) peripheral nerves that stops soon after stimulation is terminated. Recovery of EPSP amplitude takes 2 min.

Table 1.

Recovery times of EPSPs and extracellular field potentials.

Time to recovery following locomotor activity (s)
No. of measurements No. depressed during locomotion 0–59 60–119 120–179 180–239 240–300 >301
EPSPs 11 11 2 2 2 1 1 3
Feild potentials (ventral roots intact) 17 16 1 4 4 4 1 2
Field pontentials (ventral roots cut) 5 5 2 2 1 0 0 0
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Depression of group I field potentials during locomotion

Changes in the amplitude of monosynaptic field potentials evoked by group I strength stimulation of peripheral nerves recorded in eight locations within the ventral horn of the spinal cord were also examined. An example of the depression during locomotion and recovery of a group I field potential is illustrated in Fig. 7. Figure 7B shows averaged field potential traces evoked by stimulation of the PB nerve (1.2T, 4 Hz) throughout and after the period shown in Fig. 7A. Each trace is an average of 40 field potentials (i.e. over a 10 s period) except for the last one, which is an average of 32 field potentials. The control field potential amplitude was 0.67 mV. At the onset of locomotion it decreased and remained around 0.41 mV until well after locomotion ceased, not recovering until 100-130 s after locomotion (220-250 s after the start of the run).

Figure 7.

Figure 7

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Locomotor depression of group I extracellular field potentials

A, top two traces show alternating activity in rectified, integrated ENGs from extensor (SmAB) and flexor (Sart) nerves during a bout of MLR-evoked fictive locomotion. The third trace is the DC-coupled recording (4 Hz low-pass filtered) from a microelectrode located in the ventral horn. During fictive locomotion there is a 2.1 mV negative shift in the extracellular potential, which returns to baseline levels 15 s after the end of locomotion. The PB nerve was stimulated at 1.2T at 4 Hz continuously. B, PB-evoked field potentials for the corresponding periods in A. Each field potential is the average of 40 sweeps (except the last, which is an average of 32). Field potential amplitude is reduced from 0.68 to 0.41 mV (to 60 % of control) at the onset of locomotion and remains depressed after the recovery of the extracellular DC potential. Field potential amplitude recovers 100-130 s after the cessation of locomotion (220-250 s after the beginning of the run). These field potentials were recorded in a preparation with intact ventral roots.

Interpretation of ventral horn field potentials is potentially complicated by the presence of antidromically or orthodromically generated motoneurone spikes that could detract from an assessment of the orthodromic (Ia EPSP) depolarization of motoneurones. Electrode position and stimulus intensity were adjusted to reduce this complication (see Methods) but in addition, we compared the control field potential amplitude to that recorded immediately after the end of locomotion. This analysis (17 fields) allowed measurement of the field potential without fluctuating antidromic activation. During locomotion, 16 out of 17 fields were reduced (mean depression to 73 ± 8 % of control) and one was unaffected. The recovery times of the field potentials are summarized in Table 1. Fourteen of the 16 field potentials that were depressed during locomotion recovered to control amplitudes within 5 min, with a mean recovery time of 108 s. The fastest field potential recovery time was within 20 s of the end of locomotion.

In a further attempt to assess the depression of orthodromic field potentials during locomotion, in one experiment the L7 ventral root was cut to abolish antidromic activation of motoneurones. All five field potentials recorded in two locations within the L7 segment were depressed during locomotion (mean depression to 70 ± 6 % of control). The mean recovery time of these five field potentials was 108 s. In summary, 21 out of 22 ventral horn field potentials evoked by stimulation of group I afferents were depressed during locomotion (to 72 % of control). Both the magnitude of depression and the time to recovery were similar to the effects of fictive locomotion on intracellularly recorded group Ia monosynaptic EPSPs.

Since extracellularly recorded DC potential shifts have been shown to be linearly related to changes in extracellular K+ concentration (Jimenez et al. 1984), changes in the extracellular microelectrode DC recording were also analysed. Figure 7A shows that at the onset of rhythmic activity there is a negative shift in the extracellular recording of 2.1 mV. At the end of rhythmic activity the DC potential returns to its pre-locomotor level within 15 s. Twelve out of 13 extracellular field potentials in which DC potential was recorded displayed a negative shift (mean, 1.9 ± 0.5 mV) at the onset of locomotion which returned to baseline shortly after the cessation of locomotion. The more rapid recovery of the extracellular DC potential after locomotion suggests that changes in extracellular K+ concentration are not entirely responsible for prolonged field potential depression (see Discussion in Duenas & Rudomin, 1988).

Motoneurone membrane resistance decreases during locomotion

In order to evaluate the relationship between EPSP depression and changes in motoneurone membrane resistance during locomotion, intracellular current pulses were delivered in 22 motoneurones 10-30 ms before the peripheral nerve was stimulated to evoke the Ia EPSP. The area of the resulting voltage transient was used to calculate membrane resistance. In the control period mean motoneurone membrane resistance was 0.77 ± 0.54 MΩ (0.37-2.37 MΩ). During locomotion the resistance was significantly decreased (P < 0.01, Student's t test) to 61 % of control, to a mean of 0.47 ± 0.35 MΩ (0.15-1.45 MΩ). In all but two motoneurones, membrane resistance decreased. The relationship between decreased membrane resistance and decreased EPSP amplitude can be seen in Fig. 8 in which the change in amplitude of the 29 EPSPs recorded from the 22 motoneurones during locomotion is plotted against the change in motoneurone membrane resistance. While decreases in membrane resistance were often associated with decreases in EPSP amplitude (r2= 0.31), the overall relationship was weak with considerable scatter.

Figure 8.

Figure 8

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Weak correlation between EPSP amplitude and motoneurone membrane resistance during locomotion

EPSP amplitude and motoneurone membrane resistance values measured during fictive locomotion, expressed as a fraction of control values.

Mean motoneurone membrane resistance was not significantly different (P = 0.2, Student's t test) between the two locomotor phases. The phasic modulation of motoneurone membrane resistance was analysed to examine whether phasic changes in EPSP amplitude were paralleled by changes in motoneurone membrane resistance. In only 10 out of 29 cases were EPSP amplitude and membrane resistance phasically modulated in the same direction (i.e. smaller EPSP amplitude in the phase with the lowest membrane resistance).

In order to further investigate the relationship between motoneurone membrane resistance and EPSP amplitude decreases during fictive locomotion, the recovery times of membrane resistance and EPSP amplitude were compared. In general there seemed to be little relationship between the two processes. In 10 out of 16 cases EPSP amplitude recovered before motoneurone membrane resistance returned to control values. Although the motoneurone membrane resistance decreases during locomotion, the weak relationship illustrated in Fig. 8 and the lack of a relationship between EPSP recovery and membrane resistance recovery suggest that increased motoneurone conductance is not the major factor producing Ia EPSP amplitude decreases during locomotion.

DISCUSSION

The main finding in this study is that the amplitude of the group Ia monosynaptic EPSP in hindlimb motoneurones is decreased during fictive locomotion in the decerebrate cat. Most (91∖98) EPSPs were decreased in amplitude during locomotion with a mean depression to 70 % (n = 98) of the control amplitude. As will be argued, this depression is most probably the result of a presynaptic inhibition of transmitter release from Ia afferents. The facilitation of seven EPSPs suggests that there may be an active suppression of some EPSPs in decerebrate preparations that is inhibited during fictive locomotion. EPSP depression occurs at the onset of locomotion and persists beyond the cessation of locomotor activity, taking on average close to 2 min to return to the control amplitude. In some cases phasic variations in EPSP depression during flexion and extension were superimposed on this tonic reduction. Typically, the phasic modulation was small but when present maximal EPSP amplitude occurred with equal frequency during flexion and extension. Similar observations were made on extracellular field potentials with 21∖22 field potentials decreasing in amplitude during locomotion to an average of 72 % of control. These results are similar to the depression of group I field potentials recorded in the intermediate nucleus during fictive locomotion (Perreault et al. 1999). The similar depression of ventral and intermediate field potentials argues for a locomotor-specific presynaptic effect when populations of afferents are considered. The present results do not rule out the possibility of selective presynaptic actions on individual and∖or subsets of fibres from a given nerve (see Rudomin & Schmidt, 1999). The present experiments are the first to demonstrate that group I monosynaptic EPSPs are depressed at the onset of fictive locomotion and that this depression continues throughout and persists after locomotion. This finding differs from that of Shefchyk et al. (1984). Their illustrations show two EPSPs slightly modulated during locomotion around the control amplitude. This occurred rarely in the present study (see Fig. 5).

Noga et al. (1992) demonstrated in anaesthetized animals that stimulation of brainstem regions that evoke locomotion in the decerebrate preparation can depress transmission from group II afferents and, to a lesser extent, group I afferents. It is, therefore, possible that stimulation in and around the MLR could depress EPSPs and this depression could be unrelated to locomotion per se. The fact that in eight of the nine cases in which there was a delay between the start of brainstem stimulation and locomotion, EPSP amplitude was not reduced until locomotion began, suggests that EPSP depression is due to processes related to the initiation and maintenance of locomotion rather than simply MLR stimulation. Thus, data from the present and a previous study (Perreault et al. 1999) argue strongly against the suggestion (Misiaszek et al. 2000) that locomotor-related presynaptic inhibition is not derived from the central pattern generator. It would be useful, however, to also examine Ia EPSPs during spontaneous locomotion without brainstem stimulation in other preparations.

Contribution of pre- and postsynaptic mechanisms to EPSP depression

The finding of a decreased group I monosynaptic EPSP amplitude during fictive locomotion by itself does not necessarily indicate a presynaptic site for the inhibitory process. Shefchyk & Jordan (1985) observed that motoneurone membrane resistance was reduced during MLR-evoked fictive locomotion in almost half of the motoneurones studied. In the present study membrane resistance decreases occurred in almost all motoneurones in which the monosynaptic EPSP was decreased. The present use of short-duration current pulses, which may be more sensitive for determining membrane resistance changes, may account for the greater incidence of resistance decrease reported here. The average membrane resistance decrease to 61 % of control no doubt accounts for some of the depression of the Ia monosynaptic EPSP during locomotion. Analysis of membrane resistance changes in the flexion and extension phases, however, suggests that decreases in membrane resistance are only a partial explanation for EPSP amplitude depression. For example, in 19 out of 29 cases the smaller EPSP amplitude occurred in the locomotor phase in which membrane resistance was higher, i.e. in the phase in which the passive membrane properties should have contributed to a larger EPSP amplitude. In most cases analysed (10 out of 16), EPSP amplitude returned to control levels following locomotion before membrane resistance. It is evident in Fig. 8 that decreases in membrane resistance are only weakly correlated with decreases in EPSP amplitude (r2= 0.31). Using modelled data, Clements et al. (1987) suggested that postsynaptic conductance must increase at least 10-fold to account for their observed decreases in monosynaptic EPSP amplitude following conditioning stimuli. Similar results were obtained from a simulation by McCrea et al. (1990) who calculated that a 20 % decrease in membrane resistance decreased EPSP amplitude by only 4 % (see also Segev et al. 1990). Monosynaptic EPSPs are not generated in the electrotonically most distal dendritic compartments (see Segev et al. 1990) and it is unlikely, therefore, that the present use of somatic current injection to assess motoneurone membrane resistance would have missed detection of conductance changes sufficiently large to result in the EPSP depression found during fictive locomotion. Thus, decreases in motoneurone membrane resistance may contribute to, but are unlikely to fully account for, EPSP depression. Field potentials should not be greatly affected by changes in motoneurone membrane resistance since they largely reflect a change in the flow of synaptic current and not changes in intracellular membrane potential (see Perreault et al. 1999). The concomitant depression of EPSPs and field potentials is another strong argument for a pre-motoneuronal locus of the EPSP depression during locomotion.

If decreases in motoneurone resistance are unlikely to account for monosynaptic EPSP depression, then a decrease in the efficacy of synaptic transmission from primary afferent terminals to the motoneurone is likely. This could be due to either a modulation of the postsynaptic transmitter receptor channels or a presynaptic reduction of the amount of transmitter released. It has been shown in the hippocampus that ion channel phosphorylation increases synaptic current transmission through glutamate channels and dephosphorylation reduces transmission (see Smart, 1997). It has yet to be demonstrated that there is a similar process operating on the channels responsible for spinal cord Ia EPSPs. Thus it remains an open question whether this mechanism could decrease both field potential and EPSP amplitude during locomotion.

Increased extracellular K+ levels produced by repetitive activation of interneurones in the vicinity of primary afferent terminals may produce PAD (e.g. Krnjevic & Morris, 1974). Jimenez et al. (1984) demonstrated that a 1 mV DC shift indicates a 1 mmol l−1 change in extracellular K+ concentration. In the present experiments, extracellular K+ concentration was assessed indirectly by looking at the extracellular DC potential (cf. Jimenez et al. 1984). In 12 out of 13 cases the DC potential became more negative (mean, 1.9 mV) soon after the initiation of locomotion and returned to pre-locomotor levels within 12 s after cessation of locomotion. Although this finding suggests that an increase in extracellular K+ (Duenas & Rudomin, 1988) occurred, the extracellular K+ accumulated too slowly (see Fig. 7) and returned to control levels too quickly following locomotion to be the primary mechanism for the Ia monosynaptic EPSP depression.

Using intra-axonal recording, Gossard and co-workers (Gossard et al. 1991; Gossard, 1996) found a phasic depolarization of group I afferents during locomotion with a maximum depolarization during flexion and a smaller depolarization during extension. If this phasic PAD were responsible for the decrease in monosynaptic EPSP amplitude observed in the present experiments, it would follow that Ia EPSPs should be larger during the extension phase (minimal PAD). This was not the case and there was no consistent phasic EPSP modulation (see Fig. 4). Similar observations on the lack of a preferential EPSP depression in one of the phases of locomotion have been reported by Angel et al. (1996) and Shefchyk et al. (1984). The reasons for this dissociation between the pattern of PAD recorded from single axons in the dorsal columns and depression of synaptic transmission (i.e. EPSP depression) during locomotion remain unknown.

Our findings on the variability of the phase in which the largest EPSP depression occurs support Gossard's (1996) conclusion that the locomotor-related PAD does not account for the phasic modulation of Ia monosynaptic EPSPs. However, our findings from a large sample of composite EPSPs (see Fig. 4) are in conflict with the report of the largest unitary EPSP occurring in the active phase of the motoneurone (Gossard, 1996). While we have no satisfactory explanation for this discrepancy, the possibility of a differential pattern of PAD acting on individual afferents or a sampling bias cannot be ruled out.

There is strong evidence for the involvement of GABA in the presynaptic inhibition of transmission from muscle afferents in the mammalian spinal cord (see Rudomin & Schmidt, 1999). One explanation for the long recovery time of monosynaptic EPSPs and field potentials could involve the activation of the GABAB subtype of the GABA receptor during fictive locomotion. Sensory-evoked presynaptic inhibition of group I afferents is widely believed to be mediated by GABA acting on both GABAA and GABAB receptors (Curtis, 1998). The GABAA receptor actions on group Ia afferents are ionotropic and depolarizing and occur quickly while the GABAB receptor actions are metabotropic (Alford & Grillner, 1991). GABAB actions decrease the duration of primary afferent action potentials without evoking PAD (Curtis & Lacey, 1998). Recovery from GABAB actions is prolonged (Jimenez et al. 1991; Curtis et al. 1997) and GABAB receptor activation depresses both monosynaptic Ia EPSPs (Lev-Tov et al. 1988) and stretch reflexes (Capaday, 1995).

A reasonable hypothesis that emerges from these observations is that the central locomotor circuitry releases GABA which then acts on different receptors or receptor subtypes. One of these mechanisms evokes a tonic presynaptic inhibition of transmitter release from Ia afferents. This is analogous to the actions of the GABAB receptor agonist baclofen. The other presynaptic mechanism (possibly mediated by GABAA) is presumably ionotropic and produces the phasic PAD and phasic increase in fibre excitability (Duenas & Rudomin, 1988) observed during fictive locomotion. The existence of multiple mechanisms underlying the reduction of synaptic transmission from primary afferents during locomotion could account for the discrepencies reported between the patterns of PAD in Ia afferents and the phasic modulation of EPSP amplitude (Gossard, 1996). An assessment of the relative contributions of PAD and other mechanisms to Ia EPSP depression during fictive locomotion must, however, await further study.

Physiological implications of EPSP depression

It is interesting the note the parallels between the depression of monosynaptic EPSPs reported here in decerebrate cats during fictive locomotion and the depression of the monosynaptic (H) reflex in man during walking (Voigt et al. 1998). In both cases, the reflex effects of group Ia afferents are depressed with the onset of locomotion and remain depressed in some cases for several minutes after locomotion. A recent study found that reflexes evoked during and immediately after a period of locomotion were similar in amplitude (Misiaszek et al. 2000). This similarity was the basis for the suggestion that the CPG does not produce a presynaptic inhibition of transmission from Ia afferents (Misiaszek et al. 2000). We believe that because of the prolonged EPSP and reflex depression following locomotion, this conclusion is incorrect. We suggest that a tonic EPSP depression is also responsible for the tonic depression of stretch reflexes during locomotion in the decerebrate cat (Bennett et al. 1996). The depression of the stretch reflex (Bennett et al. 1996) suggests that EPSP depression more than counters the increased motoneurone excitability occurring during locomotion (Brownstone, 1992, 1994; Krawitz et al. 1997). The lack of a consistent phasic modulation of composite EPSP amplitude suggests that cyclic changes in monosynaptic or stretch reflexes (Akazawa et al. 1982; Capaday & Stein, 1986; Faist et al. 1996) during locomotion are not due to a cyclic presynaptic inhibition of transmission from Ia afferents. Similar conclusions have been reached by others (Shefchyk et al. 1984; Gossard, 1996; Ménard et al. 1999; but see Yang & Whelan, 1993). A full understanding of the control of group I reflexes during locomotion will require consideration of the relative contribution of changes in presynaptic transmitter release, motoneurone excitability and the emergence of disynaptic excitation.

Acknowledgments

The authors would like to thank Sharon McCartney for her expert technical assistance. This study was supported by the Medical Research Council of Canada. J. Quevedo was supported by the Rick Hansen Man in Motion Legacy Fund and the Manitoba Neurotrauma Initiative. B. Fedirchuk received support from the Manitoba division of the Canadian Paraplegic Association.

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