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Integrative |
1 Department of Physiology, University College London, Hampstead Campus, London NW3 2PF, UK
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Abstract |
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(Received 25 October 2005;
accepted after revision 4 January 2006;
first published online 5 January 2006)
Corresponding author M. P. Gilbey: Department of Physiology, University College London, Hampstead Campus, London NW3 2PF, UK. Email: m.gilbey{at}ucl.ac.uk
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Introduction |
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Data from in vitro studies have demonstrated that NMDA and 5-HT can cause single neurones (conditional pacemakers) and neuronal networks to generate rhythmic activity (Arshavsky, 2003), i.e. fictive locomotion generated following activation of NMDA receptors (Alford et al. 2003) and/or 5-HT receptors (Schmidt & Jordan, 2000); fictive sucking and mastication subsequent to activation of NMDA receptors (Nakamura et al. 2004a); rhythmical activity in sympathetic preganglionic neurones (Pickering et al. 1994) and fictive respiratory activity in the pre-Bötzinger complex (Peña & Ramirez, 2002) elicited by 5-HT receptors. Attempts to pharmacologically generate rhythmic neural activity in vivo are less common and have focused on locomotor outflows. Such studies show that intrathecal (I.T.) administration of NMDA consistently elicits fictive locomotion in decerebrate neuromuscularly blocked adult cats and marmoset monkeys, similar to that evoked by electrical stimulation of the mesencephalic locomotor region (Douglas et al. 1993; Fedirchuk et al. 1998). In comparison, 5-HT is less effective (Fedirchuk et al. 1998).
In the present study we aimed to generate a physiological sympathetic motor rhythm in an in situ‘isolated’ spinal cord preparation (anaesthetized rats spinalized at T10–T11 and cauda equina cut) by the I.T. application of NMDA and/or 5-HT. For this purpose, we used a rat tail circulation model (Johnson & Gilbey, 1994). In anaesthetized intact preparations, we have observed robust rhythmicity in single and population postganglionic neuronal discharges supplying the rat tail circulation (T-rhythm, 0.40–1.20 Hz; Johnson & Gilbey, 1996; Smith & Gilbey, 2000). We have proposed that rhythmic activity arises from a family of weakly coupled or uncoupled oscillators that can be reset or entrained by various synaptic inputs (Chang et al. 1999, 2000; Staras et al. 2001). We have yet to identify the nervous substrate(s) that generates the T-rhythm, although we have evidence that it is generated within the CNS below the collicular level (Smith & Gilbey, 2000; Collins & Gilbey, 2003). The sympathetic preganglionic neurones driving SNAT receive vital inputs from neurones within the rostral ventromedial medulla (RVMM) (Rathner et al. 2001; Tanaka et al. 2002; Korsak & Gilbey, 2004; Ootsuka et al. 2004; Ootsuka & Blessing, 2005; Ootsuka & McAllen, 2005), some of which contain 5-HT and/or v-glut3 transporter (Smith et al. 1998; Nakamura et al. 2004b). Here we test the hypothesis that the T-rhythm can be generated within the spinal cord and can be driven by 5-HT and/or NMDA. Some of the data have been published previously in abstract form (Marina & Gilbey, 2005a,b).
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Methods |
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Experiments were performed on 18 male Sprague–Dawley rats (280–320 g, bred in-house at UCL) and carried out in accordance with the UK Animals (Scientific Procedures) Act 1986 and associated guidelines. Animals were anaesthetized with 20% urethane (1.3 g kg–1I.P., supplemented with 5–10 mg I.V. as required). The depth of anaesthesia was monitored using stability of blood pressure, corneal reflexes and flexor responses to paw-pinch. Animals were neuromuscularly blocked before spinal cord transection (SCT) with a single dose of Pancuronium Bromide (Pavulon, Faulding Pharmaceuticals, plc, Warwickshire, UK; 1 mg kg–1I.V.). During this period (approximately 30 min) the depth of anaesthesia was assessed from the stability of blood pressure and heart rate.
The trachea was cannulated and tracheal pressure was monitored. Animals were vagotomized and ventilated artificially with O2-enriched air. The right femoral vein and artery were cannulated to allow I.V. administration of drugs and monitoring of mean blood pressure (MABP), respectively. Animals were maintained in central apnoea so that the T-rhythm would not be entrained to central respiratory drive (CRD; Chang et al. 1999). Central apnoea was induced by hyperventilation hypocapnia and was monitored by recording the diaphragmatic EMG. Blood gases were kept in the following ranges throughout the whole experiment: pH 7.50 ± 0.08 (range 7.38–7.63), PO2 141 ± 9.3 (range 122–159), PCO2 22.7 ± 5.9 (range 14–31). MABP was 108 ± 12 mmHg (range 102–113 mmHg). No significant changes in blood gases or MABP were detected under any experimental condition (P > 0.05). The bladder was cannulated to allow free flow of urine. Core temperature was maintained at 36.0–36.5°C using a thermostatically controlled heating blanket and was monitored using a thermocouple inserted into the colon.
Lumbar I.T. catheterization
Animals were fixed in a stereotaxic head-frame. The lower lumbar vertebrae were exposed and the L4 spinous process was clamped. The animal was made slightly kyphotic by gently lifting the clamp attached to the vertebra. The left inferior articular facet corresponding to L4 was removed and the ligamentum flavum incised. The dura was punctured with a 23 G x 11/4 in needle. Cerebrospinal fluid outflow indicated a subarachnoid position. A 32 G PU catheter (10 cm long, o.d. 0.0107 in and i.d. 0.005 in; Micor, Allison Park, PA, USA), reinforced with a Teflon-coated stainless steel stylet (0.003 in), was advanced rostrally (4.3 cm) through the needle (Pogatzki et al. 2000). The tip of the catheter was positioned at L1, as sympathetic preganglionic neurones supplying the tail circulation are distributed in the intermediolateral cell column between T11 and L2 and concentrated in L1–L2 (Smith & Gilbey, 1998). The needle was then removed and cyanoacrylate (Loctite superglue) was used to fix the catheter to the fascia.
In situ‘isolated’ spinal cord preparation
The preganglionic neurones regulating SNAT were isolated from descending inputs by transecting the spinal cord between T10 and T11. Afferent and somatomotor axons arising from spinal segments below L5 were sectioned by cutting the cauda equina at the level between vertebrae L5 and L6 (see Supplemental Material).
The lower thoracic and lumbar vertebrae were exposed. The synovial ligaments between T9 and T10 and between L5 and L6 were cut, and the right and left facet joints were removed. Rats were neuromuscularly blocked and the cord and the cauda equina were transected. Bleeding was minimal and the cavity was packed with moist cotton wool.
Electrophysiological recording and data acquisition
Activity was recorded from the left dorsal collector nerve (DCN) as an index of SNAT. DCNs contain both sympathetic and somatic motor axons. However, only sympathetic activity was recorded from these nerves as somatomotor innervation of the tail had been decentralized (i.e. somatomotor efferents sectioned) by cutting the cauda equina (see Smith et al. 1998 and Supplemental Material). Population sympathetic activity was recorded using a suction electrode (Huang & Gilbey, 2005). The nerve was cut, desheathed and drawn into the electrode by applying negative pressure. Nerve activity was recorded through a high impedance headstage (NL 100, Neurolog; Digitimer Ltd, UK), preamplified (x 20000; NL 104, Neurolog), filtered (80–1000 Hz; NL 25, Neurolog) and amplified (x 20). Nerve activity was then rectified and smoothed with a time constant of 100 ms (NL 703, Neurolog).
Nerve discharges, blood pressure, tracheal pressure and diaphragmatic EMG were monitored continuously on an IBM compatible computer (Dell, UK) using a 1401 plus interface and Spike2 software (Cambridge Electronic Design, UK) and digital storage oscilloscopes (VG-6023, Hitachi, Japan). For offline analysis nerve activity (prior to rectification and smoothing) and pressure signals (only for recording on tape) were sampled at approximately 11 kHz and stored on videotape and/or as a Spike2 data file. The sympathetic efferent nature of 5-HT or NMDA-induced nerve activity was confirmed in each experiment by its abolition following ganglionic blockade with trimetaphan camsylate (Cambridge Laboratories Limited, UK; 50 mg kg–1I.V.) (see Chang et al. 1999 and Supplemental Material).
Experimental protocols
I.T. injections were performed using a 50 µl Hamilton syringe. Drugs were delivered with a microinjection pump (kd Scientific, model 100) at 120 µl h–1 (10 µl followed by 2 µl of physiological saline). Sixty minutes after SCT, one of the following protocols was pursued: Experiment 1: DCN activity was monitored for 4 h without any further intervention (n= 3). Experiment 2: Animals received either 250 nmol of 5-HT (serotonin hydrochloride (Aldrich) pH 4.8, or serotonin creatinin sulphate complex (Sigma) pH 3.1, dissolved in physiological saline (n= 6)). Experiment 3: Animals received 1 µmol of NMDA ((Tocris) pH 3.0, dissolved in artificial cerebrospinal fluid (n= 3)). Experiment 4: Animals received 1 µmol of NMDA, and 30 min later, 250 nmol of 5-HT (n= 6). A further dose of 5-HT (250 nmol, I.T.) was administered 30 min after 5-HT-induced rhythmic activity had subsided. Data were pooled as similar results were obtained with both types of serotonin. The systemic administration of 5-HT (250 nmol I.V., n= 4) and the I.T. application of artificial cerebrospinal fluid or saline at pH 3 or 4.8, respectively, in spinalized animals did not have any effect on DCN activity. The doses of 5-HT and NMDA were the same as those used in other studies (Yusof & Coote, 1988; Chau et al. 2002). At the end of the experiments, animals were killed with an overdose of urethane. The location of the I.T. catheter and the completeness of SCT were verified.
Data analysis
Data were divided into 300 s sets. MABP was calculated in each set (diastolic +1/3(systolic – diastolic)). DCN mean levels of activity were assessed for each data set following smoothing with a time constant of 10 s (Spike 2 software). Drug-induced changes in mean level of activity were normalized with respect to the pretransection level (100%). Zero was taken as that seen following SCT. Latency and duration of response were taken at the points where mean level of activity started to increase or returned to zero, respectively.
The frequency of the T-rhythm was assessed using frequency domain analysis. Data files were converted into text files and analysed using Matlab computer software (Maths Works). Dominant rhythm was assessed for each data set of rectified and smoothed activity (time constant 100 ms, sampled at 100 Hz). Fast Fourier transformation (FFT; size 2048, 50% overlap) was then performed. This divided the data sets into 28 half-overlapped 20.48 s long subsections with 2048 data points in each, giving a frequency resolution of 0.049 Hz. DC components and linear trends were then removed from the subsections. An autospectrum was averaged from these 28 subsections according to the Welch Method (see Chatfield, 1996). A dominant peak was allocated to an autospectrum where the envelope of spectral density that the peak was associated with, increased by more than 50% over six bins (0.3 Hz; see Smith & Gilbey, 2000).
Time-evolving autospectra were generated to examine temporal changes in DCN activity. The time-evolving spectrum was plotted as frequency against time (sequential data set number). Data were divided into 300 s subsections, and spectral analysis was performed on each subsection as described above. The absolute power density was normalized by its maximal value across time and its magnitude was then coded using a 64-grade colour scale. Changes in the colour scale represent the change of the power density across the recording time and the frequency range (see Chang et al. 1999).
Statistical analysis
Only those animals that displayed robust rhythmic discharges for 30 min in intact conditions were considered for statistical comparisons. All data sets with rhythmic activity were included in the analysis. Values for dominant frequency and percentage power in the dominant peak were averaged in each condition. The development of 5-HT-induced rhythmic activity was assessed by plotting the mean frequency with respect to its corresponding mean level of activity at five specific data sets: (1) after SCT, (2) first data set with robust rhythmicity, (3) highest mean level of activity, (4) last data set with rhythmicity and, (5) no rhythmicity. Results are expressed as mean ±S.E.M. One-way ANOVA was used to assess statistical significance in frequency between data sets; P values < 0.05 were considered significant.
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Results |
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As observed previously (Chang et al. 1999), DCN activity in intact animals displayed robust rhythmic discharges with variable frequency and amplitude (Figs 1 and 2; A and B). Frequency domain analysis showed a band in the time evolving autospectrum and a dominant peak in the power spectrum at 0.77 ± 0.02 Hz (n= 16/18, see Figs 1 and 2; D and E). In some cases, a lung inflation cycle-related component at 2 Hz was also observed (n= 11/18 see Figs 1 and 2; D and E). DCN autospectra did not reveal rhythmic components in 2 of 18 experiments.
Effect of SCT
SCT abolished SNAT (Fig. 1A and B; n= 18); the mean level of activity was similar to that observed after ganglionic blockade or neuronal death (i.e. zero level, Fig. 1C). Three animals were monitored for 4 h and no spontaneous recovery of SNAT was observed.
Effect of 5-HT on SNAT. Application of 5-HT (250 nmol, I.T.) 60 min after SCT induced robust rhythmic discharges (see Fig. 1A and B; n= 6). The latency was 5.3 ± 0.6 min (range 2–7 min) and the duration was 103 ± 12.6 min (range 55–145 min; see Fig. 1C). T-like rhythm frequencies showed two phases that were correlated with the changes in the mean level of activity. In the ‘accelerating’ phase, the mean level of activity increased and activity became rhythmic. The first data set with robust rhythmicity (see Fig. 1D and E, triangle) showed a band and a dominant peak in the autospectrum at 0.86 ± 0.04 Hz with its first harmonic peak at 1.72 ± 0.08 Hz (Fig. 3A) and had a mean level of activity of 57.3 ± 28.6% (range 4.1–135%, Fig. 3A); the highest mean level of activity induced by 5-HT was 174 ± 67.7% and showed a band and a dominant peak in the autospectra at 0.88 ± 0.04 Hz with its first harmonic peak at 1.76 ± 0.08 Hz (Fig. 3A, see also Fig. 1D and E, square). In 4 of 6 animals, the highest level of activity induced by 5-HT was lower than the level observed in the intact condition; in 2 of 6 animals, the level was higher (range 60.8–340%, see Fig. 1C). In the ‘decelerating’ phase, the frequency of the T-like rhythm slowed (see Fig. 1D) as the mean level of activity decreased (see Fig. 1C); the last data set with rhythmicity (see Fig. 1C–E, diamond) showed a band and a dominant peak in the autospectra at 0.65 ± 0.05 Hz with its first harmonic peak at 1.30 ± 0.10 Hz (Fig. 3A) and had a mean level of activity of 44.9 ± 25.2% (range 4–138%). This frequency was significantly slower than the frequency seen in the first data set with rhythmicity; however, the mean level of activity was similar in both data sets (Fig. 3A). No rhythmic components were seen in the following data set (see Fig. 1C–E, circle) where the mean level of activity was 42.2 ± 19.4% (range 4–132%; Fig. 3A). In all the cases, nerve activity ceased 10–15 min later and returned to SCT level. In all the cases, nerve activity ceased 10–15 min later. This suggests that rhythmogenic mechanisms dissipate slowly and the rhythm becomes weaker until it can no longer be detected at a population level.
Effect of NMDA on SNAT. In contrast, NMDA application (1 µmol I.T.) generated an irregular tonic activity (Fig. 2A and B, n= 9). We did not observe rhythmic discharges in the frequency range obtained with 5-HT (see Fig. 2D and E), even though a significant difference was not detected in the mean levels of activity induced by both drugs (compare Fig. 3A and B). The latency was 2.8 ± 1.3 min (range 1–5 min); the highest mean level of activity (see Fig. 2C, circle) was 99.1 ± 26% (Fig. 3B). In 4 of 9 animals, the highest level of activity induced by NMDA was lower than the level observed in the intact condition; in 5 of 9 animals, the level was higher (range 17–157%). The highest level of activity was sustained for a few seconds and then dropped to 31.4 ± 9.9%, i.e. stable mean level of activity (range 12–69%; Fig. 3B; see also Fig. 2C, square). Three animals were monitored for 4 h with no further manipulation; activity was sustained and remained stable, but no rhythmic components were seen on the DCN autospectra.
Effect of 5-HT applied after NMDA. In six experiments 5-HT (250 nmol, I.T.) was applied 30 min after NMDA-induced tonic activity had stabilized; mean level of activity remained unchanged after 5-HT administration but tonic activity became rhythmic (see Fig. 2A–C). The latency was 26.4 ± 9.7 min and the duration was 18 ± 4.7 min (range 5–30 min). The first data set with rhythmicity (see Fig. 2D and E, triangle) showed a band and a dominant peak in the autospectra at 0.98 ± 0.13 Hz (Fig. 3B) and coincided with the highest mean level of activity induced by 5-HT (77 ± 27.9%, range 26.9–169%, Fig. 3B); the last data set with rhythmicity (see Fig. 2D and E, diamond) showed a dominant peak in the autospectra at 0.94 ± 0.10 Hz (Fig. 3B) and had a mean level of activity of 65.1 ± 29.8% (range 5.92–197%). Rhythmic discharge frequencies in the first and the last segments were not significantly different. Following the cessation of rhythmic activity SNAT returned to the irregular tonic state (see Fig. 2D and E, square).
In all the cases, it was possible to initiate sequences of rhythmic activity by performing further applications of 5-HT. The frequencies of rhythmic activity induced by 5-HT or NMDA + 5-HT in spinalized animals were not significantly different from those observed before SCT. However, percentage power in the dominant peak induced by 5-HT alone (155.6 ± 38.7% relative to pretransection) was significantly higher than the power observed with NMDA + 5-HT (31.8 ± 8.8%).
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Discussion |
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Sympathetic neuronal activity to the tail (SNAT) is driven by descending excitatory inputs from rostral ventromedial medulla
We demonstrated that SNAT was abolished after T10–T11 spinal cord transection: a critical amount of this drive appears to arise from the rostral ventromedial medulla (Tanaka et al. 2002; Korsak & Gilbey, 2004; Ootsuka et al. 2004; Ootsuka & Blessing, 2005; Ootsuka & McAllen, 2005). In contrast, ongoing sympathetic activity to other cardiovascular outflows (i.e. heart and kidney) relies vitally upon supraspinal drive from the rostral ventrolateral medulla (Horiuchi et al. 2004).
5-HT generates rhythmic sympathetic motor activity
Some neurones within the RVMM that innervate tail sympathetic preganglionic neurones demonstrate 5-HT-like immunoreactivity (Smith et al. 1998). Therefore our findings are consistent with the contention that the T-rhythm is generated by a direct action of 5-HT upon receptors located on sympathetic preganglionic neurones. When sympathetic preganglionic neurones are in ‘oscillator’ mode, inputs may reset or entrain the T-rhythm (Gilbey, 2001; Staras et al. 2001). For example, central respiratory-related inputs may entrain these ‘oscillators’, consistent with the ‘entrainment hypothesis’. In contrast, when sympathetic preganglionic neurones have a tonic firing pattern, central respiratory-related inputs may produce rhythmic sympathetic neuronal discharges through a modulation of tonic activity, consistent with a ‘radiation hypothesis’ (see Gilbey, 2004). Therefore, ‘entrainment of sympathetic oscillators’ and ‘radiation’ hypotheses are not mutually exclusive.
The rhythmogenic effect of 5-HT can be explained both by intrinsic membrane properties in individual neurones and by network mechanisms. It has been shown that 5-HT can generate rhythmic subthreshold membrane potential oscillations in single sympathetic preganglionic neurones from thoracic and lumbar segments (Pickering et al. 1994). The time course of the response obtained in vitro was slow in onset and prolonged in duration, as we observed in vivo. This suggests that 5-HT is acting via a second messenger cascade. The longer latency to onset and longer response duration that we observed in vivo, compared with a slice preparation, may be explained by a longer diffusion distance and by a longer application and contact time. Extracellular recordings in intact animals have also shown that 5-HT can induce a rhythmic firing pattern in irregularly discharging sympathetic preganglionic neurones (Lewis & Coote, 1996). At the network level, there is evidence of electrotonic coupling through gap junctions between sympathetic preganglionic neurones with spontaneous membrane oscillations in neonatal and adult rats (Logan et al. 1996; Leslie et al. 2000). It is well known that gap junction coupling can be modified by endogenously released neurotransmitters, such as 5-HT (Rorig & Sutor, 1996). Therefore, by regulating gap junction coupling, 5-HT may influence the degree of synchrony in the discharges of the population, causing recruitment of more neurones and enable electrotonic transmission of the oscillations.
NMDA generates tonic sympathetic motor activity
Although NMDA failed to elicit a T-like rhythm in our preparation, it generated a tonic activity which remained stable for at least 4 h. This is the first time that such a long-lasting effect of NMDA has been observed in sympathetic preganglionic neurones in vivo and requires further investigation. In vitro experiments have shown that EPSPs recorded from sympathetic preganglionic neurones are potentiated following a brief high-frequency stimulus (Spanswick et al. 1998), a protocol often employed to induce long-term potentiation (LTP) in the hippocampus which involves the activation of NMDA receptors. The potentiation of the EPSPs observed in the latter study also had a long time course and it was sustained over the time course of recording.
Chizh et al. (1998) observed that NMDA applied through the circulatory system of an arterially perfused trunk–hindquarters preparation of adult mouse induced common rhythms in sympathetic discharge (renal nerve and abdominal sympathetic chain) and somatomotor activity. These authors suggested that these common rhythms were produced by the somatomotor rhythm generator pervading the sympathetic circuits and were quite distinct from ‘spinal sympathetic rhythm’ generators. Our observation that NMDA failed to produce rhythmic activity in the sympathetic outflow argues against the T-rhythm arising from a common somato-sympathetic rhythm generator.
Although NMDA-induced tonic activity became rhythmic when 5-HT was subsequently administered, the rhythm was less strong than the rhythm induced by 5-HT alone. Therefore, it appears that the tonic activity induced by NMDA interferes with the rhythmicity induced by 5-HT.
The findings of Ootsuka & Blessing (2005; ear pinna, rabbit) support the idea that excitatory amino acid and 5-HT-mediated inputs, originating from the RVMM, influence cutaneous sympathetic vasomotor activity. These authors demonstrated that application of a selective 5-HT2A antagonist to the spinal cord reduced raphé-evoked increases in sympathetic activity and the remaining evoked discharge was substantially further reduced by the application of kynurenate.
Conclusions
We consider that this study is important as it bridges observations made in animals with intact nervous systems (see Gilbey, 2001) and those made in the in vitro slice preparation (i.e. see Pickering et al. 1994). It provides a vital systems perspective on detailed mechanistic data acquired from single cell recordings and raises the possibility that a sympathetic vasomotor rhythm is generated within the spinal cord.
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Supplemental material |
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This material can also be found as part of the full-text HTML version available from http://www.blackwell-synergy.com
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References |
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), highest mean level of activity (
), last data set with rhythmicity (
) and no rhythmicity (•). In the intact animal the DCN neurogram shows burst discharges with variable frequency and amplitude, and the autospectra are dominated by a band and a peak at 0.78 Hz (and a lung inflation cycle-related component at 2 Hz). SNAT was completely abolished after SCT; mean level of activity dropped to zero and rhythmical components are no longer observed in the autospectra. The I.T. administration of 5-HT induced robust rhythmic discharges. Note that DCN frequency changed with regard to the mean level of activity: the first data set with rhythmicity (
