Nitric oxide induces centrally generated motor patterns in the locust suboesophageal ganglion
Institut für Biologie II, Rheinisch-Westfälische Technische Hochschule Aachen, 52056 Aachen, Germany
*Present address: Wellcome Laboratory for Molecular Pharmacology, University College London, Gower Street, London WC1E 6BT, UK (e-mail: g.rast{at}ucl.ac.uk)
Accepted July 13, 2001
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Summary |
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Key words: nitric oxide, soluble guanylyl cyclase, pilocarpine, migratory locust, Locusta migratoria.
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Introduction |
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In insects, NO, acting on the soluble guanylyl cyclase (sGC) and thus stimulating the production of cyclic guanylyl monophosphate (cGMP), has been extensively demonstrated (Green and OShea, 1993; Müller and Buchner, 1993; Müller, 1997; Bicker, 1998; Zayas et al., 2000). NO signalling has been shown to be involved in diverse physiological contexts such as developmental processes (Truman et al., 1996; Ball and Truman, 1998; Schachtner at al., 1998; Schachtner et al., 1999; Wildemann and Bicker, 1999a), olfaction (Müller, 1994; Elphick et al., 1995; Bicker et al., 1996; Seidel and Bicker, 1997; Nighorn et al., 1998), vision (Elphick et al., 1996; Bicker and Schmachtenberg, 1997; Schmachtenberg and Bicker, 1999), memory (Müller, 1996) and motor systems (Shibanaka et al., 1994; Wildemann and Bicker, 1999b; Qazi and Trimmer, 1999).
The presence of NO/cGMP signalling in locust motor systems was proposed by Ott and Burrows (Ott and Burrows, 1998; Ott and Burrows, 1999; Ott et al., 1999), and the aim of the present study was to investigate the role of this signalling pathway in central motor pattern generation in the locust. As a model system, the central control of the mouthparts was chosen, this being a system for which muscarinic pattern generation has previously been described (Rast and Bräunig, 1997). The interrelationship between these two signalling systems was of particular interest as interactions have previously been shown in the nervous system of the moth Manduca sexta (Qazi and Trimmer, 1999). For this purpose, specific antagonists for each of the signalling pathways were tested for their potency in inhibiting pattern generation induced by NO or muscarinic agonists. If NO/cGMP signalling played a role in the pattern induced by muscarinic agonists, it would be expected that a specific inhibitor of sGC would impair the muscarinic pattern. Similarly, if muscarinic signalling played a role in nitrergic pattern generation, specific inhibitors of muscarinic receptors should also affect the NO-induced pattern.
Histochemical staining for NADPH-diaphorase activity and for the presence of cGMP upon induction with NO were used to identify structures serving as potential natural sources and targets of NO. The localisation of these structures will assist future identification and characterisation of elements of the central-pattern-generating system.
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Materials and methods |
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Electrophysiology
Extracellular potentials were measured using monopolar, tightly fitting suction electrodes feeding into Grass P15 bipolar preamplifiers whose negative input was grounded. Gain was set to 100, and the half-amplitude frequency of the high-pass filter was turned down to 0.1 Hz. Data were digitised using a personal computer equipped with the CED 1401 interface and Spike2 software (Cambridge Electronic Design, Cambridge, UK). Off-line analysis was performed using software written by the author in C running on a personal computer under the LINUX operating system. Mean bursting frequency, duty cycle, intra-burst frequency and the number of units recruited were evaluated from 50 s stretches of activity. Bursts were defined as intervals in which no inter-spike gap was longer than 200 ms. The mean bursting frequency was calculated as the number of bursts per 50 s; the mean duty cycle was defined as the mean proportion of a burst compared with the whole cycle period; intra-burst frequencies were determined as the number of spikes per burst and subsequently averaged over the 50 s recordings. The number of units recruited was estimated from the number of spike sizes and shapes that could be distinguished in the extracellular recordings by visual inspection. Statistical significance of differences was tested using the sign test for paired data. An error probability of P<0.05 was accepted as significant.
Stock solutions of drugs were prepared as follows: 100 mmol l1 sodium nitroprusside (SNP; Sigma Aldrich Chemie GmbH, Steinheim, Germany) in distilled water; 1 mol l1 hydroxylamine (Merck AG, Darmstadt, Germany) in distilled water; 0.1 mol l1 1H-(1,2,4)oxa-diazolo(4,3a)-quinoxalin-1-one (ODQ; ICN Biomedicals Inc., Aurora, Ohio, USA) in dimethyl sulphoxide (DMSO); 10 mmol l1 pilocarpine (Sigma) in saline; 10 mmol l1 oxotremorine (Sigma) in saline; 10 mmol l1 atropine (Sigma) in distilled water; 10 mmol l1 scopolamine (Sigma) in saline; 4.5 mmol l1 3-isobutyl-1-methylxanthine (IBMX; Sigma) in saline. The dosages of pilocarpine and IBMX were designed to give a maximal response (Rast and Bräunig, 2001); all other drugs were given at the lowest dose reliably yielding a response, as tested in preliminary experiments (data not shown). Stock solutions of drugs were added to a fixed bath volume using an Eppendorf pipette and dispersed by gentle agitation of the bath solution using the pipette after recordings had been established.
Histology
Ganglia destined for anti-cGMP immunohistochemistry were incubated in 5 mmol l1 SNP and 0.45 mmol l1 IBMX for 20 min at room temperature and with 100 W halogen illumination before fixation to promote the decomposition of SNP (see also Ball and Truman, 1998). Preparations were fixed in 4 % formaldehyde in phosphate-buffered saline (PBS) for 1 h at room temperature. Subsequently, they were infiltrated with 30 % sucrose for 1018 h. After embedding in Tissue-Tek mounting medium (TED Pella, Inc., Redding, California, USA), cryosections were taken at 3550 µm and immediately mounted on chrome alum/gelatine-coated slides. Sections were washed overnight at 4°C in PBS containing 0.25 % Triton X-100 (PBS-TX) and subsequently blocked for 1 h in a mixture of 5 % normal donkey serum and 0.5 % bovine serum albumin (both Sigma) in PBS-TX 0.25 % at room temperature. Sheep anti-cGMP serum (kind gift of J. De Vente to P. Bräunig) was diluted 1:600 000 when using a horseradish peroxidase (HRP)-conjugated secondary antibody or 1:100 000 when using a (CY3)-conjugated secondary antibody in the blocking medium, and sections were incubated overnight at 4°C. After repeated rinsing in 0.25 % PBS-TX, sections were incubated in a donkey anti-sheep serum conjugated with HRP or with CY3 (both from dianova GmbH, Hamburg, Germany) overnight at 4°C. Preparations were then rinsed thoroughly in PBS-TX 0.25 % and, in the case of HRP-conjugated secondary antibodies, the reaction product was developed using 30 % diaminobenzidine (DAB; Sigma) with 0.015 % H2O2 and 0.03 % NiCl in PBS for 1030 min in the dark. Preparations were dehydrated in an alcohol series and mounted in DePeX (Serva, Heidelberg, Germany; DAB reaction) or Fluoromount (Serva; CY3 fluorescence).
To identify mandibular closer motoneurones and salivary neurones in double-labelled sections, motoneurones were dye-injected with hyperpolarising current pulses (5 nA, 1 Hz, 500 ms for 20 min) using microelectrodes filled with 5 % Lucifer Yellow (Molecular Probes, Eugene, Oregon, USA) in 1 mol l1 LiCl in the tip and 1 mol l1 LiCl in the shaft (resistance 4080 M), while the salivary nerve (N7B; Altman and Kien, 1979) was backfilled with Lucifer-Yellow-labelled dextranamine (Molecular Probes). The subsequent treatment of these preparations was as described above.
For diaphorase histochemistry, ganglia were fixed in 4 % formaldehyde in PBS for 1 h at room temperature without any pretreatment. Cryosections were prepared as described above and soaked overnight at 4°C in PBS-TX 3 %. They were then preincubated in 100 mmol l1 Nitroblue Tetrazolium (NBT, Sigma) in PBS-TX 0.1 % for 1 h at room temperature in the dark. Staining was performed with 100 mmol l1 NBT and 100 mmol l1 ß-nicotinamide adenine dinucleotide phosphate in its reduced form (NADPH; Sigma) in PBS-TX 0.1 % for 16 h in the dark at room temperature or overnight at 4°C. After staining, sections were rinsed in PBS, dehydrated in an alcohol series and embedded in DePeX (Serva).
Sections were documented with an Axiophot microscope (Carl Zeiss GmbH, Jena, Germany) and a CoolPix 950 digital camera (Nikon, Tokyo, Japan). Photographs were corrected for brightness, and their contrast was enhanced using the GNU Image Manipulation Program (GIMP).
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Results |
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An interesting feature of the NADPH-diaphorase-positive neuropilar regions is the -shaped structure with dense fine processes and boutons in the ventral posterior SOG (Fig. 7H). This region differs from other stained neuropilar structures (e.g mandibular neuropile, Fig. 7H, dashed outline) in the density of the profiles but not in the intensity of the staining. While NADPH-diaphorase-positive fibres are found in the longitudinal tracts and the connectives (e.g. Fig. 7G), almost no NADPH-diaphorase staining is found in the peripheral nerves of the SOG.
Anti-cGMP immunohistochemistry
Immunohistochemistry directed against cGMP reveals cell bodies, neuropilar processes and fibres (Fig. 8, representative examples of 45 preparations). Control experiments without pretreatment with SNP and IBMX or with IBMX alone failed to show any staining. Preparations pretreated with 0.03 mmol l1 ODQ before application of SNP and IBMX were, similarly, unlabelled. This shows that all the stained structures described below accumulated cGMP directly or indirectly upon induction with NO. The most prominent stained structure is a pair of a large (5060 µm in diameter) ventral posterior cells (Fig. 8D). As in NADPH-diaphorase-stained preparations, a group of 14 cells (3040 µm in diameter) with varying relative positions is found dorsally between the circumoesophageal connectives (Fig. 8F). Large (5070 µm in diameter) but less intensely stained cell bodies are located laterally and towards the anterior end of the ganglion (Fig. 8E; see also double labellings below). Stained fibres occur in the circumoesophageal and neck connectives (data not shown). In contrast to NADPH-diaphorase staining, anti-cGMP immunoreactivity was also found widely in peripheral nerves, e.g. the labial nerve (N5) in Fig. 8D and the mandibular nerve (N1) in Fig. 8G. The number of fibres seen in the mandibular nerve (Fig. 8G) exceeds the number of efferent neurones known to project into this nerve and some of these stained for cGMP (see below), suggesting that afferent profiles show anti-cGMP immunoreactivity. Prominent anti-cGMP-immunoreactive neuropilar regions occur as very fine anterior ventral arborizations at the anterior edge of the mandibular neuropil and in a bilateral neuropilar structure that lies ventrally and posteriorly close to the midline (Fig. 8H).
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Discussion |
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Nitrergic pattern generation
A motor pattern is induced by NO donors and does not seem to be influenced by side-effects of the drugs or their degradation products since similar motor patterns can be induced by chemically distinct NO donors. The action of a specific inhibitor of sGC, ODQ (Hobbs, 1997), corroborates the conclusion that the induced pattern is the result of stimulating the NO/cGMP signalling pathway (Fig. 1B,C). The action of ODQ on sGC is probably irreversible (Hobbs, 1997), which accords with the observation that NO-induced pattern generation may not be restored after thorough washing (data not shown). The reasons for the short lifetime (2030 min) of preparations treated with NO donors are not known, but this was always long enough to allow a sequential application of drugs.
Nitric oxide has modulatory effects on central pattern generation in some model systems. For example, it increases the cycle period of breathing in the bullfrog (Hedrick et al., 1998) and of spinal swimming in Xenopus laevis tadpoles (McLean and Sillar, 2000). In the pond snail, NO donors trigger the feeding motor pattern by mimicking the activity of nitrergic chemosensory neurones (Elphick et al., 1995). These examples show that NO may have either an inhibitory or an excitatory effect on pattern generation. In insects, NO also plays a role in the chemosensory system (Müller, 1994; Elphick et al., 1995; Bicker et al., 1996; Seidel and Bicker, 1997; Nighorn et al., 1998) and, since both NADPH-diaphorase-positive and cGMP-immunoreactive fibres occur in the circumoesophageal connectives, the important question arises of whether chemosensory information from the brain contributes to the generation or modulation of feeding motor patterns via the NO/cGMP signalling pathway.
Muscarinic pattern generation
Muscarinic induction of motor patterns is common in arthropods (see Introduction). In the locust mandibular system, the action of a muscarinic agonist, pilocarpine, has been described (Rast and Bräunig, 1997) and, to support this study on a broader basis of evidence, experiments were performed with the muscarinic agonists pilocarpine and oxotremorine in parallel (Fig. 1, Fig. 4). For the same reason, different muscarinic antagonists (atropine and scopolamine) were used as specific blockers of the muscarinic motor pattern. The similarity of action of the different agents makes it unlikely that the observed effects are due to side-effects of the drugs. The results obtained with pilocarpine and atropine are in good agreement with similar experiments on locusts, stick insects and the tobacco hornworm (Ryckebusch and Laurent, 1993; Büschges et al., 1995; Johnston and Levine, 1996).
Independence of the motor patterns
The induction of mandibular motor patterns by NO and muscarinic agonists is independent, i.e neither of the signalling pathways is essential for the induction of pattern generation, but both pathways are sufficient (Fig. 4). The fact that the results of the experiments shown in Fig. 4 do not change even if the respective antagonist is applied before pattern induction by the agonist confirms that the signalling pathway being blocked is relevant neither for the induction nor for the maintenance of a motor pattern. From the above data, it is concluded that the NO/cGMP pathway and the muscarinic pathway work in parallel. This does not, however, preclude the possibility that these pathways may converge on a third pathway involved in central pattern generation further downstream, e.g. a network of premotor interneurones.
In the central nervous system of Manduca sexta larvae, cGMP production in response to application of muscarinic agonists can be blocked by NOS inhibitors. This suggests a NO-dependent and sGC-mediated rise in cGMP concentration in response to muscarinic agonists (Qazi and Trimmer, 1999). However, Qazi and Trimmer (Qazi and Trimmer, 1999) have also shown that this effect is not responsible for the increase in proleg motoneurone spike activity in response to either muscarinic agonists or NO donors. This means that, in larval Manduca sexta, both coupling between muscarinic and nitrergic pathways and, as in the proleg motoneurones, an independent parallel action of the two pathways upon a single target occur. Similarly, the possibility that, in the locust SOG, coupling of nitrergic and muscarinic pathways occurs cannot be ruled out, although this does not seem to apply for mandibular pattern generation.
Potential sources and targets of the NO/cGMP pathway
NADPH-diaphorase staining
NADPH-diaphorase staining is an indicator of the presence of NOS and has been widely used in insect nervous tissue (e.g. Dawson et al., 1991; Hope et al., 1991; Müller and Bicker, 1994; Müller, 1994; Ott and Burrows, 1998). However, it is possible that the NADPH-diaphorase method stains cells that contain a NADPH-diaphorase that is insensitive to mild formaldehyde fixation and is different from NOS. It is also possible that some NOS may fail to be revealed even under mild fixation conditions (Truman et al., 1996; Ott and Burrows, 1999). The control experiments described, however, suggest that the staining obtained in the locust SOG is likely to be due to NOS activity.
In the locust SOG, a number of structures appear to express NOS (Fig. 7), and this supports the hypothesis that, in the intact animal, NO from local physiological sources may influence pattern generation. A comparison of the neural structures stained in the SOG with data from thoracic ganglia (Ott and Burrows, 1998; Ott and Burrows, 1999) is not possible at present. The structural organisation of the three fused neuromeres of the SOG is highly derived so that any correlation between homologous parts remains unsatisfactory. However, both in thoracic ganglia (Ott and Burrows, 1998) and in the SOG, the staining is confined mainly to local and intersegmental interneurones and, in both cases, large neuropilar areas show strong NADPH-diaphorase staining. The modulatory role of NO in information processing suggested by Ott and Burrows (Ott and Burrows, 1998) may, therefore, also hold for the SOG.
Anti-cGMP immunohistochemistry
Specificity controls for the anti-cGMP serum used are described by De Vente et al. (De Vente et al., 1987; De Vente et al., 1996). The high specificity and the extraordinarily high dilution used in the present study (1:600 000) make nonspecific cross reactions extremely unlikely, and this suggests that the cGMP-like immunoreactivity observed is the result of cGMP accumulation in the labelled cells. Since the treatment with SNP induces considerable neural activity in the ganglia, it is possible that some cGMP detected in response to SNP treatment may also be produced by membrane-bound guanylyl cyclases activated by chemical messengers released during neural activity induced by NO. For example, certain neurohormones are known to induce a NO-independent rise in cGMP levels (Ewer et al., 1994; Morton and Simpson, 1995; Baker et al., 1999).
There is cGMP-like immunoreactivity in both efferent neurones and sensory fibres (Fig. 8). Double-labelling experiments show that both mandibular closer motoneurones and salivary neurone 1 (SN1) are among the large anterior lateral neurones exhibiting anti-cGMP immunoreactivity (Fig. 9). Salivary neurone 2 (SN2) does not accumulate cGMP upon induction with NO (Fig. 9). The difference between the salivary neurones with regard to sGC expression emphasizes the potential functional difference between these neurones, which is also suggested by the different transmitters found in them (for a review, see Ali, 1997). The physiological role of cGMP production in these identified neurones is not yet clear, but cGMP might modulate their membrane properties to fine-tune their response to synaptic input provided by the central-pattern-generating network.
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Acknowledgments |
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