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1Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and 2Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Submitted 24 June 2003 ; accepted in final form 9 September 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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mesencephalic locomotor region
The CNS is likely a major regulatory factor of cardiorespiratory adjustments during the early stages of a bout of exercise (17, 21, 29). It is hypothesized that the CNS participates through two principal mechanisms: central command (29) and muscle reflexes (17). Central command is a feed-forward mechanism whereby locomotor and cardiorespiratory drives are activated in parallel from several regions of the CNS (29). Increases in cardiorespiratory drive can also be evoked through activation of type III and IV primary afferents located within skeletal muscles (17). These sensory neurons synapse in the dorsal horn of the spinal cord (30) and influence secondary sensory pathways that project to various respiratory and cardiovascular regulatory regions throughout the neuraxis. It has been hypothesized that the concerted actions of central command and muscle reflexes partly underlie the ability of the CNS to appropriately match the level of cardiorespiratory activation to the intensity of a locomotor task (21, 29).
The mesencephalic locomotor region (MLR), located in the dorsal mesencephalic tegmentum, is capable of evoking increases in cardiorespiratory drive via a feed-forward, or "central command," mechanism (5). Electrical stimulation (5, 25) or introduction of various chemicals into the MLR (11) evokes locomotion in nonanesthetized, decerebrate animals. Increases in arterial pressure, heart rate, and respiration concur with locomotion and, consistent with a feed-forward mechanism of regulation, persist during fictive locomotion in a state of neuromuscular blockade (1, 2, 5). The classic anatomic substrate of the MLR is composed of the pedunculopontine (PPN) and cuneiform (CnF) nuclei (11, 25), although some studies place greater importance on the PPN in the rat model (8, 9). Indeed, the MLR is active during locomotion, as has been demonstrated by extracellular neuronal recording during spontaneous locomotion (10). It was also shown by Iwamoto and colleagues (16) that fos protein levels in the PPN and CnF are elevated after a period of treadmill exercise, suggesting that the MLR is activated and, therefore, might drive cardiorespiratory adjustments via a central command mechanism during exercise.
Previous experiments conducted in our laboratory (24) suggest that neurons in the PPN are activated during static muscle contraction and that activation of the PPN evokes increases in respiratory activity. The purpose of the present study was to begin to address the hypothesis that PPN modulates respiratory responses evoked by muscle reflexes in anesthetized rats. Diaphragmatic and cardiovascular responses to muscle contraction were recorded before and subsequent to bilateral microinjections of CoCl2, an inhibitor of Ca2+-dependent synaptic transmission in vivo (19), into the PPN. The results suggest that CoCl2 microinjections into the PPN result in attenuation of the diaphragmatic responses to muscle contraction and suggest a potential role for the PPN in the modulation of the reflex respiratory responses to muscle contraction.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Experiment Preparation
Male Sprague-Dawley rats (250–350 g) were initially anesthetized with an intraperitoneal injection of 
-chloralose (65 mg/kg, Sigma Chemical, St. Louis, MO) and urethane (800 mg/kg, Sigma Chemical). Anesthetic was subsequently supplemented on evidence of a positive hindlimb withdrawal reflex or a positive corneal reflex, which was assessed every 20–30 min.
The trachea was cannulated with PE-205 tubing (Clay Adams, Parsippany, NJ) to facilitate maintenance of a patent upper respiratory tract. Catheters (PE-50 tubing, Clay Adams) filled with heparinized physiological Ringer (7.5 µg/ml heparin, Sigma Chemical) were then installed in the left common carotid artery and left external jugular vein to allow measurement of blood pressure and administration of anesthetic, respectively. Pulsatile arterial pressure was recorded by using a model P23 pressure transducer (Gould, Oxnard, CA) connected to the arterial catheter. Heart rate was derived from the arterial pressure signal with a biotachometer (Gould). Next, a diaphragmatic electromyogram (DEMG) was obtained as previously described (4). Briefly, differential electrodes made of 0.0055-in.-diameter Tefloncoated stainless steel wires (A-M Systems, Carlsborg, WA) were inserted into the costal region of the diaphragm by using a 23-gauge needle. A stable recording of the inspiratory diaphragmatic burst was amplified (300- to 3,000-Hz bandwidth; P5 Series AC Preamplifier, Grass Instruments, Quincy, MA), full-wave rectified, and integrated in 33-ms bins (Gould Integrator Amplifier) to obtain an electromyographic correlate of the diaphragmatic contraction. Previous studies have demonstrated that changes in the amplitude of the integrated DEMG (
DEMG) peak are directly correlated with alterations in tidal volume (4, 27). Respiratory frequency was derived from the DEMG by using a biotachometer (Gould). Minute DEMG amplitude, an electrical correlate of minute ventilation, was computed as the product of respiratory frequency and DEMG amplitude.
The animal was then placed in a stereotaxic apparatus (David Kopf Instruments, Tujunga, CA). The skull was leveled, and an occipitoparietal craniotomy was performed. A single-barrel microinjection pipette (20- to 30-µm tip aperture) was made from a 1-mm-diameter glass capillary tube (World Precision Instruments, Sarasota, FL) by using a one-stage, upright pipette puller (Narishige, Tokyo, Japan). The micropipette was installed in a micropipette holder (World Precision Instruments) and filled with injection solutions, each of which were separated by a thin layer of mineral oil (Fisher Scientific, Pittsburgh, PA). The tip of the micropipette was then stereotaxically placed in the PPN by using a Kopf stereotaxic arm. Microinjections were made with a PV800 Pneumatic PicoPump (World Precision Instruments) and were measured by monitoring the movement of the meniscus of the mineral oil through a calibrated microscope reticule (Reichert Scientific Instruments, Buffalo, NY).
Unilateral static contraction of the hindlimb muscles was evoked via electrical stimulation of the right tibial nerve. The tibial nerve was carefully dissected and then placed on a shielded platinum bipolar electrode connected to a S88 stimulator with an SIU5 isolation unit (Grass Instruments). The surgical opening was filled with warm mineral oil to prevent desiccation. Next, the Achilles tendon was isolated by cutting the calcaneus near the insertion of the tendon. Finally, the limb was fixed in space with a patellar precision clamp to prevent limb movement during muscle contraction. The motor threshold (MT; minimum current intensity necessary to evoke muscle twitch) of the hindlimb preparation was then determined. Static contraction of the hindlimb muscles was subsequently evoked via deliverance of alternating current square-wave pulses (0.1-ms pulse width, 40-Hz, current intensity at 2x MT) for a period of 20 s to the tibial nerve. The tension generated in the triceps surae muscles during contraction was measured by a force transducer (Grass) connected to the Achilles tendon. At the conclusion of the data collection, the nerve was crushed distal to the electrode and stimulated at 2x MT to ensure that the observed cardiorespiratory responses were due specifically to muscle contraction and not to direct stimulation of tibial nerve afferents.
Data Collection
Protocol I (16 rats). After a 30-min postoperative recovery period, the diaphragmatic and cardiovascular responses to unilateral static contraction of the hindlimb muscles were recorded. Preinjection responses were recorded a second time after a 20-min recovery period to test for response reliability. Vehicle microinjections (microinjection 1; 100 nl Ringer; pH 6.9–7.0) were then executed bilaterally into the PPN. The coordinates used for stereotaxic microinjections were determined from Paxinos and Watson (23): 0.7–1.0 mm rostral, 1.6–2.0 mm lateral, and 2.5–2.8 mm dorsal to interaural zero. Reflex responses to static contraction of the hindlimb were then recorded 10 min after bilateral vehicle microinjections (microinjection 1) into the PPN. Subsequent to another 20-min recovery period, bilateral microinjections of 50 mM CoCl2 (microinjection 2; 100 nl; pH 6.9–7.0) dissolved in Ringer were executed in the PPN. Twenty seconds of static muscle contraction were then evoked 10 min later to document the effects of CoCl2 microinjections on the reflex diaphragmatic responses to muscle contraction. Responses were also recorded at 30 and 60 min after CoCl2 microinjections to test for recovery of the responses from synaptic blockade. Finally, 100 nl of 5% Chicago blue dye (Sigma Chemical) were injected bilaterally to allow for postmortem histological verification of the PPN microinjection sites.
Before data collection, 4 of 16 rats from protocol I were barodenervated to test the dependence of the diaphragmatic responses observed during muscle contraction on changes in blood pressure. Briefly, heart rate responses to an injection of phenylephrine (4 µg iv; Sigma Chemical) were recorded before barodenervation. The carotid sinuses were subsequently denervated bilaterally. The surgery included careful stripping of the carotid sinus of its innervation and associated connective tissue, transection of the superior laryngeal branch of the vagus nerve, removal of the superior cervical ganglion, and painting of the carotid sinus above a shielded vagus nerve with 10% phenol in ethanol. Heart rate responses to intravenous phenylephrine were observed 30 min later to test the efficacy of the barodenervation.
Protocol II (9 rats). Subjects that were tested under protocol II underwent a similar experimental procedure as those tested under protocol I with one difference: microinjection 2 of protocol II was vehicle rather than CoCl2. Implementation of a second round of vehicle microinjections in lieu of CoCl2 was done to exclude the possibility that observed effects were due to adaptation of muscle reflex responses to stimulus repetition, temporal degradation of the experimental preparation, or nonspecific effects of the microinjection technique.
Histological Confirmation of Injection Sites
After experimental protocols, rats were perfused intracardially with 4% paraformaldehyde/1 mM MgCl2 (Fisher Scientific) in 0.1 M phosphate buffer (pH = 6.8). Brains were postfixed for 2–4 h and infiltrated with 20% sucrose/5 mM MgCl2. Midbrains were then cut into two series of alternating 30-µm sections on a sliding microtome (American Optical, Buffalo, NY) with a freezing stage (Sensortek, Clifton, NJ). One series was stained to identify the reduced NADP (NADPH)-diaphorase positive neurons of the PPN, as described by Vincent et al. (28), whereas the other series was left unstained to confirm the area of the injectate.
Data Analysis
Data were recorded digitally (sampling rate: 200/s) by using a PowerLab analog/digital board and associated software (ADInstruments, Mountain View, CA). Peak responses and averages of the cardiovascular and diaphragmatic parameters during the entire 20 s of muscle contraction were contrasted with baseline means from the entire 60 s immediately before the onset of muscle contraction. Differences among preinjection responses and those responses measured 10 min after vehicle and CoCl2 microinjections were tested by using one-way repeated-measures ANOVA with Tukey's post hoc analyses (SigmaStat software package, SPSS, Chicago, IL), with P < 0.05 considered statistically significant. Data from protocol I were contrasted to protocol II data by using unpaired t-tests.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Electrical stimulation of the tibial nerve at 2x MT evoked static contraction of hindlimb muscles of the anesthetized rat. As depicted in Fig. 1 and Table 1, the tension generated in the triceps surae muscles during tibial nerve stimulation among all subjects was 
1 kg (range = 600–1,350 g) and was not statistically different among successive trials within each subject (1-way repeated-measures ANOVA). Figure 1 also depicts the typical diaphragmatic responses to static muscle contraction in the anesthetized rat. Rats exhibited an increase in diaphragmatic activity in response to static muscle contraction, characterized by increases in respiratory frequency (peak 9.0 ± 1.0 breaths/min; average 4.7 ± 0.6 breaths/min) and minute DEMG amplitude (peak 14.6 ± 3.3 units/min; average 7.3 ± 2.4 units/min), although peak DEMG amplitude by itself was statistically unchanged during muscle contraction throughout the experiments. Diaphragm activity quickly returned to baseline after cessation of hindlimb muscle contraction.
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CoCl2 in PPN Blunts Diaphragmatic Responses to Muscle Contraction (Protocol I; n = 10)
Figure 1 and Table 1 demonstrate that bilateral microinjections of vehicle into the PPN did not affect any of the diaphragmatic responses to muscle contraction. In contrast, bilateral microinjections of 50 mM CoCl2 into the PPN were associated with blunted diaphragmatic responses to muscle contraction (Table 1). The increases in respiratory frequency that accompanied muscle contraction 10 min after cobalt injections in the PPN were significantly attenuated to 30% of its preinjection magnitude (Table 1). The blunted rise in respiratory frequency induced by muscle contraction was also reflected in an attenuated increase in minute DEMG amplitude in contrast to baseline (Table 1). Diaphragmatic responses to muscle contraction remained depressed at 30 min postCoCl2 microinjections into the PPN and exhibited a tendency toward recovery at 60 min post-CoCl2 microinjections, with the respiratory frequency response to muscle contraction rebounding to 5.0 ± 0.5 breaths/min. The respiratory frequency response to electrical stimulation of the distal tibial nerve after nerve crush was -0.2 ± 0.4 breaths/min.
Similar effects on diaphragmatic responses to muscle contractions were observed in barodenervated animals after CoCl2 injections into the PPN. Intravenous injections of phenylephrine evoked increases in arterial pressure of 68 ± 3 mmHg before barodenervation and 81 ± 5 mmHg after barodenervation. Heart rate decreased 40 ± 16 beats/min before barodenervation (P < 0.05, paired t-test) in contrast to a statistically insignificant 4 ± 3 beats/min after barodenervation. Similar to nonbarodenervated animals, respiratory frequency responses to muscle contraction increased 10.2 ± 2.1 breaths/min. Cobalt microinjections were localized to the PPN in two of four of the barodenervated animals and were associated with respiratory frequency responses that were blunted to 65 and 19% of preinjection responses.
Attenuation of Diaphragmatic Responses Was Not Due to Response Adaptation (Protocol II; n = 8)
Figure 2 contrasts the reflex respiratory frequency and minute DEMG amplitude responses to muscle contraction after the second round of microinjections observed in protocol I (CoCl2) vs. protocol II (vehicle). The respiratory frequency and minute DEMG amplitude responses to muscle contraction in protocol II were not blunted relative to responses after the first round of vehicle microinjections. Moreover, the increases in respiratory frequency and minute DEMG amplitude after CoCl2 microinjections in protocol I are significantly blunted in contrast to the increases in these variables after secondary vehicle microinjections in protocol II (P < 0.05, unpaired t-tests).
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Cardiovascular Responses to Muscle Contraction
Rats exhibited baseline reflex cardiovascular responses to muscle contraction that consisted of a decrease in mean arterial blood pressure (MAP; -22.1 ± 3.2 mmHg) and a modest increase in heart rate (8.6 ± 3.6 beats/min). These responses were statistically unaffected after cobalt microinjections into the PPN. Furthermore, MAP responses to muscle contraction were similar after microinjection 2 in both protocol I and protocol II, suggesting that CoCl2 microinjections had no specific effects on the MAP responses to muscle contraction (Fig. 2).
Histology
Histological localization of the injection sites in the PPN was confirmed in coronal sections with NADPH-diaphorase histochemistry. Figure 3 depicts the histological confirmation of a microinjection of CoCl2 from the experiment shown in Fig. 1. Experiments in which there was infiltration of the Chicago blue dye into the NADPH diaphorase positive PPN were included in the data analyses above (i.e., 10 of 16 experiments for protocol I; 8 of 9 experiments for protocol II). Several of the protocol I experiments were characterized by injections of CoCl2 that spread into both the PPN and the CnF. However, in a subset of seven animals from protocol I in which injections were confined to the PPN, CoCl2 injections were associated with blunted respiratory frequency responses to muscle contraction (Fig. 4).
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Three subjects in protocol I failed to exhibit infiltration of Chicago blue into the PPN or CnF. In two of these experiments, there was no change in the respiratory frequency responses to muscle contraction after microinjections of CoCl2; in the other experiment, there was a slight decrease in the respiratory frequency response to muscle contraction but no change in the minute DEMG response to muscle contraction. Three additional experiments in protocol I were characterized by microinjections of CoCl2 into the CnF on at least one side but which completely missed the PPN. In two of these experiments, the microinjections of CoCl2 were associated with attenuation of the diaphragmatic responses to muscle contraction but resulted in no change in these responses in the third experiment. Finally, it is important to note that none of the microinjections in any of these experiments impinged on other pontine respiratory regulatory regions, notably the parabrachial nuclei and the periaqueductal gray.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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DEMG amplitude is similarly blunted after microinjections of CoCl2 into the PPN. MAP and heart rate responses to muscle contraction in these animals were statistically unaffected after microinjections of CoCl2 into the PPN. Similar diaphragmatic responses to muscle contraction were observed before and after CoCl2 microinjections into the PPN in a small subset of barodenervated animals, suggesting that the observed effects are not absolutely dependent on blood pressure feedback during muscle contraction. The purpose of protocol II was to exclude the possibility that the observed decrements in the reflex diaphragmatic responses to muscle contraction were due to response adaptation to a repetitive stimulus. The design of this experiment was identical to that of protocol I, except for replacement of the CoCl2 injectate with a second bilateral microinjection of vehicle into the PPN. Data from protocol II corroborated the specificity of the effects of CoCl2 microinjections observed with protocol I; that is, replacement of the CoCl2 microinjection with a second injection of vehicle failed to produce a significant attenuation of the diaphragmatic responses to muscle contraction. Taken together, these experiments suggest a potential role for the PPN in modulation of reflex respiratory responses to muscle contraction.
Injection of CoCl2 into neural tissue is a technique used to elucidate the importance of a brain region in the regulation of a physiological function. Co2+ obstructs the ionophore of the voltage-gated Ca2+ channel (12) and thus induces blockade of Ca2+-dependent release of neurotransmitter from presynaptic terminals (19). Consequently, presynaptic action potentials cannot influence postsynaptic neurons via "classic" neurotransmitters in the presence of CoCl2, effectively causing a reversible blockade of neural pathways that synapse in the treated area (19). Fibers of passage are spared of dysfunction with this technique (19). Thus, through the elimination of Ca2+-dependent synaptic transmission with CoCl2 in vivo (19), it is possible to identify brain areas that are important sites of information processing and regulation in particular physiological processes.
In the present investigation, we employed CoCl2 injections to determine whether pathways that synapse in the PPN contribute a modulatory influence to the reflex diaphragmatic responses to muscle contraction. The results from this study suggest that the PPN is a site at which pathways relevant to modulation of reflex respiratory responses to muscle contraction synapse. Because muscle reflexes are thought to play an important role in driving and fine-tuning the respiratory adjustments that accompany exercise (17, 29), it is thus reasonable to hypothesize that the PPN may play a role in driving or modulating respiratory adjustments that accompany physical activity.
The PPN has been considered at least part of the anatomic substrate of the MLR in the albino rat. Electrical stimulation of the PPN (25) or chemical disinhibition with GABAA-receptor antagonists (11) have been shown to evoke coordinated nonweight-bearing locomotion in decerebrate or lightly anesthetized rats. Thus, given its potential role in the regulation of locomotor drive, it seems reasonable that the PPN would be influenced by afferent motor reflex pathways. An interesting aspect of previous research on the MLR of the rat is that the PPN appears to be one of its most important components. Garcia-Rill et al. (8) demonstrated that the NADPH diaphorase-positive PPN constitutes the region of lowest electrical stimulation threshold to evoke locomotion from the MLR. In addition, it was shown that locomotion was evoked by specific agonists and antagonists only when there was evidence of spread of the injectate into the PPN (9), leading the authors to suggest that the PPN is the anatomic substrate of the MLR in the rat.
To be consistent with the conclusion that the PPN may be the most important, although perhaps not exclusive, component of the MLR, we established the criterion that CoCl2 microinjections had to have infiltrated the PPN bilaterally for acceptance among the data analysis pool. In 10 of 16 protocol I experiments, CoCl2 microinjections were confirmed to infiltrate the PPN bilaterally and were associated with blunted diaphragmatic responses to muscle contraction. In seven of these experiments, in which the injectate appeared to infiltrate the PPN only, attenuation of the respiratory frequency responses to muscle contraction was observed. Cobalt injections that missed both the PPN and CnF generally were not associated with changes in the diaphragmatic responses to muscle contraction. However, two of three experiments in which injectates infiltrated only the CnF, itself a proposed component of the MLR, were associated with blunted diaphragmatic responses to muscle contraction. Further experimentation is necessary to fully address the issue of the potential for the CnF to modulate the reflex diaphragmatic responses to muscle contraction.
The PPN has previously been hypothesized to play a role in the regulation of cardiorespiratory drive during exercise in the context of the MLR and central command. Eldridge et al. (5) demonstrated that electrical stimulation of the MLR of the cat results in increases in MAP, heart rate, and ventilation. Their postulation that the MLR is part of the central neural substrate of central command was driven by the demonstration that the MLR evokes increases in cardiorespiratory drive in a feedforward manner in cats paralyzed with gallamine triethiodide. Similar findings in the decerebrate and lightly anesthetized rat models were published subsequently (1, 2). Synthesis of previous research and the present study raise the interesting possibility that the MLR is a site at which cardiorespiratory drives from central command and muscle reflex pathways are integrated. Such a mechanism has been proposed to underlie the ability of the CNS to ensure a level of cardiorespiratory activation that is appropriate for the intensity of the locomotor task (21, 29). Integration of muscle reflex and central command drives has been previously shown in cardiorespiratory brain regions, including the ventrolateral medulla (22) and the dorsal horn of the spinal cord (3).
The possibility that mesencephalic regions facilitate the cardiovascular adjustments observed during muscle contraction was highlighted by Iwamoto and colleagues (15), who documented an attenuation of the pressor response to muscle contraction in midcollicular decerebrate cats after transections of the rostral medulla. The PPN might be a potential mesencephalic modulatory region of the cardiovascular adjustments that accompany muscle contraction, given its potent ability to drive increases in arterial pressure and heart rate (1, 2, 5, 24). Although the results of the present study do not support a role for the PPN in driving the cardiovascular responses to static muscle contraction in the anesthetized rat, the possibility remains that the PPN modulates reflex cardiovascular responses to muscle contraction in nonanesthetized rats or other species, which exhibit more typical pressor responses to muscle contraction (6, 7, 13, 18, 20, 26). Along similar lines, it would be interesting to test our hypothesis in rat preparations with pressor responses to muscle contraction as reported by Ishide et al. (14). Although their model contrasts with our preparation on several levels, including anesthetic regimen, higher tibial nerve stimulation intensity, and markedly lower average force generation, it could shed light on a potential role for the PPN in modulation of pressor responses to muscle contraction. Further research is needed to address these issues.
In conclusion, our data are consistent with the hypothesis that the PPN has a modulatory influence on the increases in diaphragmatic activity that accompany muscle contraction in anesthetized rats. Because the PPN likely comprises a major part of the anatomic substrate of the MLR, it is reasonable to hypothesize that the MLR might regulate respiratory drive during exercise through both muscle reflex and central command mechanisms. Although many details of the role of the PPN in the modulation of respiratory drive during exercise and other stressors remain to be elucidated, it, nonetheless, appears that the PPN may have the capacity to modulate respiratory activity through feed-forward and reflex mechanisms. The PPN warrants further attention in future studies of central neural modulation of respiration during exercise.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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GRANTS
This work was supported by National Heart, Lung, and Blood Institute Grant HL-06296. E. D. Plowey was supported by a National Institutes of Health Systems and Integrative Biology Training Grant (5T32GM07143-23).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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