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1Department of Physiology, Medical College of Wisconsin, 2Department of Physical Therapy, Marquette University, and 3Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin
Submitted 18 March 2006 ; accepted in final form 26 May 2006
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ABSTRACT |
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neural control of breathing
E) (a rapid increase followed by a slow increase and finally a steady state); 2) a curve-linear relationship between E, alveolar ventilation, and O2 (oxygen consumption/metabolic rate); and 3) the near homeostasis of blood gases throughout submaximal exercise (8, 9, 23, 39). At 60% of maximal O2, E begins to increase at a greater rate than O2 in humans. The homeostasis of blood gases at submaximal exercise is specific to humans as other species hyperventilate at both submaximal and maximal exercise. For over a century, numerous studies have attempted to identify the mechanism or signal that mediates the exercise hyperpnea. Numerous hypotheses have been proposed, and data were obtained that appeared to be consistent with each hypothesis. However, data from all studies on any single hypothesis have never unequivocally supported any hypothesis; thus the mechanism mediating the hyperpnea remains obscure (6–9, 11, 12, 21–23, 28, 29, 38, 39).
One hypothesis that warrants further investigation is that the cerebellar fastigial nucleus (CFN) is important to the exercise hyperpnea. Several studies have demonstrated a potential role of the cerebellum and CFN in cardiorespiratory control. For example, studies have provided evidence that there are 1) projections from the CFN to medullary respiratory nuclei; and 2) respiratory-modulated and chemosensitive neurons in the CFN (1, 34–36). Moreover, recently using positron emission tomography, Thorton et al. (32) showed that humans imagining exercise under hypnosis demonstrated a bilateral activation of the cerebellum in the area of the CFN. In addition, Dormer and colleagues (1, 10) provided evidence that lesioning the CFN in dogs reduced heart rate (HR) and blood pressure (BP) during treadmill exercise. Based on these studies, it is conceivable that the CFN is involved in modulating the exercise hyperpnea. The purpose of the present study was to test the hypothesis that an intact CFN is necessary for the normal ventilatory response required to meet the gas exchange requirements of submaximal exercise.
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METHODS |
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Experimental Design
To assess the role of the CFN in the exercise hyperpnea, the goats were studied at rest and during exercise after 1) an initial instrumentation surgery, 2) subsequent chronic bilateral implantation of microtubules into the CFN, 3) unilateral or bilateral injection of the serotonin (5-HT) receptor antagonist methysergide into the CFN, and 4) creating lesions by injection of the neurotoxin ibotenic acid. Ibotenic acid has been used extensively to create lesions to gain insight into physiological control mechanisms (18, 33), and this neurotoxin was our initial choice for the present study. However, as detailed in the RESULTS, the dramatic effects of this neurotoxin on posture and locomotion prevented us from obtaining data immediately after the lesion was created. Therefore, we decided to create a reversible neuronal dysfunction in the CFN. We chose to utilize the reversible 5-HT receptor antagonist methysergide because of the high density of 5-HT receptor neurons in the CFN (13, 14), which we have also documented for goats (unpublished findings). As reported elsewhere (25), eight of these same goats were also initially studied after implantation of the microtubules to ascertain the physiological effect of creating a focal acidosis in the CFN.
Surgical Procedures
Instrumentation surgery. An initial surgery was performed to elevate a 5-cm segment of the carotid arteries. In this and a subsequent surgery, the goats were anesthetized initially with a combination of ketamine and xylazine, intubated, and mechanically ventilated. Throughout surgery, anesthesia was maintained with 1–1.5% halothane in oxygen. Under sterile conditions, the carotid arteries were isolated from the vagi, elevated superficial to the muscle, and the skin sutured. After surgery, the goats received ceftifur sodium (2 mg/kg) daily as an antibiotic for 1 wk.
Microtubule implantation surgery.
After 
3 wk, a second surgery was performed to chronically implant two microtubules into the CFN (n = 12) or elsewhere in the cerebellum as a control (n = 2). Arterial BP, HR, and rectal temperature were continuously monitored throughout the duration of surgery. An occipital craniotomy was created, and the dura mater was excised to expose the dorsal cerebellum and dorsal aspect of the medulla for visualization of obex. The dorsal surface of the medulla, obex, and the midline were all used as reference points for stereotaxic coordinates in the dorsoventral, rostrocaudal, and mediolateral planes. The microtubules were made of 18-gauge stainless steel tubes that were cut to 70 mm in length. The tip of the microtubules was placed at obex, 45° from the horizontal plane, and then it was raised 18–21 mm above obex and 1–2 mm lateral to the midline. We then advanced the microtubules with the use of a micromanipulator until the tip made contact with the dorsal surface of the cerebellum, which served as our zero point for microtubule advancement into the cerebellum. An electrical simulating electrode was inserted through the microtubules and extended 2 mm beyond the tip of the microtubules. All but the last 1 mm of the stimulating electrode was insulated. The electrical stimulation electrode was grounded directly to the microtubules or at a site on the neck of the goat. We used a Grass SD9 square-pulse stimulator to deliver an 80-Hz, 5-V, 1-ms pulse width, 200-ms duration, and a 2-ms delay for 30 s (1, 35, 36). We began to electrically stimulate the tissue 10 mm from the dorsal surface of the cerebellum and continued to advance the microtubules and stimulating electrode in 1- or 2-mm increments until electrical stimulation elicited an increase in BP and HR. Other studies have also shown these increases in BP and HR when the rostral CFN (rCFN) is electrically stimulated. At this location, the microtubules were secured with screws and dental acrylic to the bone (1, 35, 36).
Laboratory personnel monitored the goats continuously for a minimum of 24 h after the microtubule implantation surgery. Most goats were unable to maintain normal sternal recumbent posture or stand for 3–6 h postsurgery, but eventually all fully recovered. Food and water intake was monitored closely in all goats daily after the implantation surgery. Brain edema was minimized with dexamethasone injections (0.4 mg·kg–1·day–1 iv for 3 days, then decreasing by 0.05 mg·kg–1·day–1, 3 times/day) for 1 wk. Infection was minimized with chloramphenicol injections (20 mg/kg iv, 3 times/day) for 3 days, and daily injections thereafter of ceftifur sodium (2 mg/kg im, 1 time/day), and gentamycin (3 mg/kg im, 1 time/day). Buprenorphine was administered 3–12 h after implantation to minimize pain.
Exercise Protocol and Physiological Measurements
The ventilatory response to exercise was studied for several days before and after 4 wk of recovery from microtubule implantation surgery. For these studies, the goats stood on a treadmill for a 30-min rest period and then walked for 4 min at 1.8 miles/h at 5% grade, followed by 4 min at 1.8 miles/h at 15% grade. During some studies (n = 9), we only recorded BP and HR and sampled 2 ml of arterial blood in duplicate between 3 and 5 and 28 and 30 min of the rest period, and in triplicate between 2 and 3.5 min of each workload (nonmask). Nonmask studies were predicated on the history of this laboratory, where humans and ponies were studied during exercise without a mask, because of the potential that the mask would be a confounding factor in the ventilatory response to exercise (29). In separate studies (n = 6), we taped a tight-fitting custom breathing mask to the snout and attached a two-way breathing valve to the mask. Inspiratory airflow was monitored continuously with a pneumotachograph attached to the inspiratory side of the two-way breathing valve. In some of these studies (n = 3), we also collected expired gas in a tissot spirometer and analyzed it for the fractions of expired CO2 and O2 to calculate O2. The data were recorded on a Pentium 3 computer by the data collection program Windaq.
Methysergide Studies
The goats were monitored [inspired pulmonary ventilation (I), breathing frequency (f), tidal volume (VT), BP, and HR] during rest as previously mentioned for 30 min, during which two sets of arterial blood samples were drawn to measure arterial partial pressure of CO2 (PaCO2), arterial partial pressure of O2 (PaO2), and pH. At the end of the control period, 0.5 µl of 1 mM methysergide (5-HT nonspecific receptor antagonist), was injected unilaterally or bilaterally. For these injections, we attached a 0.5-µl Hamilton microsyringe to a 20-gauge 70-mm stainless steel injection tube. The tubes were loaded with 0.5 µl of methysergide and inserted down the inner lumen of the microtubules. The injection was completed over 30 s. The goats' respiratory and cardiovascular parameters were monitored for 30 min following the injection(s). At the end of this 30-min period, 2 ml of duplicate arterial blood were drawn, and then this was immediately followed by the aforementioned exercise protocol.
Ibotenic Acid Studies
To create neurotoxic lesions, either a 0.5-, 1-, 5-, or a 10-µl Hamilton microsyringe was attached to a 20-gauge, 70-mm stainless steel injection tube. After the tubes were loaded with 50 mM ibotenic acid, the tube was inserted down the inner lumen of the 70-mm microtubules, and the injection was completed over 30 s. After 1 h, the procedure was repeated on the contralateral side. The initial volume injected was always 0.5 µl, because we anticipated that the lesions could cause difficulty in maintaining posture and ambulation. Only one volume was injected on any day, and usually the injections were at weekly intervals. We progressively increased the volume of injection in hopes of maximizing the size of the lesion. After the neurotoxin injections, goats usually had difficulty standing; thus postinjection exercise studies were not completed until 24–48 h later, and then for several days thereafter.
Histological Studies
After completion of these protocols, the animals were euthanized (Beuthanasia), and the brain was perfused with PBS solution (pH = 7.35–7.4) and 4% paraformaldehyde fixative in PBS. The cerebellum was then removed, postfixed in 4% paraformaldehyde solution for 24 h, and cryoprotected in a 30% sucrose solution. The cerebellum was then frozen and serial sectioned (25 µm) in a horizontal or transverse plane, and the sections adhered to chrom alum-coated slides. The tissue was then stained with hematoxylin and eosin, cover slipped, and examined microscopically. The microtubule implantation site was identifiable by visualization of an area of absent or disrupted tissue, 
1.25 mm along the rostral-caudal axis. The volume of the cerebellum was calculated using the volume of an ellipsoid formula, which is 4/3
* a * b * c (where a, b, and c are the radii in 3 planes: rostral-caudal, dorsal-ventral, lateral-lateral). These measurements were made in the cerebellums of 15 goats. The cross-sectional area of tissue damage inside and outside the CFN created by the microtubules was calculated by measuring the average radius of tissue disruption (0.625 mm) and the average distance (height) the microtubules penetrated inside and outside the CFN. These two measurements were inserted into the formula of the volume of a cylinder ( x radius2 x height) to calculate the volume of damage inside and outside the CFN caused by the microtubules. Wenninger et al. (33) and Hodges et al. (18) in our laboratory previously found that, in goats where microtubules were implanted into different medullary nuclei but no ibotenic acid was injected, the tissue disruption was confined to a distance of 0.5 mm surrounding the microtubule tract. In contrast, at medullary sites in which ibotenic acid was injected, the tissue damage and neuron death extended to at least a distance of 1.5 mm surrounding the microtubules (33). Based on these data and because it was not possible to distinguish whether the tissue damage beyond the microtubules was caused by microdialysis (25), reversible agents, or ibotenic acid, we will refer to all damage beyond that of the microtubules itself as due to ibotenic acid. Using hematoxylin and eosin-stained slides visualized under a light microscope, living and dead neurons were counted bilaterally in the CFN. Living neurons were defined as those that had an irregular shape, an intact nucleus, and were dark pink or purple in color, whereas dead neurons were defined as those that were round, with no nucleus, and light pink in color.
Data and Statistical Analyses
We calculated I, BP, HR, f, VT, and O2. The calculated breath-by-breath data were binned into 15-s averages for the control and exercise periods. The mean data were statistically analyzed using one-way ANOVA to compare preimplant data to postimplant, and postimplant to post-botenic acid data for all of the physiological variables. A two-way ANOVA was also used to compare the differences in living and dead neurons after ibotenic acid injections to preimplant controls. If the two-way ANOVAs found significance, then a Bonferroni post hoc analysis was used to isolate the specific differences. A one-way ANOVA was used to calculate statistical differences between the different treatments and their effect on the change in PaCO2 between rest and exercise workloads 1 and 2 (see Figs. 2 and 3, and Tables 2 and 3). If one-way ANOVA found significance, then the Bonferroni post hoc analysis was used to isolate the specific differences. An unpaired t-test was used to compare the changes in average weights for goats before and after microtubule implantation, to compare masked vs. nonmasked changes in PaCO2 from rest, and to compare the chronic effect on PaCO2 at each workload for exercise studies greater than 6 days to studies before bilateral injections of 10-µl ibotenic acid (see Fig. 3). The threshold for significance was set at P < 0.05.
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RESULTS |
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Figure 1 shows the placement of the microtubule tips inside the CFN (n = 12) or outside the CFN (n = 2) for individual goats. The average calculated volume of a goat's cerebellum was 13,718 ± 488 mm3, and, of this volume, 71.4 ± 8.3 mm3 or 0.5% of the cerebellum was damaged by the combination of microtubule implantation and ibotenic acid injections. The total calculated bilateral volume of a goat's CFN was 116 ± 1.1 mm3, and the average volume destroyed (totally devoid of neurons) by the microtubules and ibotenic acid was 17 ± 0.26 mm3 (14.7%). Of this total, we estimate that 8 mm3 (7%) was due to the microtubules and 9 mm3 (7.7%) was due to ibotenic acid. Despite the finding that only 14.7% of the CFN were devoid of neurons in the lesioned goats, there was a 55.0% decrease (Table 1, P < 0.001, n = 10) in living neurons in the CFNs of these goats compared with the CFNs of goats that either had microtubules implanted outside the CFN or had no microtubules implanted (1,670 ± 192 vs. 3,720 ± 553), respectively. The large deficit in neurons was due to the neurotoxin destroying some but not all neurons over a large area and because the microtubules were placed in the CFN where, in control goats, there was the highest density of neurons. There was no correlation between the volume of ibotenic acid or the number of ibotenic acid injections and the total number of living and dead neurons counted.
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Lesions were created in goats primarily inside (n = 12) or completely outside (n = 2) the CFN. Although these experiments were not designed to study posture, locomotion, or behavior, informal observations were made. Most animals were not able to maintain the normal sternal recumbent posture for several hours to several days after bilateral lesions created by the implantation of microtubules in or outside the CFN, and no animal was able to exercise on the treadmill again for a minimum of 3 wk after this surgery. In addition, for several hours to days after ibotenic acid injections, animals experienced difficulty standing, walking, and maintaining a sternal recumbent posture, which is the reason we also created reversible neuronal dysfunction using methysergide. However, injection of methysergide also resulted in difficulty in ambulation, and, therefore, we were able to obtain acceptable physiological data on only four goats.
Effects of Microtubule Implantation and Ibotenic Acid During Rest and Treadmill Exercise
At rest for intact goats, I was 8.2 ± 0.9 l/min, f was 20.7 ± 1.7 breaths/min, VT was 0.4 l/breath, mean arterial blood pressure was 70.9 ± 7.1 mmHg, HR was 93.0 ± 9.5 beats/min, PaCO2 was 40.1 ± 1.4 Torr, PaO2 was 103.3 ± 1.3 Torr, and pH was 7.43 ± 0.01 (Table 2). Exercise increased most physiological variables in a workload-dependent manner, except for PaCO2, PaO2, and pH (Table 2). PaCO2 decreased from rest during exercise, and there were no significant (P < 0.05) changes in PaO2 and pH from rest to exercise. There were no significant attenuations of any physiological variables due to microtubule implantation or 0.5-µl injections of ibotenic acid (Table 2, P > 0.05). Six days after bilateral injections of 10-µl ibotenic acid, VT at the second workload was significantly reduced from 1.32 ± 0.27 (Table 2, P < 0.05) to 0.58 ± 0.06 l/breath.
Change in PaCO2 as an Index of the Effects of Treadmill Exercise
As in past studies, the change in PaCO2 between rest and exercise was utilized to determine whether different perturbations affected the capability of the respiratory system to meet the metabolic demands of exercise. Due to concerns that a mask would interfere with the physiological response to exercise, goats were studied with and without a mask. Since there was no significant difference in PaCO2, PaO2, or pH between masked and nonmasked studies, the data were pooled.
As is typical for goats (18, 33), before implantation, PaCO2 decreased from rest during mild and moderate treadmill exercise by –2.0 ± 0.39 and –3.5 ± 0.45 Torr (Table 3, Fig. 2, P > 0.05, n = 11), respectively. This decrease in PaCO2 during the first and second levels of exercise was not significantly altered by microtubule implantation (–2.5 ± 0.39 and –4.2 ± 0.68 Torr, Table 2, Fig. 2, P > 0.05, n = 11) or by neurotoxic lesions created by bilateral injections of 0.5 µl (Fig. 2, P > 0.05, n = 6), 1 µl (–2.4 ± 0.52 and –3.7 ± 0.92 Torr), or 5 µl ibotenic acid (–1.7 ± 0.64 and –1.4 ± 0.16 Torr). However, the chronic effect of bilaterally lesioning the CFN with 10 µl ibotenic acid was a significant (Table 3, Fig. 3, P < 0.05, n = 4) attenuation of the change in PaCO2 from rest from –2.9 ± 0.50 to –1.6 ± 0.66, and from –4.2 ± 0.73 to –1.4 ± 0.64 Torr at workloads 1 and 2, respectively. Since, in initial goats, the 1- and 5-µl injections had minimal effects on PaCO2 during exercise, in subsequent goats we by-passed these volumes and proceeded to the 10-µl injections.
In one goat where a lesion was made with 10-µl ibotenic acid in the rCFN, the change in PaCO2 from rest was attenuated from –5.9 to –4.6 Torr (Table 3). In contrast, in three goats where only the caudal CFN was lesioned, and in two goats where 10 µl ibotenic acid were injected outside the CFN, there was no consistent effect of the neurotoxin on the exercise PaCO2 at both workloads (Table 3).
Physiological Effects of Injecting Methysergide Inside and Outside the CFN on the Change in PaCO2 From Rest at Two Workloads of Treadmill Exercise
Methysergide injected bilaterally or unilaterally into the CFN had no consistent effects on PaCO2 at the first workload. In contrast, at the second workload, bilateral and unilateral injections into the CFN slightly attenuated the change in PaCO2 from rest to steady state (Table 4). This effect of methysergide was also found in one goat when injected outside the CFN.
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DISCUSSION |
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Limitations of This Study
A major challenge in studying the exercise hyperpnea is to create a perturbation in a hypothesized pathway for mediating the hyperpnea and have an animal capable of performing physiological exercise. In this regard, the present study was comparable to our laboratory's past study in which we lesioned the dorsal lateral spinal columns of ponies in an attempt to attenuate information from the exercising muscles to the medullary respiratory centers (29). Both spinal and cerebellar lesions had profound effects on posture and locomotion, resulting in nearly 1 mo of recovery before exercise could be performed again. The plasticity required for locomotion may have been accompanied by plasticity in the mediation of the hyperpnea; thus, as for our spinal lesion studies, the pre- vs. post-surgical lesion studies may have underestimated the role of the CFN in the exercise hyperpnea.
We reasoned that, compared with the effects of the surgical lesions, the posture and locomotion deficits would be attenuated when we injected methysergide or ibotenic acid to create reversible and irreversible dysfunction, respectively. However, even though attenuated, the goats were either unable or had difficulty walking on the treadmill immediately after these injections. As a result, our database for these studies is limited, and the earliest we could obtain data after injection of the neurotoxin was at least 24 h postinjection. These effects of the neurotoxin increased as the injection volume increased, which we anticipated, and therefore was the reason that we began with a low volume and progressively increased the volume of the injection. Moreover, the gait after methysergide and the initial studies after ibotenic acid were often abnormal; thus we are not certain the data reflect the true effect of the neuronal dysfunction on the exercise hyperpnea. However, the marked posture and locomotor effects and the 55% destruction of neurons indicate that the small attenuation of the exercise hyperventilation was not due to the possibility that we utilized too small volumes of injections and/or created lesions that were too small. We did not find a relationship between the physiological effects and the volume of the CFN destroyed or the total deficit in CFN neurons. Similarly, we found in the same goats that the physiological effects of focal acidosis in the CFN did not correlate with the volume acidified or the magnitude of the acidification (25). We speculate that the absence of correlation between the physiological effects and anatomic deficits (neuron deficit and volume destroyed) is in part due to variation between goats in neuronal density in the CFN and the heterogeneous distribution of chemosensitive, glutamate, and 5-HT neurons in the CFN of goats.
In most of the goats in this study, we previously found that microdialysis-induced focal acidosis increased breathing in the rCFN and decreased breathing in the caudal CFN (25). In most of the goats, surgical and neurotoxic lesions were created in both the rCFN and caudal CFN; thus it is conceivable that we caused dysfunction in neurons that had opposite effects on the exercise hyperpnea. However, in the few instances when the ibotenic acid and methysergide injection was primarily in either the rCFN or caudal CFN, there was no effect on the PaCO2 response to exercise. Despite these limitations, we can confidently conclude that a 55.0% reduction in CFN neurons does not dramatically affect the exercise hyperpnea.
Theories of the Exercise Hyperpnea
The mechanism(s) mediating the exercise hyperpnea has not been elucidated. For over a century, hypotheses have been formulated and tested regarding the mechanism(s) mediating the exercise hyperpnea. Many of these can be classified as "neural" in that it has been proposed that the signal originates in the brain (central command) or in the exercising muscles (spinal afferents) and reaches the medullary respiratory centers via neural pathways. Several other theories can be classified as "humoral" in that a by-product of exercise is sensed by a receptor within the lungs, heart, or carotid bodies, and the receptor then signals the medullary respiratory centers. Data have been found to both support and contradict each theory. Therefore, because several of these pathways had been shown to be capable of affecting breathing, but not critical for the hyperpnea, Yamamoto (38) proposed the "redundancy or occlusion" theory of the hyperpnea. He proposed that multiple mechanisms are capable of mediating the hyperpnea; thus, even if a major pathway is lesioned, an alternative pathway remains to mediate the hyperpnea. Our laboratory tested this hypothesis by lesioning three major proposed pathways (spinal afferent, lung, carotid bodies) in ponies, and we found that exercise hyperpnea was accentuated rather than attenuated; thus support for this theory was not obtained.
As summarized earlier, the recent findings of the Patterson group (32) and Dormer and Stone (10) suggested that the CFN might be critical to a normal exercise hyperpnea. Within the limitations of our study, the hypothesis was not validated. If the CFN was critical, then, rather than a very modest attenuation of the exercise hyperventilation, we should have found hypoventilation. Conceivably, the slight attenuation of the hyperventilation we observed may reflect a "coordination" role the CFN exerts for all neural and humoral stimuli that change during exercise. In this respect, the CFN differs from the medullary raphe nucleus, the retrotrapezoid nucleus, the facial nucleus, and the paragigantocellularis reticularis nuclei, because we have previously shown that lesions in each of these nuclei did not have even the small effect presently observed (18, 33). Finally, because of the potential for redundancy in the exercise hyperpnea mechanism as proposed by Yamamoto (38), other pathways for mediation of the exercise response may have compensated for lesioning of the CFN. Or with lesions of other redundant pathways, the CFN might assume a more critical role in mediation of the exercise hyperpnea.
Acute Effects of Methysergide
Geurts et al. (14) established the localization of four 5-HT receptor subtypes in the rat cerebellum with several residing in the deep cerebellar nuclei (CFN, interpositus, dentate). Gardette et al. (13) demonstrated in vitro that 5-HT increased the spontaneous firing rate of the deep cerebellar nuclei by 109% in 91% of the tested cells. In a series of studies, Mitchell and colleagues (15–17, 26) demonstrated that 5-HT released from the raphe is necessary for the short-term modulation of exercise. However, Fluoxetine (Prozac), a reuptake inhibitor of 5-HT, depressed respiratory control at rest, but had minimal effects during exercise in goats when injected intravenously (16). These studies suggested that 5-HT may affect the exercise hyperpnea. We, therefore, tested this hypothesis by blocking 5-HT receptors through injection of methysergide, the nonspecific 5-HT receptor antagonist, directly into the CFN. Due to the low number of animals on whom it was feasible to obtain data and the lack of consistency in those studies, it is difficult to definitively ascribe a role of 5-HT receptors in the exercise response, but any effect would appear to be minor.
Effects of Injecting Methysergide and Ibotenic Acid Into and Outside the CFN on Posture and Locomotion
It is well established that the vermis in which the CFN lies receives visual, auditory, and vestibular input as well as somatic sensory input from the head and proximal parts of the body. The vermis coordinates posture and locomotion via the CFN projections to cortical and brain stem areas, which then give rise to the medial descending systems that control the proximal limbs and muscles of the body. A series of inactivation studies using the GABA agonist muscimol over the last decade have demonstrated that the rCFN is involved in the control of posture (2, 20, 24), whereas the caudal CFN is involved in the control of visually guided eye movements (27, 30, 31). Dormer et al. (1, 10) demonstrated in dogs that almost all lesions caused postural and locomotor deficits, but complete recovery from these lesions was achieved within 10–20 days. Only dogs that had most of the CFN-damaged lesions were anxious and uneasy during treadmill running due to nonrecoverable vestibulomotor deficits (10). The postural and locomotor deficits described in the aforementioned studies were also observed in our goats in the hours and days following injections of ibotenic acid and methysergide inside and outside the CFN; thus our study in goats has confirmed findings in previous studies in rats, dogs, and monkeys.
We conclude that the CFN functions in the pathway necessary for the respiratory system's ability to meet the gas exchange requirements of submaximal exercise, but is not the source of the exercise hyperpnea. Additionally, we have reconfirmed that the CFN and, more generally, the cerebellum are more important for posture and locomotion.
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ACKNOWLEDGMENTS |
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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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, Workload 1 (1.8 miles/h at 5% grade); 
, workload 2 (1.8 miles/h at 15% grade). This figure represents the nonsignificant changes in PaCO2 from rest to steady-state exercise at 2 workloads (n = 4) for 6 days following bilateral injections of 0.5 µl ibotenic acid (P > 0.05). Preimplant represents the response of intact goats, whereas postimplant represents the response after microtubule implantation.
, Location of the tips of the microtubules (n = 2) that were implanted outside the CFN in a control animal. One animal in which a microtubule was implanted into the dentate nucleus is not shown due to the plane of this figure. rCFN and cCFN, rostral and caudal CFN, respectively.