Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, Illinois 60637
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ABSTRACT |
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Telgkamp, Petra and Jan-Marino Ramirez. Differential Responses of Respiratory Nuclei to Anoxia in Rhythmic Brain Stem Slices of Mice. J. Neurophysiol. 82: 2163-2170, 1999. The response of the neonatal respiratory system to hypoxia is characterized by an initial increase in ventilation, which is followed within a few minutes by a depression of ventilation below baseline levels. We used the transverse medullary slice of newborn mice as a model system for central respiratory control to investigate the effects of short-lasting periods of anoxia. Extracellular population activity was simultaneously recorded from the ventral respiratory group (VRG) and the hypoglossus (XII) nucleus (a respiration-related motor output nucleus). During anoxia, respiratory frequency was modulated in a biphasic manner and phase-locked in both the VRG and the XII. The amplitude of phasic respiratory bursts was increased only in the XII and not in the VRG. This increase in XII burst amplitude commenced ~1 min after the anoxic onset concomitant with a transient increase in tonic activity. The burst amplitude remained elevated throughout the entire 5 min of anoxia. Inspiratory burst amplitude in the VRG, in contrary, remained constant or even decreased during anoxia. These findings represent the first simultaneous extracellular cell population recordings of two respiratory nuclei. They provide important data indicating that rhythm generation is altered in the VRG without a concomitant alteration in the VRG burst amplitude, whereas the burst amplitude is modulated only in the XII nucleus. This has important implications because it suggests that rhythm generation and motor pattern generation are regulated separately within the respiratory network.
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INTRODUCTION |
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The neuronal network controlling mammalian
breathing responds to hypoxia in a biphasic manner (Bureau et
al. 1984; Haddad and Jiang 1993
). Initially,
ventilation is increased (augmentation), but during prolonged hypoxia
the augmentation is followed by a depression and cessation of
respiratory activity (apnea) (Lawson and Long
1983
; Neubauer et al. 1990
). However,
this is a simplified description of the events that characterize the
hypoxic response of the respiratory system. Recordings from
respiration-related areas of the brain reveal that severe hypoxia or
anoxia affects central respiratory activity in a differential manner.
The augmentation in one respiration-related area does not necessarily
correspond to the activation of other areas. For example, activities of
phrenic and intercostal (Sears 1964
; St. John and
Bartlett 1979
) as well as hypoglossal motoneurons (XII)
(Hwang et al. 1983
) increase significantly during the
hypoxic augmentation. At the same time a significant proportion of
bulbospinal neurons in the ventral respiratory group (VRG) and the
dorsal respiratory groups (DRG) show no change or exhibit a depression
in discharge frequency, whereas some neurons in the VRG increased their
activity (St. John and Bianchi 1985
; St. John and
Wang 1977
). Thus it remains unclear whether the population of
respiratory neurons in the VRG increase their activity during hypoxia
like the neurons in the motor nuclei or whether the population activity
decreases in the VRG. An overall decrease in the VRG population
activity would be surprising, because it is generally assumed that one
particular region of the VRG, the pre-Bötzinger complex, is
essential for respiratory rhythm generation (Ramirez and Richter
1996
; Rekling and Feldman 1998
;
Smith et al. 1991
). Conceptually this issue is of great
interest because it remains unknown whether the initial augmentation
results in a general excitation of the respiratory network including
the VRG and its motor output or whether alternatively the anoxic
response is the result of a complex modulatory process that regulates
different regions of the respiratory control system in a differential
manner. To better characterize the anoxic response of the respiratory
system, we used the medullary slice preparation from neonatal mice
postnatal days 1-7. The effect of anoxia on the
respiratory network was assessed by recording simultaneously extracellular population activities from the hypoglossus (XII) nucleus
and the VRG (Fig. 1). This experimental
approach allowed us for the first time to directly compare the anoxic
effects on two different respiratory neuron population activities. This
is new because previous studies focused either on a characterization of
only the XII activity during hypoxia (Ramirez et al.
1997
), or characterized the hypoxic response of only single VRG
neurons (Ramirez et al. 1998
). Like the analysis of
single neuronal activity in other in vitro and in vivo studies
(Ballanyi et al. 1994
; England et al.
1995
; Richter et al. 1993
), the previous studies
demonstrated important properties of single cell types within the VRG
but provided no direct insight into the population response of the VRG.
In the simultaneous population recordings from the XII and the VRG, as
performed here, we describe not only in more detail the sequence of
events that characterize the anoxic augmentation in different cell
populations, but we will also demonstrate that respiratory burst
amplitude and frequency are altered independently in the VRG and XII.
These findings have important implications for the underlying
mechanisms of anoxic augmentation.
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METHODS |
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Preparation
Male and female mice (CD-1; Charles River Laboratories, see
www.criver.com/1999rm/htdocs/cdmice_swiss.html) of postnatal age 0-7
days were deeply anesthetized with ether, then decapitated at the
spinal level of C3-C4. The
preparation procedure has been described previously in detail
(Ramirez et al. 1996), thus we will summarize only the
most important steps. The brain was removed from the skull and
immediately transferred into ice-cold artificial cerebrospinal fluid
(ACSF) containing (in mM) 118 NaCl, 3 KCl, 1.5 CaCl2, 1 MgCl2 * 6 H2O, 25 NaHCO3, 1 NaH2PO4, and 30 D-glucose and equilibrated with carbogen (95%
O2-5% CO2, pH 7.4). The
brain stem was fixed on an agar block and secured in a vibratome with the rostral end up. Thin slices were sectioned serially from rostral to
caudal until reaching the rostral boundary of the pre-Bötzinger complex. The level of the pre-Bötzinger complex was recognized by
cytoarchitectonic landmarks, such as the absence of the facial nucleus
and the presence of inferior olive (IO), nucleus of the solitary tract
(NTS), hypoglossal nucleus (XII), and nucleus ambiguus (NA). The
rostrocaudal distance between the caudal end of the facial nucleus and
the obex was ~700 µm in newborn mice. Portions of the VRG and XII
were isolated in a 500- to 600-µm slice that was obtained ~200 µm
caudal to the caudal end of the facial nucleus. The slice was
immediately transferred into a recording chamber.
Submerged under a stream of ACSF (temperature, 29°C; flow rate 11 ml/min), the preparation was stabilized for 30 min in ACSF. The potassium concentration in the ACSF was raised to 8 mM over a period of 30 min and maintained at this concentration to keep rhythmic activity regular for up to 13 h. Anoxia was induced by bubbling the ACSF with 95% N2-5% CO2 (pH 7.4). Exposure to anoxia was restricted to a period of 5 min. Although the anoxic stimulus in the in vitro situation is different from the hypoxic stimulus in vivo in that the oxygen concentration switches from norm- or even hyperoxic to anoxic conditions, the response patterns are similar to those described for the in vivo and chemo-deafferented animal.
Recording and data evaluation
Extracellular population activities of neurons in the
hypoglossal nucleus and VRG were recorded with electrodes that had an impedance of 120-150 k, when filled with CSF. The electrodes were
positioned with the visual aid of a binocular microscope (Zeiss,
Axioskop) and the acoustic aid of a loudspeaker monitoring neuronal
acitivity that was evoked when touching the slice surface with the
electrode. Signals were amplified (1,500 times), band-pass filtered
(low-pass 1.5 kHz, high-pass 250 Hz), and electronically integrated
(Paynter filter, set at a time constant of 40-50 ms; Fig. 1,
integrated traces). The data were digitized with a Digidata board (Axon
Instruments), stored on a PC (Dell Pentium computer) and analyzed
off-line with the software programs Axotape (Axon Instruments) and IGOR
(Brain Waves). Inspiratory bursts were detected in IGOR with a manually
chosen threshold to determine relative time course of respiratory
frequency and tonic and phasic burst amplitude for the different phases
of anoxia. In both the XII and the VRG only recordings with good
signal-to-noise ratio were analyzed (such recordings showed
significantly larger amplitudes of integrated inspiratory activity than
the variances of the noise and expiratory activity). A potential
problem in analyzing the amplitude of the integrated traces was the
superimposition of respiratory burst activity and tonic activity (that
resulted in a baseline shift of the integrated activity). Tonic
activity and respiratory burst activity did not add up in a strictly
linear manner. We therefore obtained two measurements during phases of tonic activation. In the figures, measurements excluding tonic activity
are represented as white bars, and those with additional tonic activity
are indicated by black bars.
Only one anoxic response per slice was examined and analyzed, because respiratory frequencies often increased after repeated anoxic exposures. The data were statistically analyzed and graphs created in Prism (GraphPad Software). Means are presented as means ± SE. Significance was determined using variance analysis and the paired Student's t-test comparing means of control conditions with the means of different phases of the anoxic response. Significance was assumed when P < 0.05.
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RESULTS |
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The effects of anoxia on XII and VRG activity were evaluated from the integrated traces of the extracellularly recorded population activity (Fig. 1). In these integrated traces, respiratory bursts were characterized by rapid upward deflections; changes in tonic activity were evident in slow changes in the baseline of integrated activity (Fig. 2). Introduction of anoxia altered 1) frequency and 2) amplitude of phasic-respiratory activity, as well as 3) amplitude of tonic activity in VRG and XII (Fig. 2). These alterations will be described in the next paragraph.
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Qualitative description of the anoxic response
FREQUENCY OF RESPIRATORY BURSTS. The frequency of respiratory bursts was transiently increased in the VRG and the XII nucleus upon introducing anoxic conditions. The rhythmic burst activity occurred phase-locked in the VRG and XII (Fig. 2B). Thus the time courses of frequency alteration were the same in both areas. In two of nine preparations, this frequency increase was above control levels for the entire 5 min of the examined anoxic period (Fig. 2A). However, in most preparations (7 of 9 preparations) the frequency increase was followed by a decrease in respiratory frequency below control frequencies as depicted in Fig. 2B. This is illustrated in sequential histograms, in which instantaneous frequency values are plotted against time (Fig. 3) The frequency histograms of seven slices were superimposed in Fig. 3A. Here the frequency values of each slice are represented by a different symbol. Zero on the x-axis indicates the onset of anoxia. Note that there is considerable variability in the occurrence of the maximal frequency and the onset of the frequency depression. Two extreme examples are shown in Fig. 3B. The mean frequency values obtained for these slices at any given time during anoxia are shown in Fig. 3C. These values indicate that on average the frequency value is modulated in a biphasic manner during anoxia.
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AMPLITUDE OF RESPIRATORY BURSTS.
The amplitude of the respiratory bursts was differentially modulated in
the XII and in the VRG. In the examined preparations using CD-1 mice,
anoxia enhanced the amplitude of phasic respiratory rhythmic activity
in the XII (Fig. 2A, rapid upward deflections, top
trace, thin arrows), whereas no or only little alteration occurred
in the VRG (Fig. 2A, rapid upward deflections, bottom trace). The modulation of the amplitude is illustrated in
sequential histograms in Fig. 4. In these
histograms phasic respiratory burst amplitude values (in a period of
30 s) in the VRG and XII were plotted against time (Fig. 4,
A and B, left panel). We plotted changes of
amplitudes both including () and excluding (
) tonic activity at
times when those activities overlapped (Fig. 4, A and
B, right panel). Amplitudes were normalized against control respiratory bursts to compensate for different recording qualities. Changes in tonic activity were evaluated by comparing the amplitude values measured during three to five interburst intervals in anoxia with respective amplitude values obtained during three to five interburst intervals in control conditions.
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ANOXIA-INDUCED ALTERATION IN TONIC ACTIVITY. The anoxia-induced alteration in tonic activity was reflected in a slow upward shift in the baseline of integrated traces in the XII and VRG (Fig. 2A, wide arrow). In the XII, tonic activity always returned to baseline levels during the first 3 min of anoxia. In the VRG, tonic activity decreased in most cases (6 of 9) below control levels during the 5 min of anoxia. Thus the VRG showed a biphasic modulation of tonic activity. Because it is difficult to determine the zero of our extracellular recordings because of some tonic intraburst activity even under control conditions, we measured the amplitude of tonic activity (Fig. 6, B and C, black bars) for quantitative comparisons using the following procedure. The baseline in control conditions was set as 0 and the amplitude of control respiratory phasic activity set as 100%. This normalizing procedure eliminated differences between different recordings. The amplitude of tonic activity was given as a percentage relative to the phasic activity at control conditions.
Quantification of the anoxic effect
The sequential histograms in Figs. 3-5 have indicated that the amplitude and frequency were modulated in a transient manner: an initial increase in the frequency was followed by a depression. The burst amplitude in XII was enhanced during the entire 5 min of anoxia, but the average histogram (Fig. 5C) indicates that there was also a transient peak in the AM. Similarly, the increase in tonic activation of the XII and VRG were transient events. This raises the question, whether the peak of the FM occurred at the same time as the peak of the burst AM and the peak of the tonic activation. This issue could not be addressed adequately by comparing the times of maximal frequency, burst amplitude, and tonic activation, because the onset of these modulations varied considerably between different slices (Figs. 3B and 5B). Therefore we addressed this issue by measuring the modulation of the different parameters at different stages of the anoxic response. Measurements were obtained during the following stages of anoxia:
1) First minutes of anoxia before the onset of the pronounced increase in tonic activity.
2) During the maximal frequency augmentation.
3) Following the pronounced tonic augmentation.
4) During maximal frequency depression and tonic amplitude depression in VRG.
During each of these stages, the mean frequency and amplitude values of respiratory rhythmic bursts were determined for each experiment. Despite different time courses of the anoxic response, this procedure allowed a direct comparison of the different parameters during the different anoxic stages.
1) One to two minutes before the onset of tonic activity, the frequency increased on average by 37 ± 25% (from 0.389 to 0.472 Hz, mean ± SE, n = 8; Fig. 6A1). Overall, however, the mean frequency increase (n = 8) was not significant, because 50% of the slices (n = 4) did not show a significant frequency increase before the onset of tonic and phasic amplitude activation of the XII. Figure 6A1, right panel, shows a Box-Whisker plot of the FM to illustrate the variabilities between the different preparations. The whiskers show the range of data; they extend from the smallest to the largest values. The box extends from the 25th percentile to the 75th percentile; the horizontal line represents the median (50th percentile).
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2) The maximal frequency augmentation of respiratory
rhythmic activity (124.5 ± 45.7% increase, n = 9; Fig. 6A2) occurred after the onset of phasic and tonic AM
in the XII (see Fig. 2A). At this stage, the frequency was
significantly enhanced compared with the control conditions. Similarly,
when compared with the control conditions, the phasic and tonic XII
amplitude were significantly enhanced during the peak frequency (Fig.
6B2; left panel: mean values, right panel: Box
and Whisker plots). The concurrent phasic and tonic activation is
illustrated in Fig. 6B2 by superimposing an open (phasic
modulation, 104.4% ± 59.62 increase) and a black bar (tonic
modulation, 153.5% increase, left panel). In contrast to
the AM of the phasic XII activity, there was no significant AM of the
phasic VRG bursts (7.72 ± 12.92%, n = 9, see
Fig. 6C2, open bar). Mean maximal tonic VRG activity reached
a level of 25.7 ± 10.33% (n = 9; Fig.
6C2). The maximal frequency increase did not precisely
coincide with the maximal tonic activation of either the XII or the
VRG. In the XII, the maximal increase in tonic activation occurred
after the maximal frequency and the tonic activity declined rapidly
shortly after. In the VRG, tonic activity increased fast and remained
at an increased level for a longer period than the maximal increase in
tonic activation and was independent from the FM.
3) After the cessation of the tonic XII activation (see Fig.
2A), respiratory XII burst amplitude was still significantly increased (209.6 ± 73.75%, n = 6; Fig.
6B3). In contrast, the amplitude of respiratory VRG bursts
was not significantly altered (1.03% ± 12.6 of control,
n = 9, Fig. 6C3). At this stage of the
anoxic response, the frequency of respiratory rhythmic activity was
either still enhanced (Fig. 2) or already depressed compared with
control conditions (Fig. 3A). On average, it was below the maximal frequency values and was at this stage not significantly different from control conditions (30.6 ± 27.5%;
n = 9; Fig. 6A3).
4) The maximal depression occurred toward the end of the
5-min period of anoxia and was characterized by a significant
depression in the VRG tonic and phasic activity (59.9 ± 15.7%,
n = 9; Fig. 6C4, black and open bar). At
this stage, the frequency of respiratory activity was significantly
decreased (34.71 ± 15.03% n = 6; Fig. 6A4) despite a considerable variability between experiments
as indicated in the Box-Whisker plot (Fig. 6A4, right
panel). The maximal depression in the amplitude of VRG activity
occurred at a time when the amplitude of the phasic XII bursts was
still augmented in 80% of the slices (see, e.g., Fig. 2B).
However, as indicated in the Box-Whisker plot (Fig. 6B4, right
panel), there was variability and in two slices the XII amplitude
had returned to baseline levels. On average, the amplitude at this
stage was not significantly different from control conditions
(115.2 ± 65.3%, n = 6, Fig. 6B4).
There was also no significant tonic depression in the XII nucleus
(
19.8 ± 9.6%, n = 7; Fig. 6B4,
black bar, left panel).
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DISCUSSION |
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Here we have demonstrated that anoxia affects two
respiration-related areas within the brain stem in a differential
manner: the VRG and the XII nucleus. The VRG contains the
pre-Bötzinger complex, the presumed site for respiratory rhythm
generation (Smith et al. 1991), and the XII nucleus
represents a respiratory motor output nucleus (e.g.,
Withington-Wray et al. 1988
). The respiratory frequency
was phase-locked between the two areas and showed a similar modulation.
This was expected, because the respiratory rhythm presumably originates
in this preparation within the VRG and projects from there to the XII
nucleus (Funk et al. 1993
). However, the following
differential effects were observed for other parameters of respiratory activity.
1) The modulation of tonic activity and of respiratory
frequency were independently affected. In the VRG, tonic activity
decreased sometimes below control levels while the frequency was still
enhanced. This suggests that an overall excitatory effect cannot be the only explanation for the frequency increase. Given that the tonic activity in the integrated trace included also expiratory activity, this effect could be explained by an earlier shut down of expiratory compared with inspiratory neurons, as has been discussed earlier (Ballanyi et al. 1994).
2) The frequency modulation and the modulation of the amplitude of phasic XII bursts do not occur simultaneously, because the XII burst amplitude remained augmented during the frequency depression.
3) The respiratory burst amplitude was significantly
enhanced only in the XII nucleus and not in the VRG. In most
experiments, the burst amplitude commenced to decrease in the VRG while
the amplitude of the hypoglossal bursts was still enhanced. This
suggests that the modulation of burst amplitude is regulated
independently or via different mechanisms in these two areas. The AM in
the XII has previously been observed by Ramirez et al.
1997. As shown in Fig. 5C of Ramirez et al.
1997
, there were some neonates that had an AM, but the
modulation averaged over several animals was not statistically
different from the control. This is different from our current finding,
where the majority of neonates showed a significant AM (Fig.
6B). This difference may be explained by differences in the
metabolic state of the slices. A manuscript by Wilken et al.
(1998)
indicated that neonatal slices that were treated with
creatine exhibit a pronounced and significant augmentation. Therefore
it is conceivable that the slices examined in this study had a larger
ATP pool to begin with, and even untreated neonates exhibited a
pronounced augmentation. This difference in the metabolic state could
be due to slight differences in the preparation time. Although we
prepare the slices in principal as described before, the slicing
technique became much more routine and preparing a slice takes usually
<5 min. We also use a different vibratome (FHC), which might result in
a slightly different preservation of the slices. Another difference is
that the results were obtained with different mouse strains (we used
CD-1 mice; see METHODS).
4) In the present study we demonstrated that the
amplitude of tonic modulation differed between the VRG and XII nucleus.
The XII exhibited a pronounced larger tonic activation than the VRG. This tonic activation has been previously mentioned in hypoglossal recordings of the unanesthetized, but not the anesthetized in vivo
animal (Weiner et al. 1982). Thus our data are
consistent with the unanesthetized in vivo animal. The fact that the
tonic activation is stronger in the XII than in the VRG may reflect a
higher excitability of XII neurons in response to anoxic insults. A
higher anoxic excitability of XII neurons compared with neocortical and
hippocampal cells has been described previously (Donnelly et al.
1992
; O'Reilly et al. 1995
). The authors showed
that hypoglossal neurons exhibited stronger depolarizations and a
higher depolarization rate. Because this depolarization results in an
increase in the frequency of action potentials, we assume that the high
tonic activity observed in our experiments probably reflects this
depolarization. Although a high excitability has been attributed to
brain stem neurons in general (Haddad and Jiang 1993
;
Jiang and Haddad 1991
), our data suggest that this
generality may not be justified as the VRG responded with a reduced
tonic modulation compared with the XII. However, it must be emphasized
that this difference is based on integrated population recordings,
which provide no direct insights into the mechanisms that are
responsible for this difference. But they are consistent with
intracellular recordings from VRG neurons that exhibited only a weak
depolarization (Ramirez et al. 1998
).
Because the XII and VRG serve different functions in respiratory
control, the differential modulation of respiratory parameters has
interesting conceptual implications and suggests that the anoxia-induced augmentation and depression cannot be attributed to just
a "general" excitation and subsequent shut-down of brain stem
neurons. Our experiments show that both excitation and depression exhibit region-specific differences. The different responses of the VRG
and XII are of particular interest, because it is generally assumed
that the respiratory rhythm is generated within the VRG (Bianchi
et al. 1995; Duffin and van Alphen 1995
)
or more specifically within the pre-Bötzinger complex
(Rekling and Feldman 1998
; Smith et al.
1991
). In the VRG cell population, the increase in the excitability induced by anoxia is less pronounced than in the XII. This
finding supports in vivo data that indicate that the activity of some
VRG cells declines during anoxia (England et al. 1995
;
Richter et al. 1991
, 1993
). It has been
shown that specific subpopulations of VRG neurons in neonatal mice in
vitro, like, e.g., biphasic expiratory cells and some inspiratory
cells, ceased their firing, whereas other subpopulations (50% of the
inspiratory cells) remained active even during anoxic conditions
(Ballanyi et al. 1994
; Ramirez et al.
1998
; Völker et al. 1995
). This partial inactivation of respiratory neurons could explain the decrease in the
integrated inspiratory burst amplitude and the early depression of
tonic activity of neurons of the VRG population.
However, it is remarkable that despite this partial inactivation, the
reconfigured network is able to generate stable respiratory rhythmic
activity. Even more remarkably, the frequency is initially enhanced and
hypoglossal burst amplitude increased. The lack of an enhanced phasic
amplitude in the VRG has an interesting implication because it suggests
that the enhanced amplitude in the XII motor output that is typical for
the anoxic augmentation cannot be attributed to an increased direct
drive from the VRG to the XII nucleus. It rather seems that the
enhanced amplitude of the XII burst has to be attributed to either a
neural mechanism localized within the XII nucleus or to a modulation at
sites downstream to the VRG/pBC. There are some direct projections from
the VRG to the hypoglossus nucleus (Dobbins and Feldman
1995), and therefore one possible mechanism might involve
changes in synaptic transmission. However, the evidence for
monosynaptic projections from the VRG to the hypoglossus nucleus are
minimal (Lipski et al. 1994
). Therefore another possible
mechanism for the amplification of the inspiratory drive involves
paucisynaptic connections or additional inputs from further areas in
the slice preparation. Examples for those would be nonrespiratory
neurons in the dorsomedial medullary reticular formation that provide
input into the XII (Woch et al. 1998
) or inspiratory
premotor neurons in the tegmental field (Wilson et al.
1998
). An independent regulation of respiratory drives and frequency has previously been described also for the ventilation in the
in vivo neonatal monkey, where respiratory drives were enhanced during
decreased respiratory frequencies and decreased minute ventilation
(LaFramboise and Woodrum 1985
). Similarly, St. John and Bianchi (1985)
attributed the augmentation
of the motor output to a modulation of respiratory activity within the XII and phrenic motor nuclei. Possible mechanisms that lead to a
differential modulation of the motor output during anoxia are as yet
unknown. However, it is well established that these motor nuclei
receive various modulatory inputs that affect the respiratory drive
(see, e.g., Dong and Feldman 1995
; Funk et al.
1994
). Because neuromodulators are known to be released during
hypoxia (Goiny et al. 1991
; Lindefors et al.
1986
; Yan et al. 1995a
,b
), they may be involved
in mediating the differential response within the motor nuclei and the
VRG. Alternatively, ion channel properties might differ between the VRG
and XII motor nucleus, which might result in the differential response
of these functionally different areas. The transverse slice preparation
appears to be an ideal model system to further study the underlying
mechanisms that lead to this differential anoxic response.
Although we did not determine the mechanisms that lead to regional
differences in the anoxic response of VRG and XII nucleus, our results
indicate that the frequency and amplitude modulation is regulated in a
differential manner within the respiratory network. This is an
experimental evidence for the hypothesis formulated earlier by Feldman
and colleagues, that rhythm- and pattern-generating mechanisms are
separate (Feldman et al. 1990). This independent regulation could be interpreted as part of an adaptive process that
decreases the activity in the neuronal network that is responsible for
respiratory rhythm generation, while it enhances the intensity of the
motor output locally within the motor nucleus.
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ACKNOWLEDGMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grant 60120 to J.-M. Ramirez.
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FOOTNOTES |
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Address for reprint requests: J.-M. Ramirez, Dept. of Organismal Biology and Anatomy, University of Chicago, 1027 E. 57th St., Chicago, IL 60637.
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.
Received 13 October 1998; accepted in final form 15 June 1999.
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REFERENCES |
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