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Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, Illinois 60637-1508
Submitted 5 August 2003; accepted in final form 1 June 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). Hyperthermia has also been implicated in sudden infant death syndrome (SIDS) (Fleming 1990; Harper et al. 2000; Poets et al. 1999; Russell and Vink 2001) as the body temperature of SIDS victims is typically markedly elevated on death (Fleming 1990). Here we examine mechanisms that may account for hyperthermic apnea.
The hypothalamus can clearly play a role in modulating RF with changes in body temperature (Boden et al. 2000; Inomoto et al. 1983; Ni et al. 1996). However, temperature can also directly affect the activity of the respiratory neural network located in the medulla. One area that seems to play a critical role in the generation of inspiratory activity is the pre-Bötzinger complex (PBC). This area is both necessary for the generation of normal respiratory activity (Gray et al. 2001; Ramirez et al. 1998) and sufficient to generate fictive respiratory activity when isolated in the brain stem slice preparation (Lieske et al. 2000; Smith et al. 1991). This slice preparation also contains the hypoglossal nucleus (XII), a motor output that is modulated in-phase with inspiratory activity. Brain stem-slice preparations containing the PBC and XII nucleus revealed that the PBC may modulate RF during brain stem temperature changes independently of influences from higher brain structures, such as the hypothalamus (Peever et al. 1999; Tryba and Ramirez 2003). Elevated temperatures increase fictive RF while inspiratory burst amplitude and duration decline in this in vitro preparation as similarly described in vivo (Galland et al. 1993; Tryba and Ramirez 2003). How is fictive respiratory activity modulated with temperature in the slice preparation? To begin to understand the mechanisms underlying RF modulation during hyperthermia, we compared the hyperthermic response of respiratory pacemaker neurons before and after they were synaptically isolated from respiratory network activity. Respiratory pacemaker neurons are thought to play a critical role in the generation of the respiratory rhythm in neonatal mammals (Rekling and Feldman 1998; Smith et al. 1991; Thoby-Brisson and Ramirez 2001).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Medullary brain slice preparation
All experiments used the transverse, rhythmic medullary brain-slice preparation (Funk et al. 1994; Ramirez et al. 1996). Mice (0–7 day old CD-1 outbred mice, Charles River Laboratories, Wilmington, MA) were deeply anesthetized with ethyl ether (Sigma; delivered by inhalation). On cessation of reflex activity, animals were quickly decapitated at the C3/C4 spinal level (Ramirez et al. 1996). The brain stem was dissected-out in ice-cold artificial cerebral spinal fluid (ACSF) that was equilibrated with carbogen (95% O2-5% CO2). Rhythmic 650-µm-thick slices containing the ventral respiratory group (VRG) (Ramirez et al. 1996) were obtained by slicing the medulla using a microslicer (Leica, VT1000S, Nussloch, Germany). Slices were submerged under circulating artificial cerebrospinal fluid (ACSF; 30°C; flow rate 15 ml/min) containing (in mM) 118 NaCl, 3 KCl, 1.5 CaCl2, 1 MgCl2*6H2O, 25 NaHCO3, 1 NaH2PO4, and 30 D-glucose, equilibrated with carbogen (95% O2-5% CO2, pH = 7.4 at room temperature, 
22°C). KCl was elevated from 3 to 8 mM over a span of 30 min before commencing recordings (Tryba et al. 2003). All chemicals were obtained from Sigma (St. Louis, MO). The pH of four different ACSF batches had a mean pH of 7.43 ± 0.01 (mean ± SD) at 30°C and a pH of 7.46 ± 0.02 at 40°C (n = 4; P = 0.034, paired t-test). The mean difference between the ACSF pH at 30 and 40°C was 0.04 ± 0.02 pH units.
Bath temperature was monitored and automatically adjusted to within ±0.7°C (range) of the set temperature using a Warner Instrument (Hamden, CT) TC-344B temperature regulator with an in-line solution heater (SH-27B). Hyperthermia was achieved by warming the ACSF bathing the brain-slice preparation. Reported temperatures refer to preparation bath ACSF temperature. Unless otherwise noted, the ACSF temperature in the preparation bath was actively heated from 30 to 40°C and then allowed to passively cool to 30°C at which point the bath temperature was actively maintained at 30°C. ACSF temperature at various locations within the bath were routinely uniform. In these experiments, we raised the bath temperature from 30 to 40°C at a rate of 
7°C/min, which is much more rapid than during heat stroke. The rapid heating protocol was chosen because, we used whole cell current clamping to record from PBC neurons during heating and our success in maintaining seals increased using a protocol having shorter recording times. Because warmer saline has a lower oxygen partial pressure, we used slices from young (P0- to P7-day old) mice that do not have a marked response to hypoxia but have a hyperthermic-response (Tryba and Ramirez 2003).
Electrophysiological recordings
INTEGRATED VRG POPULATION ACTIVITY.
Extracellular recordings were obtained with electrodes positioned on the slice surface of the VRG. The VRG signal collected was amplified and filtered (low-pass: 1.5 kHz, high-pass: 250 Hz), rectified and integrated using an electronic filter (time constant: 60 ms, Figs. 1, A and B) (Ramirez et al. 1996). The integrated VRG population activity is in-phase with that of the hypoglossal motor nucleus (i.e., 1:1 coupling), thus the VRG population bursts can serve as a marker of fictive inspiration (Telgkamp and Ramirez 1999; Tryba and Ramirez 2003). The frequency of VRG integrated inspiratory bursts during fictive eupnea was used to define RF.
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) (Figs. 1, A and B). Patch electrodes were manufactured from filamented borosilicate glass tubes (Clark G150F-4; Warner Instruments, Hamden, CT) filled with a solution containing (in mM) 140 K-gluconic acid, 1 CaCl2*6H2O, 10 EGTA, 2 MgCl2*6H2O, 4 Na2ATP and 10 HEPES. Only inspiratory neurons active in-phase with population activity were recorded in this study (the technique is described in Tryba et al. 2003). The discharge pattern of each cell type was first identified in the cell-attached mode prior to breaking the seal. Experiments were then performed in the whole cell patch-clamp mode and only inspiratory neurons were considered in this study. Inspiratory neurons were isolated and identified as pacemakers or nonpacemakers based on previously described criteria (Thoby-Brisson and Ramirez 2001; Tryba et al. 2003); pacemaker neurons are located in the PBC (Rekling and Feldman 1998; Smith et al. 1991; Thoby-Brisson and Ramirez 2001). The Vm values were corrected for liquid junction potentials as described by Neher (1992). In current-clamp, neurons were isolated from chemical synaptic input using a mixture of glutamatergic, GABAergic or glycinergic antagonists. These drugs were bath applied at the final concentrations of: 40 µM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; Tocris, Ellisville, MO), 10 µM (RS)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid [(RS)-CPP Tocris], 1 µM strychnine (Sigma), and 20 µM bicuculline Free-Base (Sigma). CNQX and CPP are AMPA and N-methyl-D-aspartate (NMDA) receptor antagonists, whereas bicuculline free base and strychnine are GABA and glycine receptor antagonists, respectively; bath application at these concentrations have been shown to be effective in the PBC slice preparation in other studies (Thoby-Brisson and Ramirez 2001; Thoby-Brisson et al. 2000; Tryba et al. 2003). Note that unlike bicuculline methiodide, the bicuculline free-base derivative is a specific GABA receptor antagonist that does not block apamin-sensitive Ca2+-activated K+ currents (Debarbieux et al. 1998; Johnson and Seutin 1997). Neurons shown in Figs. 4B (n = 4) and 5, A and B (n = 7), were isolated from chemical synaptic transmission using 200 µM Cd2+ (Elsen and Ramirez 1998). In cases where cadmium was used, it was applied as it rapidly blocks chemical synaptic transmission by blocking calcium currents (Elsen and Ramirez 1998). Cadmium is also used as a tool to discriminate between different types of pacemaker neurons as it indicates that bursting in these pacemakers persists in the presence of voltage-gated calcium channel blockade. Neurons that continue to burst in Cd2+ are cadmium-insensitive pacemaker neurons as previously described by Thoby-Brisson and Ramirez (2001). The remaining pacemakers studied here (n = 5) were isolated from chemical synaptic transmission using CNQX, CPP, bicuculline and strychnine in the absence of Cd2+; these data may include both cadmium-sensitive and -insensitive types of pacemakers as described by Thoby-Brisson and Ramirez (2001). In all, this study encompasses n = 16 total pacemakers (n = 11 isolated in Cd2+ and n = 5 isolated in a mixture of synaptic antagonists).
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QUANTITATIVE METHODS. Student's t-test were used to test for significant differences between mean pacemaker burst frequency (paired t-test), burst amplitude (% control, 1-sample t-test) and duration data (paired t-test) when the bath temperature was maintained at 30 and 40°C temperatures; comparisons were made for data collected over a 40-s duration (n = 5). Burst duration was defined as the time from first to last action potential within a burst. Burst amplitude was measured as the absolute value of the depolarization burst peak height from baseline and normalized as percent of control. Values were assumed to be significant at P < 0.05. Comparison of pacemaker burst frequency while embedded in the respiratory network and after isolation from chemical synaptic transmission was made using ANOVA analysis. As the pacemakers are temperature-sensitive, pacemaker data included in this analysis had heating profiles with similar time courses. For this reason, only a limited number of pacemaker neurons could be combined in the analysis. We also only included data from neurons the membrane potential of which returned to baseline after heating. Several neural recordings had to be excluded from data analysis because the recording became unstable at elevated temperatures. Mean values are followed by ±SD except where noted.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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During hyperthermia, both panting and nonpanting mammals modify their breathing by increasing RF and decreasing both inspiratory amplitude and duration. At elevated temperatures, fictive respiration generated in the VRG also includes an increase in RF and decline in amplitude and duration of inspiratory bursts (Tryba and Ramirez 2003). These changes in population activity may be due to network interactions and/or pacemaker properties. To examine this issue, we recorded from inspiratory neurons in control ACSF at 30°C (Fig. 1, A and B) while we transiently increased the bath temperature to 40°C and allowed it to cool to the control temperature (from 40 to 30°C).
Is the hyperthermic-enhancement of fictive respiratory frequency and reduction in population burst amplitude and burst duration correlated with similar changes in pacemaker bursting properties at elevated temperatures? In the absence of VRG network activity, synaptically isolated PBC pacemaker neurons increased their bursting frequency when the bath temperature was increased from 30°C (0.34 ± 0.12 Hz) to 40°C (1.3 ± 0.38 Hz; P < 0.001) (Figs. 2, A and B, and 3, A and B, n = 5). The mean frequency increased throughout heating (P < 0.001; ANOVA, Fig. 3A). The increase in frequency with temperature was fit by the equation, ln(F) = (T – To)/A, where ln = natural logarithm, F = the isolated pacemaker frequency, To = 36.47°C, A (1/slope) = 6.609 and T = temperature (Fig. 3B; r2 = 0.59; slope is non-zero P < 0.0001). Thus the equation predicts a 2.13-fold increase in pacemaker bursting frequency per 5°C increase in temperature for heating over this temperature range. In addition to the increase in isolated pacemaker frequency, the amplitude of the depolarizing drive potential underlying a burst (i.e., burst amplitude) increased at 40°C (169.7 ± 45.5%; n = 5, P = 0.026; Figs. 2, A and B, and 3C), while the burst duration at 30°C (1.44 ± 0.80 s) was reduced at 40°C (0.39 ± 0.21s; Fig. 3D, n = 5; P = 0.019). It is possible that the enhanced depolarizing drive potential underlying a burst observed at 40°C could reach inactivation, and in some cases, it did with heating (Fig. 2B), potentially reducing the number of action potentials/burst. The enhanced depolarization makes it difficult to precisely count action potentials within bursts as the spike amplitude can be truncated due to inactivation. With that caveat stated, we did not find significant differences in the mean number of action potentials/burst for 10 bursts taken from isolated pacemaker neurons at 30°C (22.02 ± 9.8; mean ± SE) versus 40°C (12.7 ± 4.1; n = 5, P = 0.204).
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), we analyzed data from experiments with overlapping temperature profiles during heating, but note that during passive cooling of the bath to 30°C, the SD of the bath temperature increased (Fig. 4A). When the bath temperature was transiently increased to 40°C and returned to the control temperature (30°C), pacemaker burst frequency increased and decreased in parallel with that of the intact network (Fig. 4A). After isolation from chemical synaptic transmission with 200 µM Cd2+ (n = 4), pacemaker burst frequency paralleled that observed in the intact network at control temperatures, during heating and during hyperthermic-augmentation of fictive respiration (Fig. 4B, bins 1–9, P > 0.05). Cooling was initiated at approximately the same time in each of the experiments, yet during initial cooling of the bath from 40°C, the burst frequency of the isolated pacemakers was less than when it was embedded in the intact network (Fig. 4B; bins 10 and 11: P < 0.001 and P < 0.008, respectively; n = 4). This deviation may reflect the increase in bath-temperature SD during passive cooling from 40 to 30°C (i.e., cooling at different rates; Fig. 4B). However, as the temperature was further decreased to 30°C, the bursting frequency of these neurons was similar to when they were embedded in the network or isolated from synaptic input (bins 12–20, P > 0.05, Fig. 4B; n = 4). Conditional bursting of inspiratory pacemaker neurons
Not all neurons continued to burst at 30°C after isolation from chemical synaptic transmission, but some neurons (n = 7) became rhythmic after heating and burst robustly at 40°C. In those cases, when the bath temperature was 30°C, the isolated neurons were either silent (n = 3) or fired action potentials in clusters that did not resemble bursts (n = 4; Fig. 5A). However, raising the bath temperature induced bursting with the first distinct burst occurring at a mean temperature of 36.8 ± 1.2°C (n = 7) and continuing when the temperature was elevated to 40°C (Fig. 5B; n = 7) and (as in Figs. 2, A and B, and 3C) bursts including an enhanced underlying depolarization (Fig. 5, A and B). Qualitatively similar changes where observed when the cell was embedded in the network (Figs. 5, C and D).
Hyperthermic fictive apnea
The respiratory network (Tryba and Ramirez 2003) and isolated pacemakers (Figs. 6, A and B) can generate stable fictive eupneic activity at temperatures of 30 and 40°C. However, we found that there is an upper critical temperature range at which pacemaker bursting mechanisms failed to generate endogenous rhythmic activity when the bath temperature was raised >40°C (Fig. 6C). The mean temperature at which synaptically isolated pacemakers failed to continue to generate endogenous bursting was 41.8 ± 0.9 (n = 5; Fig. 6, C and D). In all cases examined, bursting properties recovered after cooling (Fig. 6C).
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Embedded in the respiratory network, nonpacemaker neurons increase their frequency of rhythmic activity when the bath temperature is elevated to 40°C (Fig. 7, A and B, n = 8). However, at the control temperature (30°C), nonpacemakers became either silent (n = 5) or tonically active (n = 3) after isolation from chemical synaptic input. These neurons remained either tonically active or silent after raising the bath temperature to 40°C (Fig. 7, A and B) and did not show a significant difference in Vm at 30°C (–54.5 ± 6.8 mV) versus 40°C (–54.7 ± 6.4 mV; P = 0.803, n = 8).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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. Although caution should be used when extrapolating in vitro findings to the situation in vivo, these data are consistent with the findings that there are upper and lower critical body temperatures for sustaining respiration. In rats, a body temperature of 41.5°C is lethal to half of a population primarily due to respiratory as well as cardiac autonomic failure (Hubbard et al. 1976) and an average lethal core temperature for eutherian mammals is between 42 and 44°C (Adolf 1947). In fact, in most mammals, a body temperature >40°C severely compromises physical performance (Fuller et al. 1998).
Modulation of RF is a major mechanism by which most mammals dissipate heat (Altman and Dittmaer 1966; Saiki and Mortola 1996). At hyperthermic temperatures, most mammals (including nonpanting species) increase RF but decrease inspiratory amplitude and duration. This increases ventilation to dissipate heat. As in vivo, fictive eupneic activity at the population level includes an increase in RF accompanied by a reduction in inspiratory activity burst amplitude and duration (Tryba and Ramirez 2003).
Our data indicate that elevated temperatures directly modulate respiratory pacemaker bursting properties, by increasing the bursting frequency of isolated pacemakers (Fig. 3, A and B), enhancing the depolarization underlying their bursts (Fig. 3C), reducing burst duration (Fig. 3D), and additionally, inducing bursting properties in some inspiratory neurons that did not burst at 30°C (Fig. 5, A and B). Interestingly, during heating, the bursting frequency of PBC pacemakers directly paralleled that of the intact network, both before and after synaptic isolation (Fig. 4, A and B). Additionally, the approximate twofold/5°C increase in isolated pacemaker frequency we observed is similar to the rate of increase in respiratory network output (fictive RF) that occurs for temperatures between 25 and 35°C in vitro (Peever et al. 1999). In contrast to pacemakers, the activity of isolated nonpacemaker neurons was not significantly altered during hyperthermia. These data suggest that pacemakers rather than nonpacemaker neurons may be responsible for FM of fictive respiration during an increase in temperature. Pacemakers are also thought to underlie hypoxic modulation of RF (Thoby-Brisson and Ramirez 2000). However, we cannot rule out the possibility that synaptic interactions may also play an important role in modulating the response of the respiratory network to temperature changes. Indeed, while changes in the frequency (Fig. 3, A and B) and duration (Fig. 3D) of synaptically isolated pacemaker bursts were similar to those of respiratory network population activity during heating (Fig. 4, A and B) (Tryba and Ramirez 2003), fictive inspiratory population activity amplitude declined (Tryba and Ramirez 2003). This effect on the population amplitude is opposite to the hyperthermic effect on the amplitude of individual, synaptically isolated pacemaker in which burst amplitude increased (Fig. 3C).
This discrepancy is not too surprising, because the integrated population amplitude is not only determined by the amplitude of the depolarizing drive potential in individual neurons. Integrated population amplitude depends on various factors including the number of neurons active during inspiration and the intraburst spike frequency of inspiratory pacemaker and nonpacemaker neurons as well as the synchrony between neurons. A reduced population amplitude could also be due to changes in synaptic interactions among network members (Kelty et al. 2002). At hyperthermic temperatures, there is enhancement of both glycinergic and glutamatergic spontaneous miniature postsynaptic potentials with inhibition being enhanced to a greater extent than excitation (Kelty et al. 2002). This may not only reduce the number of neurons active during each fictive inspiratory burst but may also modulate pacemaker activity as inhibition can suppress pacemaker bursting (Tryba et al. 2003). We therefore hypothesize that pacemaker properties play an important role in determining the frequency response and possibly the burst duration of the respiratory network activity, but that the hyperthermic response of the respiratory network, which includes also a modulation in amplitude of population activity, will be the result of a complex interaction between cellular and synaptic properties.
At the population level, the hyperthermic response is consistent with fictive eupneic activity (Tryba and Ramirez 2003) that includes both cadmium-sensitive and -insensitive pacemakers (Thoby-Brisson and Ramirez 2001). Although not specifically tested here, note that heating may differentially modulate these different types of pacemakers.
In this study, the pH of the ACSF increased (on average) by 0.04 ± 0.02 pH units when the temperature was raised from 30 to 40°C. Both VRG population and PBC pacemaker bursting frequency increase with a decrease in pH (Johnson et al. 1998). Thus the increase in VRG population (Tryba and Ramirez 2003) and PBC pacemaker bursting frequency at elevated temperatures that we demonstrated is opposite to what one would expect if an elevation in pH played a significant role in determining the fictive RF in our studies. Peever et al. (1999) also examined the issue of how the frequency of respiration (hypoglossal activity) is influenced by temperature and pH in transverse brain stem slice preparations. While motor output (hypoglossal bursting) RF was modulated by temperature, at any given temperature, large pH changes did not significantly modify the fictive RF. Thus although the ACSF pH changes with changes in temperature, the principal effect on RF observed here is likely due to temperature rather than pH changes.
An important observation was that bursting properties of respiratory pacemakers can be conditionally dependent on temperature; that is, some synaptically isolated pacemakers failed to generate endogenous rhythmic bursting at both hypothermic (30°C; Fig. 5A) and hyperthermic temperatures (>40°C; Fig. 6, C and D). To our knowledge, there are few other reports of modulation of pacemaker properties at elevated temperatures (e.g., lobster stomatogastric system: Johnson et al. 1992; mollusks:Gola 1976; Thompson et al. 1986; Treistman and Bablanian 1985). Interestingly, some pacemakers initiated bursting activity within a normothermic range (36.8 ± 1.2°C), suggesting that expression of pacemaker properties is temperature-sensitive. Note that the mouse mean basal temperature is 36.5 ± 0.1°C (Wikström et al. 1998) and normothermia for eutherian species is between 36 and 38°C (Morrison and Ryser 1952). More importantly, because many in vitro respiration studies—including our own—were performed at hypothermic temperatures (to preserve preparation viability), it should be considered that the full repertoire of respiratory neurons may not be appreciated under these conditions. Our finding may have important implications for various modeling studies that address the role and significance of pacemaker neurons in respiratory rhythm generation (Butera et al. 1999; Rybak et al. 1997).
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. K. Tryba, Dept. of Organismal Biology and Anatomy, University of Chicago, 1027 E. 57th St., Chicago, IL 60637-1508 (E-mail: Andrew.Tryba{at}ttuhsc.edu).
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REFERENCES |
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 M. K. Klose, D. Chu, C. Xiao, L. Seroude, and R. M. Robertson Heat Shock-Mediated Thermoprotection of Larval Locomotion Compromised by Ubiquitous Overexpression of Hsp70 in Drosophila melanogaster J Neurophysiol, November 1, 2005; 94(5): 3563 - 3572. [Abstract] [Full Text] [PDF]
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VRG). The population activity is predominated by inspiratory neurons, giving rise to fictive inspiratory bursts in the integrated traces (
) and pacemaker bursts (
) in response to heating the bath artificial cerebrospinal fluid (ACSF) from 30 to 40°C (temperature). Bins are of equal 30s duration. B: mean pre-Bötzinger complex (PBC) pacemaker burst frequency histogram when synaptically embedded in the respiratory network (
, the mean (±SE) ratio of Freq. T/Freq. T-1 (i.e., the factor by which frequency increased for each degree increase in temperature). B: the increase in frequency with increase temperature (shown in A, n = 5) can be fitted to a logarithmic equation that predicts a 1.16-fold increase in pacemaker bursting frequency for a 1°C increase in temperature during heating between 
