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. 2005 Sep 28;25(39):8938-47.
doi: 10.1523/JNEUROSCI.2415-05.2005.

Regulation of ventral surface chemoreceptors by the central respiratory pattern generator

Patrice G Guyenet  1 , Daniel K Mulkey, Ruth L Stornetta, Douglas A Bayliss
Affiliations

Regulation of ventral surface chemoreceptors by the central respiratory pattern generator

Patrice G Guyenet et al. J Neurosci. .

Abstract

The rat retrotrapezoid nucleus (RTN) contains neurons described as central chemoreceptors in the adult and respiratory rhythm-generating pacemakers in neonates [parafacial respiratory group (pfRG)]. Here we test the hypothesis that both RTN and pfRG neurons are intrinsically chemosensitive and tonically firing neurons whose respiratory rhythmicity is caused by a synaptic feedback from the central respiratory pattern generator (CPG). In halothane-anesthetized adults, RTN neurons were silent below 4.5% end-expiratory (e-exp) CO2. Their activity increased linearly (3.2 Hz/1% CO2) up to 6.5% (CPG threshold) and then more slowly to peak approximately 10 Hz at 10% CO2. Respiratory modulation of RTN neurons was absent below CPG threshold, gradually stronger beyond, and, like pfRG neurons, typically (42%) characterized by twin periods of reduced activity near phrenic inspiration. After CPG inactivation with kynurenate (KYN), RTN neurons discharged linearly as a function of e-exp CO2 (slope, +1.7 Hz/1% CO2) and arterial pH (threshold, 7.48; slope, 39 Hz/pH unit). In coronal brain slices (postnatal days 7-12), RTN chemosensitive neurons were silent at pH 7.55. Their activity increased linearly with acidification up to pH 7.2 (17 Hz/pH unit at 35 degrees C) and was always tonic. In conclusion, consistent with their postulated central chemoreceptor role, RTN/pfRG neurons encode pH linearly and discharge tonically when disconnected from the rest of the respiratory centers in vivo (KYN treatment) and in vitro. In vivo, RTN neurons receive respiratory synchronous inhibitory inputs that may serve as feedback and impart these neurons with their characteristic respiratory modulation.

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Figures

Figure 1.
Figure 1.
Blood gases in rats exposed to hypercapnia at steady state. a, Relationship between arterial pCO2 (from blood gas analyzer) and end-expiratory CO2 (from capnometer). b, Relationship between pHa and arterial pCO2 (both from blood gas analyzer). c, Relationship between pHa and end-expiratory CO2 (from capnometer). Data are from six rats, three of which were treated with KYN. Note linear semilog relationship between pHa and end-expiratory CO2.
Figure 2.
Figure 2.
Response of one RTN chemosensitive neuron to hypercapnia in a vagotomized rat. a, Experimental system. Single neurons were recorded 2–300 μm below the bottom edge of the facial motor nucleus (FN) after identifying this boundary with antidromic field potentials elicited by stimulating the mandibular branch of the facial nerve. b, Graded concentrations of CO2 were added to the breathing mixture as indicated by the step changes in end-expiratory CO2 (top trace). Bottom traces represent from top to bottom the discharge rate of the neuron (integrated rate histogram), the PND rectified and smoothed (iPND), and the original extracellular recording of the neuron meant to illustrate the stability of the recording over time. The CO2 threshold of the neuron and that of PND (Tneuron, TPND) are indicated by dotted lines. The expanded time scale excerpts illustrate the regularity of the neuronal discharge below PND threshold (left) and the central respiratory modulation of the neuron at high levels of CO2 (right). The filled arrowheads identify the onset of PND, and the open ones identify the onset of the post-inspiratory period. c, Perievent histograms of the neuronal discharge triggered on the ventilation cycle (left, period corresponding to bar 1 in a) or iPND (right, period corresponding to bar 2 in a). d, Steady-state relationship between neuronal firing rate or mvPND [neural minute × volume in arbitrary units (a.u.)] and end-expiratory CO2 at steady state. Note the curvilinear aspect of both plots and the fact that PND threshold is higher than that of the RTN neuron. e, Different CO2-sensitive RTN neuron also from a vagotomized rat (from top to bottom, tracheal CO2 in percentage, iPND, and extracellular action potentials). f, PND-triggered activity histogram of neuron shown in e recorded at 7% end-expiratory CO2. g, PND-triggered activity histogram of neuron shown in e recorded at 9.5% end-expiratory CO2.
Figure 3.
Figure 3.
Effect of CO2 on PND and RTN neuron activity at steady state: group data. a, Averaged firing rate of nine cells in seven rats with intact vagus nerves. The data points from all cells were regrouped into five bins according to the CO2 level at which each determination was made (<5.5, 5–5-6.5, 6.5–7.5, 7.5–8.5, >8.5%), and the values were averaged within these bins (mean ± SE shown for both axis). In this and the next two panels, the dotted and solid lines were traced by hand only to emphasize the divergence from linearity at high levels of e-exp CO2 levels. b, Averaged firing rate of 13 cells in four vagotomized rats (data processed as in a). c, Averaged firing rate of all 22 cells. d, Relationship between mvPND and e-exp CO2 at steady state in five intact rats. e, Relationship between mvPND and e-exp CO2 at steady state in five vagotomized rats. f, Relationship between mvPND and CO2 at steady state (pooled data from 5 intact and 5 vagotomized rats). a.u., Arbitrary units.
Figure 4.
Figure 4.
Structure of RTN neurons. a1, PND-triggered activity histogram of a CO2-sensitive RTN neuron in a rat with intact vagus nerves. Note that tracheal CO2 and PND are synchronized. The open arrow points to the beginning of the post-inspiratory phase; the long filled arrow indicates the start of the late-expiratory phase (E2). a2, Structure of the neuron shown in a1. Note the extensive dendrites within the marginal layer (ML) of the ventral medullary surface (VMS). Cb, Cell body; Amb, nucleus ambiguus; FN, facial motor nucleus. b1, b2, Discharge pattern and structure of a different RTN neuron recorded in a different vagotomized rat. The small filled arrow indicates the onset of PND. The other arrows have the same meaning as in a1. a.u., Arbitrary units.
Figure 5.
Figure 5.
Central respiratory pattern of RTN neurons. The patterns were classified according to the number and timing of the periods of reduced discharge probability relative to PND. The nomenclature reflects the assumption that the maximum discharge rate (apex of the histogram) is primarily defined by the intrinsic response of the cell to pH and that changes in firing probability down from this maximum are caused by inhibitory inputs. The early-I/post-I pattern was dominant, and several variants are shown. The pattern change caused by elevating CO2 is shown for cells 48-4 and 48-5. Histogram G12-4 is shown at a higher time resolution. This pattern is interpreted as a series of inhibitions that occur during the early-I, post-I, and E2 phases, i.e., throughout except during late inspiration. The X at the top right corner of some of the histograms identifies the rat as vagotomized. Patterns 2a and 2b differ according to whether inspiratory inhibition is decrementing (2a) or incrementing (2b). Note that the nadir can occur in early-I, post-I, or late-expiration (E2) depending on the cell.
Figure 6.
Figure 6.
Kynurenic acid eliminate the respiratory modulation of RTN neurons. a1, a2, Excerpt of original recordings showing the discharge pattern of the same neuron before and after KYN administration (rat with intact vagus nerves). b1, b2, Perievent activity histograms of the same neuron before and after KYN. The histograms were triggered on tracheal CO2. c1, c2, Interspike interval distribution histogram for the same cell before and after KYN administration. The mean discharge rate of the cell was the same at the time when the histograms were made (10 Hz). a.u., Arbitrary units.
Figure 7.
Figure 7.
Response of RTN neurons to hypercapnia at steady state in rats treated with kynurenic acid. a, Example of original recording traces. Arterial pressure (AP) is low attributable to central sympatholytic action of KYN. b, Same cell at expanded time scale to illustrate regularity of discharges. c, Plot of discharge rate of the cell versus end-expiratory CO2 at steady state. d, Replot of the same data after conversion of end-expiratory CO2 values into pHa values using the relationship shown in Figure 1c. e, Relationship between discharge rate and e-exp CO2 for the 11 cells recorded. Individual regression lines are shown, and the number shown above the plots represent the mean ± SE of their individually determined slopes. f, Relationship between discharge rate and calculated pHa for the 11 cells recorded. Individual regression lines are shown, and the number shown above the plots represent the mean ± SE of the individually determined slopes. g, Relationship between discharge rate and e-exp CO2 for the 11 cells. The data were analyzed as in Figure 3a–c, i.e., individual points from all cells (data from e) were regrouped into five bins according to the CO2 level at which each determination was made (<5.5, 5–5-6.5, 6.5–7.5, 7.5–8.5, >8.5%), and the values were averaged within these bins (mean ± SE for both axis shown). h, Relationship between discharge rate and pHa. The data were processed as in g except that only four bins were used (pH <7.275, 7.275–7.325, 7.325–375, >7.375). In g and h, the slope of the regression line through the four or five resulting data points is shown.
Figure 8.
Figure 8.
Response of RTN neurons to acidification in vitro: effect of temperature. a, Experimental design. Neurons were recorded within 200 μm of the ventral medullary surface below the caudal end of the facial motor nucleus (FN). The facial motor nucleus was identified by retrograde labeling with Fluoro-Gold (Amb, nucleus ambiguus). b, Example of one RTN neuron exposed to various levels of bath pH at 23 and 35°C (top trace, integrated rate histogram, 10 s bins; bottom trace and excerpts, original recording at 2 different time scales). c, Second example of an RTN neuron studied at both temperatures. d, Relationship between discharge rate and bath pH for 12 neurons recorded at 23°C and 12 neurons recorded at 35°C, six being recorded at both temperatures (p < 0.001 by ANOVA for effect of temperature). The regression lines through the data points from pH 7.2–7.55 are shown to emphasize the deviation from linearity at very acidic pH (6.9). e, f, Relationship between discharge rate and bath pH (range of 7.2–7.55) for each of the 12 cells. Individually determined regression lines are shown, and the mean ± SE of their slope is indicated. g, Relationship between discharge rate and pH for 10 RTN neurons that were considered pH insensitive.
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