Central Chemoreceptor Modulation of Breathing via Multipath Tuning in Medullary Ventrolateral Respiratory Column Circuits

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cross-correlation, inspiratory and expiratory neurons, pre-Bötzinger complex, respiratory network, spike train

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Ventrolateral respiratory column (VRC) circuits that modulate breathing in response to changes in central chemoreceptor drive are incompletely understood. We employed multielectrode arrays and spike train correlation methods to test predictions of the hypothesis that pre-Bötzinger complex (pre-BötC) and retrotrapezoid nucleus/parafacial (RTN-pF) circuits cooperate in chemoreceptor-evoked tuning of ventral respiratory group (VRG) inspiratory neurons. Central chemoreceptors were selectively stimulated by injections of CO2-saturated saline into the vertebral artery in seven decerebrate, vagotomized, neuromuscularly blocked, and artificially ventilated cats. Among sampled neurons in the Bötzinger complex (BötC)-to-VRG region, 70% (161 of 231) had a significant change in firing rate after chemoreceptor stimulation, as did 70% (101 of 144) of the RTN-pF neurons. Other responsive neurons (24 BötC-VRG; 11 RTN-pF) had a change in the depth of respiratory modulation without a significant change in average firing rate. Seventy BötC-VRG chemoresponsive neurons triggered 189 offset-feature correlograms (96 peaks; 93 troughs) with at least one responsive BötC-VRG cell. Functional input from at least one RTN-pF cell could be inferred for 45 BötC-VRG neurons (19%). Eleven RTN-pF cells were correlated with more than one BötC-VRG target neuron, providing evidence for divergent connectivity. Thirty-seven RTN-pF neurons, 24 of which were chemoresponsive, were correlated with at least one chemoresponsive BötC-VRG neuron. Correlation linkage maps and spike-triggered averages of phrenic nerve signals suggest transmission of chemoreceptor drive via a multipath network architecture: RTN-pF modulation of pre-BötC-VRG rostral-to-caudal excitatory inspiratory neuron chains is tuned by feedforward and recurrent inhibition from other inspiratory neurons and from “tonic” expiratory neurons.

central chemoreceptors monitor brain CO2/pH and, with their chemoresponsive follower neurons, provide an essential component of the drive to breathe. The retrotrapezoid nucleus/parafacial region of the brain stem (RTN-pF) contains central chemoreceptors (Abbott et al. 2009; Gourine et al. 2010; Guyenet et al. 2010) and is a rostral extension of the medullary ventrolateral respiratory column (VRC), a network containing circuits essential for generating and modulating the motor pattern for breathing (Onimaru et al. 2008; Smith et al. 2009). The VRC extends caudally through the Bötzinger complex (BötC), largely composed of inhibitory expiratory neurons (Fedorko et al. 1989; Jiang and Lipski 1990; Lindsey et al. 1989; Merrill and Fedorko 1984), and the pre-Bötzinger complex (pre-BötC), a core “compartment” for inspiratory rhythm generation (Smith et al. 1991) that may also have a CO2/pH chemosensory function (Koizumi et al. 2010; Nattie 2001; Peever et al. 2001; Solomon et al. 2000). The most caudal region of the VRC is the ventral respiratory group (VRG) with its premotoneuron and motoneuron populations. The VRG includes bulbospinal neurons that drive phrenic motoneurons innervating the diaphragm (Bianchi et al. 1995; Lois et al. 2009) and may also contain chemoreceptors (Nattie and Li 1996).

Although axonal projections of RTN-pF neurons with properties characteristic of chemoreceptors have been traced to every segment of the VRC (Abbott et al. 2009), the organization of chemoreceptor reflex circuits within the VRC remains incompletely understood (Guyenet et al. 2010). In a recent study, we employed multielectrode arrays and spike train analysis to test hypotheses on network mechanisms for the respiratory modulation and central chemoreceptor-evoked responses of RTN-pF neurons (Ott et al. 2011). Here, we report complementary results from that work. Correlational linkages support a new network model for chemoreceptor-mediated tuning of pre-BötC-VRG circuits and respiratory drive. The model incorporates tonic columnar expiratory neurons in a multipath architecture.

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Citation / Publisher Attribution

Journal of Neurophysiology, v. 107, issue 2, p. 603-617