Central chemoreceptor modulation of breathing via multipath 1 tuning in medullary ventrolateral respiratory column circuits

44 Ventral respiratory column (VRC) circuits that modulate breathing in response to changes in 45 central chemoreceptor drive are incompletely understood. We employed multi-electrode arrays 46 and spike train correlation methods to test predictions of the hypothesis that pre-Bötzinger 47 complex (pre-BötC) and retrotrapezoid nucleus/parafacial (RTN-pF) circuits cooperate in 48 chemoreceptor-evoked tuning of ventral respiratory group (VRG) inspiratory neurons. Central 49 chemoreceptors were selectively stimulated by injections of CO2-saturated saline into the 50 vertebral artery in 7 decerebrate, vagotomized, neuromuscularly blocked, and artificially 51 ventilated cats. Among sampled neurons in the Bötzinger complex (BötC)-to-VRG region, 70% 52 (161 of 231) had a significant change in firing rate following chemoreceptor stimulation, as did 53 70% (101 of 144) of the RTN-pF neurons. Other responsive neurons (24 BötC-VRG; 11 RTN54 pF) had a change in the depth of respiratory modulation without a significant change in average 55 firing rate. Seventy BötC-VRG chemoresponsive neurons triggered 189 offset-feature 56 correlograms (96 peaks; 93 troughs) with at least one responsive BötC-VRG cell. Functional 57 input from at least one RTN-pF cell could be inferred for 45 BötC-VRG neurons (19%). Eleven 58 RTN-pF cells were correlated with more than one BötC-VRG target neuron, providing evidence 59 for divergent connectivity. Thirty-seven RTN-pF neurons, 24 of which were chemoresponsive, 60 were correlated with at least one chemoresponsive BötC-VRG neuron. Correlation linkage maps 61 and spike-triggered averages of phrenic nerve signals suggest transmission of chemoreceptor 62 drive via a multipath network architecture: RTN-pF modulation of pre-BötC-VRG rostral-to63 caudal excitatory inspiratory neuron chains is tuned by feed-forward and recurrent inhibition 64 from other inspiratory neurons and from “tonic” expiratory neurons. 65 MULTIPATH TUNING IN VRC CIRCUITS