The primary hypothesis of this study was that the cough motor pattern is produced, at least in part, by the medullary respiratory neuronal network in response to inputs from "cough" and pulmonary stretch receptor relay neurons in the nucleus tractus solitarii. Computer simulations of a distributed network model with proposed connections from the nucleus tractus solitarii to ventrolateral medullary respiratory neurons produced coughlike inspiratory and expiratory motor patterns. Predicted responses of various "types" of neurons (I-DRIVER, I-AUG, I-DEC, E-AUG, and E-DEC) derived from the simulations were tested in vivo. Parallel and sequential responses of functionally characterized respiratory-modulated neurons were monitored during fictive cough in decerebrate, paralyzed, ventilated cats. Coughlike patterns in phrenic and lumbar nerves were elicited by mechanical stimulation of the intrathoracic trachea. Altered discharge patterns were measured in most types of respiratory neurons during fictive cough. The results supported many of the specific predictions of our cough generation model and suggested several revisions. The two main conclusions were as follows: 1) The Bötzinger/rostral ventral respiratory group neurons implicated in the generation of the eupneic pattern of breathing also participate in the configuration of the cough motor pattern. 2) This altered activity of Bötzinger/rostral ventral respiratory group neurons is transmitted to phrenic, intercostal, and abdominal motoneurons via the same bulbospinal neurons that provide descending drive during eupnea.

Autonomic nervous system (ANS) dysfunction, exaggerated inflammation and impaired vascular repair are all hallmarks of hypertension. Considering the bone marrow (BM) is a major source of the inflammatory cells (ICs) and endothelial progenitor cells (EPCs), we hypothesized that impaired BM-ANS interaction contributes to dysfunctional BM activity in hypertension. In the SHR, we observed a >30% increase in BM and blood ICs (CD4.8+), and a >50% decrease in EPCs (CD90+.CD4.5.8-) compared to the normotensive Wistar-Kyoto (WKY) rat. Increased tyrosine hydroxylase (70%) and norepinephrine (NE, 160%), and decreased choline acetyl transferase (30%) and acetylcholine esterase (55%) indicated imbalanced ANS in SHR BM. In WKY, night time-associated elevation in SNA (50%) and BM NE (41%) was associated with increased ICs (50%) and decreased EPCs (350%), while BM sympathetic denervation decreased ICs (25%) and increased EPCs (40%). In contrast, these effects were blunted in SHR, possibly due to chronic downregulation of BM adrenergic receptor α2a (by 50-80%) and β2 (30-45%). Application of NE resulted in increased BM IC activation/release, which was prevented by pre-administration of Ach. Electrophysiological recordings of femoral SNA (fSNA) showed a more robust fSNA activity in SHR compared to WKY, peaking earlier in the respiratory cycle, indicative of increased sympathetic tone. Finally, manganese-enhanced magnetic resonance imaging (MEMRI) demonstrated that pre-sympathetic neuronal activation in SHR was associated with an accelerated retrograde transport of the GFP-labeled pseudorabies virus from the BM. These observations demonstrate that a dysfunctional BM ANS is associated with imbalanced EPCs and ICs in hypertension.

Sympathetic nerve activity (SNA) is modulated by respiratory activity which indicates the existence of direct interactions between the respiratory and sympathetic networks within the brainstem. Our experimental studies reveal that TE prolongation evoked by baroreceptor stimulation varies with respiratory phase and depends on the pons. We speculate that the sympathetic baroreceptor reflex, providing negative feedback from baroreceptors to the rostral ventrolateral medulla and SNA, has two pathways: one direct and independent of the respiratory–sympathetic interactions and the other operating via the respiratory pattern generator and is hence dependent on the respiratory modulation of SNA. Our experimental studies in the perfused in situ rat preparation and complementary computational modelling studies support the hypothesis that baroreceptor activation during expiration prolongs the TE via transient activation of post-inspiratory and inhibition of augmenting expiratory neurones of the Bötzinger Complex (BötC). We propose that these BötC neurones are also involved in the respiratory modulation of SNA, and contribute to the respiratory modulation of the sympathetic baroreceptor reflex.

This study tested predictions from a network model of ventrolateral medullary respiratory neurone interactions for the generation of the cough motor pattern observed in inspiratory and expiratory pump muscles. Data were from 34 mid‐collicularly decerebrated, paralysed, artificially ventilated cats. Cough‐like patterns (fictive cough) in efferent phrenic and lumbar nerve activities were elicited by mechanical stimulation of the intrathoracic trachea. Neurones in the ventral respiratory group, including the Bötzinger and pre‐Bötzinger complexes, were monitored simultaneously with microelectrode arrays. Spike trains were analysed for evidence of functional connectivity and responses during fictive cough with cycle‐triggered histograms, autocorrelograms, cross‐correlograms, and spike‐triggered averages of phrenic and recurrent laryngeal nerve activities. Significant cross‐correlogram features were detected in 151 of 1988 pairs of respiratory modulated neurones. There were 59 central peaks, 5 central troughs, 11 offset peaks and 2 offset troughs among inspiratory neurone pairs. Among expiratory neurones there were 23 central peaks, 8 offset peaks and 4 offset troughs. Correlations between inspiratory and expiratory neurones included 20 central peaks, 10 central troughs and 9 offset troughs. Spike‐triggered averages of phrenic motoneurone activity had 51 offset peaks and 5 offset troughs. The concurrent responses and multiple short time scale correlations support parallel and serial network interactions proposed in our model for the generation of the cough motor pattern in the respiratory pump muscles. Inferred associations included the following. (a) Excitation of augmenting inspiratory (I‐Aug) neurones and phrenic motoneurones by I‐Aug neurones. (b) Inhibition of augmenting expiratory (E‐Aug) neurones by decrementing inspiratory (I‐Dec) neurones. (c) Inhibition of I‐Aug, I‐Dec and E‐Aug neurones by E‐Dec neurones. (d) Inhibition of I‐Aug and I‐Dec neurones and phrenic motoneurones by E‐Aug neurones. The data also confirm previous results and support hypotheses in current network models for the generation of the eupnoeic pattern.

Current models propose that a neuronal network in the ventrolateral medulla generates the basic respiratory rhythm and that this ventrolateral respiratory column (VRC) is profoundly influenced by the neurons of the pontine respiratory group (PRG). However, functional connectivity among PRG and VRC neurons is poorly understood. This study addressed four model-based hypotheses: 1) the respiratory modulation of PRG neuron populations reflects paucisynaptic actions of multiple VRC populations; 2) functional connections among PRG neurons shape and coordinate their respiratory-modulated activities; 3) the PRG acts on multiple VRC populations, contributing to phase-switching; and 4) neurons with no respiratory modulation located in close proximity to the VRC and PRG have widely distributed actions on respiratory-modulated cells. Two arrays of microelectrodes with individual depth adjustment were used to record sets of spike trains from a total of 145 PRG and 282 VRC neurons in 10 decerebrate, vagotomized, neuromuscularly blocked, ventilated cats. Data were evaluated for respiratory modulation with respect to efferent phrenic motoneuron activity and short-timescale correlations indicative of paucisynaptic functional connectivity using cross-correlation analysis and the "gravity" method. Correlogram features were found for 109 (3%) of the 3,218 pairs composed of a PRG and a VRC neuron, 126 (12%) of the 1,043 PRG-PRG pairs, and 319 (7%) of the 4,340 VRC-VRC neuron pairs evaluated. Correlation linkage maps generated for the data support our four motivating hypotheses and suggest network mechanisms for proposed modulatory functions of the PRG.