Physiological and pathophysiological interactions between the respiratory central pattern generator and the sympathetic nervous system

Abstract

Respiratory modulation seen in the sympathetic nerve activity (SNA) implies that the respiratory and sympathetic networks interact. During hypertension elicited by chronic intermittent hypoxia (CIH), the SNA displays an enhanced respiratory modulation reflecting strengthened interactions between the networks. In this chapter, we review a series of experimental and modeling studies that help elucidate possible mechanisms of sympatho-respiratory coupling. We conclude that this coupling significantly contributes to both the sympathetic baroreflex and the augmented sympathetic activity after exposure to CIH. This conclusion is based on the following findings. (1) Baroreceptor activation results in perturbation of the respiratory pattern via transient activation of postinspiratory neurons in the Bötzinger complex (BötC). The same BötC neurons are involved in the respiratory modulation of SNA, and hence provide an additional pathway for the sympathetic baroreflex. (2) Under hypercapnia, phasic activation of abdominal motor nerves (AbN) is accompanied by synchronous discharges in SNA due to the common source of this rhythmic activity in the retrotrapezoid nucleus (RTN). CIH conditioning increases the CO2 sensitivity of central chemoreceptors in the RTN which results in the emergence of AbN and SNA discharges under normocapnic conditions similar to those observed during hypercapnia in naïve animals. Thus, respiratory–sympathetic interactions play an important role in defining sympathetic output and significantly contribute to the sympathetic activity and hypertension under certain physiological or pathophysiological conditions, and the theoretical framework presented may be instrumental in understanding of malfunctioning control of sympathetic activity in a variety of disease states.

Chemoreception and neuroplasticity in respiratory circuits

“…The first is a consequence of excitatory projections from RTN late-E population to RVLM suggested in our previous publications (Baekey et al, 2010, Molkov et al, 2011, Rybak et al, 2012, Molkov et al, 2014b) to explain appearance of late-E discharges in the sympathetic activity during hypercapnia. The RTN late-E population receives excitatory drive from the RTN central chemoreceptors which increases with blood CO 2 level due to their intrinsic CO 2 chemosensitivity.…”

“…The model was developed as an extension of previous models (Baekey et al, 2010, Molkov et al, 2011, Rybak et al, 2012, Molkov et al, 2014b) to include a population of 2 nd -order cells in the NTS receiving peripheral chemoreceptor inputs and their efferent projection to ventromedullary compartments. The schematic of the extended model is shown in Fig.…”

“…Previously, we described these changes in terms of direct sensitization of the RTN to the partial pressure of CO 2 in the blood (Molkov et al, 2011, Rybak et al, 2012, Molkov et al, 2014b). The previous model does not describe the mechanism by which CIH induces plasticity in the respiratory CPG.…”

“…The model presented here is based on a previous model of central chemoreceptor sensitization from (Molkov et al, 2011, Molkov et al, 2014b), which in turn combined a model describing the origin of abdominal late-E activity (Molkov et al, 2010) and a model describing sympathy-respiratory coupling in the context of the baroreflex (Baekey et al, 2010). All of these models descend from the model described by Rybak et al (2007) and Smith et al (2007), which explains the change in respiratory patterns due to successive pontine and medullary transections performed in rats.…”

Contribution of peripheral and central chemoreceptors to sympatho‐excitation in heart failure

“…Sympathetic discharge is actively modulated by respiration (Guyenet, ; Molkov et al . ). Recent studies suggest that enhanced coupling between sympathetic and respiratory neural drive contribute to augmented sympatho‐excitation in CHF (Costa‐Silva et al .…”