Interaction between the pulmonary stretch receptor and pontine control of expiratory duration

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Highlights

  • Pontine medial parabrachial nucleus (mPBN) neurons control breathing frequency.

  • Pulmonary Stretch Receptors (PSRs) produce a nonlinear increase E-duration (TE).

  • mPBN activity decreases TE and attenuates the strength of the PSR control of TE.

  • Interaction between PSR and mPBN inputs involve the E-decrementing neurons.

  • Edec neurons and PSR input inhibit pre-I activity of pre-I neurons delaying I-onset.

Abstract

Medial parabrachial nucleus (mPBN) neuronal activity plays a key role in controlling expiratory (E)-duration (TE). Pulmonary stretch receptor (PSR) activity during the E-phase prolongs TE. The aims of this study were to characterize the interaction between the PSR and mPBN control of TE and underlying mechanisms. Decerebrated mechanically ventilated dogs were studied. The mPBN subregion was activated by electrical stimulation via bipolar microelectrode. PSR afferents were activated by low-level currents applied to the transected central vagus nerve. Both stimulus-frequency patterns during the E-phase were synchronized to the phrenic neurogram; TE was measured. A functional mathematical model for the control of TE and extracellular recordings from neurons in the preBötzinger/Bötzinger complex (preBC/BC) were used to understand mechanisms. Findings show that the mPBN gain-modulates, via attenuation, the PSR-mediated reflex. The model suggested functional sites for attenuation and neuronal data suggested correlates. The PSR- and PB-inputs appear to interact on E-decrementing neurons, which synaptically inhibit pre-I neurons, delaying the onset of the next I-phase.

Introduction

Slowly adapting pulmonary stretch receptors (PSRs) mediate the Hering-Breuer reflex which regulates inspiratory duration (TI) and expiratory duration (TE) (Younes and Remmers, 1981). During the inspiratory (I) phase of the respiratory cycle, PSR activity increases with lung inflation, which inhibits inspiration by decreasing TI. This also limits tidal volume. This part of the reflex loop is referred to as the Hering-Breuer I inhibitory reflex (HBII). PSR activity during the expiratory (E) phase that occurs during lung deflation toward the functional residual capacity (FRC) level prolongs TE. This phase-dependent part of the reflex loop has been referred to as the Hering-Breuer E Facilitatory (HBEF) reflex. Tonic PSR activity persists at and below FRC and contributes to the prolongation of TE (Bartoli et al., 1973; Knowlton and Larrabee, 1946; Larrabee and Knowlton, 1946) and plays a key role in the control of breathing frequency.

The mechanisms underlying the HBII and HBEF reflexes have been investigated by manipulating PSR activity during the I- and E-phases (Cross et al., 1980; Bartoli et al., 1975; Clark and Euler, 1972; Knox, 1973; Younes and Polacheck, 1981; Zuperku et al., 1982a). Such studies have shown that the threshold for switching from one phase to the other is a monotonic decreasing exponential function of time into the respective phase, where the threshold preventing phase switching is highest at the onset of the phase. Complementary results have been obtained by electrical stimulation of the medial parabrachial nucleus (mPBN) using voltage levels of delayed pulse trains to determine the switching threshold (Cohen, 1971; Euler et al., 1976). In addition, some of these studies provided detailed information about the nature of the central processing of the PSR inputs in the control of phase-timing (Younes et al., 1987; Zuperku et al., 1982a; Cohen and Feldman, 1977).

Since inputs from both the PSRs as well as the mPBN alter TI and TE, it is expected that they interact with one another to control phase timing. However, the nature of this interaction is poorly understood. Electrolytic lesions (Feldman and Gautier, 1976; Knox and King, 1976) or synaptic block by microinjections of NMDA receptor antagonists (Ling et al., 1994; Navarrete-Opazo et al., 2020) or GABA-A receptor agonists (Dhingra et al., 2017; Dutschmann and Herbert, 1998, 2006) of neurons in the parabrachial/Kölliker–Fuse (PB/KF) regions have been used to understand the interaction between the involved nuclei. However, these approaches do not provide the timing precision that is required to reveal the characteristics of this interaction. In addition, little is known about the neuronal substrate that mediates any interaction. Accordingly, to better understand the nature of the interaction of these two phase-timing inputs in the control of breathing frequency, the present study used precisely-timed electrical stimulation patterns of the PSR afferent fibers in the cervical vagus nerve and of neurons in a mPBN subregion that controls breathing frequency, primarily through the control of TE (Zuperku et al., 2017). There are three components of this study: 1) the interaction of these two inputs on the control of expiratory duration (TE), 2) the mathematical modeling of the control of TE by PSR inputs and possible sites for the mPBN modulation of TE and 3) the interaction of these two inputs at the neuronal level within the pre-Bötzinger/Bötzinger (preBC/BC) region. The results of this study indicate that the mPBN controls the gain of the HBEF reflex: specifically, increased mPBN activity attenuates the reflex, which leads to an increase in breathing frequency (fB). The modeling and neuronal data suggest the possible underlying mechanisms.

Section snippets

Animals

This research was approved by the subcommittee on animal studies of the Zablocki Department of Veterans Affairs (VA) Medical Center in accordance with provisions of the Animal Welfare Act, the Guide for the Care and Use of Laboratory Animals, and VA policy. Experiments were performed on Beagle dogs of either sex, weighing 9–12 kg. Inhalational anesthesia was induced by mask and maintained with isoflurane at 1.5–2.5 % end-tidal concentration. The animals were monitored for signs of inadequate

AMPA-Induced mPBN subregion activity

An example of the interaction between electrical PSR stimulation and AMPA microinjection into the mPBN region is shown in Fig. 3, which clearly demonstrates the attenuating effect of the mPBN region AMPA injection on the PSR mediated reflex. Pre-microinjection data shows the progressive increase in TE as the PSR step frequency increases (Fig. 3A). The PSR input was applied every other cycle. The PSR input sequence was repeated during the continuous microinjection of 20μM AMPA into the mPBN

Gain modulation by mPBN

The results of this study provide strong evidence that the subregion of medial mPBN nucleus, which plays a key role in the control of breathing frequency (Zuperku et al., 2017), also controls the gain of the HBEF reflex. Our data analysis indicates that a synergistic interaction exists that allows breathing frequency, when required, to increase to a greater extent by decreasing the strength of the HBEF reflex, which per se prolongs the E-phase. It is a proportional control (Figs. 4B & 6 A),

Acknowledgments

The authors thank Jack Tomlinson and John G. Krolikowski, Biological Laboratory Technicians, Zablocki VA Medical Center, for excellent technical assistance. This work was supported by Merit Review Award 5 I01 BX000721-08 from the Department of Veterans Affairs Biomedical Laboratory Research and Development Program (E.J. Zuperku, PI); the National Institutes of Health Grant 1 R01 GM112960-01 (A.G. Stucke, PI); the Department of Anesthesiology, Medical College of Wisconsin; and the Childrens

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