Respiratory pattern modulation by the pedunculopontine tegmental nucleus

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Abstract

This study demonstrates respiratory modulation caused by stimulation of the pedunculopontine tegmental nucleus (PPT), a structure not classically included in the pontine respiratory neuronal network. The long-lasting increase in variability of respiratory parameters following glutamate microinjection into PPT in anesthetized, spontaneously breathing Sprague Dawley rats was more pronounced under ketamine than nembutal anesthesia. The induced respiratory perturbations were characterized by intermittent apneas and increased variability of expiratory (Te) and total (Tt) breath durations in all animals. Although the baseline spontaneous breathing patterns (mean values of all respiratory parameters and their variabilities) were equivalent under ketamine and nembutal anesthesia, different anesthetic agents did affect respiratory responses to PPT stimulation by glutamate in terms of latency, duration, and structure. We conclude that glutamatergic stimulation of PPT has a significant impact on the brainstem respiratory pattern generator.

Introduction

Considerable anatomical, electrophysiological and immunocytochemical evidence implicates the pedunculopontine tegmental region (PPT) of the pons in the generation and/or relay of brainstem phasic events (BPEs) during rapid eye movement (REM) sleep (Datta, 1995, Datta, 1997, Datta, 2000, Datta and Hobson, 2000, Datta et al., 1998, Datta et al., 2001a, Datta et al., 2001b).

During REM sleep, respiratory timing and volume become markedly variable, reflecting powerful phasic disturbances (Pack, 1988), which include apnea (Bulow, 1963, Webb, 1974). Although the mechanisms underlying increased respiratory pattern variability during REM sleep remain unclear, the frequent BPEs characteristic of this state represent a likely source for respiratory perturbations. In fact, field potentials and eye movement markers of BPEs correlate with disordered diaphragm muscle activation in cats (Kline et al., 1986), with central apnea in rats (Carley and Radulovacki, 1999), with obstructive apnea in bulldogs (Hendricks and Pack, 1994) and with irregular activation of diaphragm and upper airway muscles as well as apnea and hypopnea in man (Millman et al., 1988). The immediate temporal association of pontine P-waves (a close electrophysiological marker of BPEs) with central apnea in rats suggested that BPEs may be a primary source of respiratory perturbation during REM sleep (Carley and Radulovacki, 1999).

Numerous studies have demonstrated that cholinergic activation of the medial pontine reticular formation can elicit many features of REM sleep, including increased respiratory variability (Gilbert and Lydic, 1990, Gilbert and Lydic, 1991, Gilbert and Lydic, 1994, Kubin, 2001). However, little has been done to examine a specific role for PPT in regulating respiratory pattern (Lydic and Baghdoyan, 1989, Lydic and Baghdoyan, 1993). Since local glutamate injections into the PPT of rats have been shown to excite P-wave neurons (Datta, 1997) we decided to probe the impact of PPT activation and BPE generation on respiratory pattern by microinjecting glutamate into the PPT of rats. Because the excitability and network properties of brainstem neurons can be grossly altered by general anesthesia, we characterized respiratory responses to PPT stimulation under both a barbiturate agent (nembutal) and a dissociative agent (ketamine). Our findings demonstrate for the first time that PPT stimulation induces long-lasting respiratory perturbation, including apneas, and that this effect can be anatomically and functionally dissociated from generation of BPEs per se.

Section snippets

Materials and methods

Experiments were performed in spontaneously breathing adult, male, anesthetized Sprague Dawley rats, weighing 200–300 g. Animals were maintained on a 12 h light–dark cycle and were housed at 25 °C with free access to food and water. Principles for the care and use of laboratory animals in research were strictly followed, as outlined by the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences Press, Washington, DC, 1996).

Nine rats were anesthetized with nembutal (Abbot

Characteristics of spontaneous respiratory pattern and EEG under anesthesia

Respiratory responses to glutamate injection into PPT may be importantly influenced by the baseline state of the respiratory control system. To test for anesthetic agent-specific differences in respiration prior to any injection (baseline interval, see Section 2 above), we compared the mean values and coefficients of variation (CV) for respiratory timing and volume parameters using one-way ANOVA. As demonstrated in Fig. 1, we found no significant difference (P>0.05 for each) in any parameter

Discussion

This study demonstrates significant respiratory modulation by the PPT, a structure not classically included in the pontine respiratory neuronal network, in anesthetized spontaneously breathing rats. Local PPT stimulation by glutamate produced sustained respiratory disturbances, including intermittent apnea, under two different anesthetic regimens. Under ketamine anesthesia, respiratory responses lasted more than 1 h and were marked by disturbances of both timing and tidal amplitude. Under

Acknowledgements

This work was supported by NIH grant AG16303.

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