Learning to breathe: Habituation of Hering–Breuer inflation reflex emerges with postnatal brainstem maturation
Introduction
The Hering–Breuer inflation reflex (HBR, Hering, 1868, Breuer, 1868) is a ‘classic’ reflex in respiratory control that is described in practically every physiology textbook. In brief, lung inflation activates slowly adapting pulmonary stretch receptors. The receptor input is relayed via the vagus nerve to ‘pump’ cells located in and around the ventro-lateral nucleus of the solitary tract (Clark and Euler, 1972, Berger and Dick, 1987, Bonham and McCrimmon, 1990, Bonham et al., 1993, Miyazaki et al., 1998, Miyazaki et al., 1999). Pump cells project to and release inhibitory neurotransmitters on inspiratory neurons in the lateral respiratory column (Ezure and Tanaka, 2004; see Kubin et al., 2006); thus, contributing to the termination of inspiration (see Euler, 1981, Euler, 1983, Bianchi et al., 1995, Kubin et al., 2006).
The HBR is often considered as an inhibitory sensory feedback loop that shapes the respiratory motor pattern. Removing HBR feedback via cooling of the vagal nerve or vagotomy instantly transforms the respiratory pattern to a slower breathing rhythm with increased inspiratory amplitude and longer duration of expiration (Marckwald, 1887, Stella, 1938, Clark and Euler, 1972).
Although the HBR is an established mechanism, doubts about its physiological significance arose from findings that show little or no effect of the HBR in adult humans (summarized in Kubin et al., 2006). In particular, the HBR does not affect the respiratory pattern in humans until a high lung volume is reached. Thus, the threshold for HBR is well above end-inspiratory lung volume during resting breathing (Bechbache et al., 1979, Cunningham and Gardner, 1977, Duffin et al., 2000). In contrast, the HBR is important for the stabilization of the breathing pattern in neonatal rats (Fedorko et al., 1988). So, the HBR appears to becomes less significant with postnatal maturation of the cardio-respiratory control circuits as observed in humans (Gerhardt and Bancalari, 1981, Rabbette et al., 1991, Rabbette and Stocks, 1998, BuSha et al., 2002) and mammals in general (Trippenbach, 1994).
A plausible explanation for diminished role of the HBR in adults is provided by pioneering investigations of Chi-Sang Poon and co-workers demonstrating that the HBR habituates in rats (Siniaia et al., 2000, Poon, 2004, Song and Poon, 2004, MacDonald et al., 2009, Tadjalli et al., 2010). Thus, if postnatal maturation of brainstem circuitry is mandatory before these networks become permissive for synaptic plasticity (see Dutschmann et al., 2004, Dutschmann et al., 2008, Dutschmann et al., 2009, Dutschmann and Dick, 2012), then HBR habituation does not occur in the neonatal stages of brainstem development.
Therefore we investigated HBR habituation in juvenile rat by using repetitive brief electrical stimulation of the central vagus nerve across 3 different stages of postnatal brainstem development. Habituation is the decrease in strength of the response to a stimulus that is presented repeatedly. In the present study, the initial vagal stimuli suppressed inspiratory activity but as the stimulus was repeated, the phrenic bursting ‘broke-through’ during vagal stimulation. The phrenic bursting during the stimulus indicated habituation. Importantly, HBR habituation did not emerge until postnatal day 16. Subsequent experiments show an identical habituation of inspiratory suppression in response to repetitively applied sustained lung inflation in juvenile rat preparations. The experiments using physiological stimulus of sustained lung inflation are consistent with a postnatal emergence of synaptic plasticity linked to HBR habituation.
Section snippets
Materials and methods
Experiments were performed at the Georg August University Göttingen (Germany) and at the Florey Institute of Neuroscience and Mental Health (Australia). Approval for experiments was obtained from both Institutional Animal Care Ethics Committees. The experimental procedures were performed in accordance with international guidelines for the care and use of laboratory animals.
Developmental changes in inspiratory depression in response to Hering–Breuer inflation reflex (HBR)
Postnatal maturation of HBR is illustrated by representative examples of the response to repetitive tonic vagal nerve simulation in a neonatal (Fig. 1A) and juvenile preparation (Fig. 1B). In each age group, the first stimulus consistently suppressed PNA for 10 s at least (see Fig. 1). In preparations of the neonatal age group (n = 5), analysis of vagally mediated TE prolongation was not significantly different between the 1st (11.82 ± 0.41 s) and 15th (12.26 ± 0.46 s) stimulus (see Fig. 2 ANCOVA,
Physiological significance of the Hering–Breuer reflex (HBR)
The results of the present study confirm previous observations that identified HBR habituation in the adult rat (Siniaia et al., 2000; Song, 2004; Song and Poon, 2004, MacDonald et al., 2007, MacDonald et al., 2009). HBR habituation was demonstrated using two different experimental approaches: repetitively applied short vagal stimulus trains and lung inflations. The novel finding in the present study is the postnatal emergence of HBR habituation and maturation as a mechanistic explanation for
Acknowledgements
This study was supported by the Bernstein Center for Computational Neurosciences (BCCN, 01GQ0432, M. Dutschmann) and NHLBI (Cluster Grant R33 HL087377, M. Dutschmann, and T. E. Dick). M.D. is currently supported by an ARC Future fellowship and Florey Institute of Neuroscience and Mental Health.
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These authors contributed equally to the work.