Brainstem Nuclei Associated with Mediating Apnea-Induced Respiratory Motor Plasticity

Simon Lui,John Peever,Arash Tadjalli,Zoltan Torontali

doi:10.1038/s41598-018-28578-5

Abstract

The respiratory control system is plastic. It has a working memory and is capable of retaining how respiratory stimuli affect breathing by regulating synaptic strength between respiratory neurons. For example, repeated airway obstructions trigger a form of respiratory plasticity that strengthens inspiratory activity of hypoglossal (XII) motoneurons. This form of respiratory plasticity is known as long-term facilitation (LTF) and requires noradrenaline released onto XII motoneurons. However, the brainstem regions responsible for this form of LTF remain unidentified. Here, we used electrophysiology, neuropharmacology and immunohistochemistry in adult rats to identify the brainstem regions involved in mediating LTF. First, we show that repeated airway obstructions induce LTF of XII motoneuron activity and that inactivation of the noradrenergic system prevents LTF. Second, we show that noradrenergic cells in the locus coeruleus (LC), which project to XII motoneurons, are recruited during LTF induction. Third, we show that targeted inactivation of noradrenergic LC cells during LTF induction prevents LTF. And lastly, we show that the nucleus tractus solitarius (NTS), which has known projections to the LC, is critical for LTF because its inactivation prevents LTF. Our results suggest that both the LC and NTS are involved in mediating apnea-induced LTF, and we hypothesize that a NTS → LC → XII circuit mechanism mediates this form of respiratory motor plasticity.

Highlights

Understanding motoneuron physiology is important because respiratory motoneurons are critical in triggering effective breathing movements
We found that genioglossus amplitude, breath frequency, end-tidal CO2 and O2 saturation remained stabled during the 60 min time-window (RM ANOVA, genioglossus: F = 1.33, p = 0.2757; breath frequency: F = 1.988, p = 0.1148; ET-CO2: F = 1.485, p = 0.2272; O2 saturation: F = 1.546, p = 0.2776; Fig. 1), indicating that genioglossus activity does not change over the 60 min recording period and that long-term facilitation (LTF) of genioglossus muscle activity is attributable to recurrent apneas per se
We demonstrate that noradrenergic cells in the locus coeruleus (LC) are activated following LTF induction and that pharmacological inactivation of LC activity prevents LTF, suggesting that noradrenaline release - likely from the LC - is required for LTF expression

Summary

Introduction

Understanding motoneuron physiology is important because respiratory motoneurons are critical in triggering effective breathing movements. Intermittent episodes of hypoxia or airway obstruction induce a form of respiratory motoneuron plasticity known as long-term facilitation (LTF)[1,2,3,4]. We previously demonstrated that repeated airway obstructions trigger LTF of hypoglossal motor outflow (i.e., apnea-induced LTF) and that this form of respiratory plasticity is mediated by a noradrenergic mechanism[4]. We found that blocking α1-noradrenergic receptors at the level of hypoglossal motor pool prevented LTF, suggesting that noradrenaline release likely underlies LTF4. We found that pharmacological inactivation of the noradrenergic system prevented LTF, indicating that a noradrenergic mechanism underlies this form of respiratory motor plasticity. We found that noradrenergic cells in the locus coeruleus (LC) are activated during LTF and that they project to hypoglossal motoneurons, suggesting that LC neurons are anatomically and temporally poised to mediate LTF. We hypothesize that a NTS → LC → XII could be the circuit mechanism that mediates this form of respiratory motor plasticity

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Conclusion