Emerging principles and neural substrates underlying tonic sleep-state-dependent influences on respiratory motor activity

Abstract

Respiratory muscles with dual respiratory and non-respiratory functions (e.g. the pharyngeal and intercostal muscles) show greater suppression of activity in sleep than the diaphragm, a muscle almost entirely devoted to respiratory function. This sleep-related suppression of activity is most apparent in the tonic component of motor activity, which has functional implications of a more collapsible upper airspace in the case of pharyngeal muscles, and decreased functional residual capacity in the case of intercostal muscles. A major source of tonic drive to respiratory motoneurons originates from neurons intimately involved in states of brain arousal, i.e. neurons not classically involved in generating respiratory rhythm and pattern per se. The tonic drive to hypoglossal motoneurons, a respiratory motor pool with both respiratory and non-respiratory functions, is mediated principally by noradrenergic and glutamatergic inputs, these constituting the essential components of the wakefulness stimulus. These tonic excitatory drives are opposed by tonic inhibitory glycinergic and g-amino butyric acid (GABA) inputs that constrain the level of respiratory-related motor activity, with the balance determining net motor tone. In sleep, the excitatory inputs are withdrawn and GABA release into the brainstem is increased, thus decreasing respiratory motor tone and predisposing susceptible individuals to hypoventilation and obstructive sleep apnoea.

State-dependent vs. central motor effects of ethanol on breathing

“…The suppressant effects of ethanol on state-dependent arousal processes were also observed in sleep, e.g., as judged by the reduced ratio of high-frequency (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) to low-frequency (0.5-2 Hz) EEG power (i.e., the ␤ 2 -to-␦ 1 ratio) with ethanol in non-REM sleep (Fig. 4).…”

“…This primary influence of ethanol on state-dependent inputs to the respiratory system would also explain why GG activity was suppressed by ethanol at physiologically relevant concentrations, but diaphragm activation and respiratory rate were unchanged. Several lines of evidence indicate that hypoglossal motor output is more strongly influenced by state-dependent influences than is diaphragm activity (20,26,28,40,46), with electrophysiological data from rodents showing that the source of inspiratory drive to hypoglossal motoneurons is different from the source of drive to phrenic motoneurons: predominantly from the reticular formation (lateral tegmental field) for the former and from bulbospinal dorsal and ventral respiratory group neurons for the latter (11,20,44). In the present study, ethanol-induced alterations in state-dependent drives to the hypoglossal motor pool could certainly result in reduced motor excitability and GG muscle activity, independent of a potential effect of ethanol at the motor pool per se.…”

“…4G), likely indicating that this one EEG measure is insensitive as a sole marker of brain stem arousal state. Moreover, ethanol may be exerting suppressant effects on deeper brain stem structures, such as components of the reticular formation and ascending arousal systems (e.g., glutamatergic, serotonergic, noradrenergic, and/or cholinergic inputs), which provide major sources of drive to the hypoglossal motor pool modulating the expression of tonic and respiratory-related motor activities (11,20,21,44).…”

Brainstem: neural networks vital for life

“…Tonic excitatory drives, mediated by noradrenalin and glutamate, are active in wakefulness, but withdrawn in sleep when GABA-mediated inhibition predominates. The pathways for arousal are separate from those that generate the respiratory rhythm; they contribute to the muscle relaxation that occurs in sleep, which has consequences for upper airway patency (Horner 2009). …”

“…The shift in sleep from excitatory to inhibitory modulation of hypoglossal respiratory modulation has consequences for upper airway patency (Horner 2009). Central and obstructive sleep apnoea might be explained by either poor excitatory and/or excessive inhibitory drive to motoneurons regulating upper airway muscles, for example.…”