Genioglossus muscle activity and serotonergic modulation of hypoglossal motor output in obese Zucker rats

Abstract

Obese Zucker rats have a narrower and more collapsible upper airway compared with lean controls, similar to obstructive sleep apnea (OSA) patients. Genioglossus (GG) muscle activity is augmented in awake OSA patients to compensate for airway narrowing, but the neural control of GG activity in obese Zucker rats has not been investigated to determine whether such neuromuscular compensation also occurs. This study tests the hypotheses that GG activity is augmented in obese Zucker rats compared with lean controls and that endogenous 5-hydroxytryptamine (5-HT) contributes to GG activation. Seven obese and seven lean Zucker rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and they were implanted with GG and diaphragm wires for respiratory muscle recordings. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid and the 5-HT receptor antagonist mianserin (100 microM). Compared with lean controls, respiratory rates were increased in obese rats across sleep-wake states (P=0.048) because of reduced expiratory durations (P=0.007); diaphragm activation was similar between lean and obese animals (P=0.632). Respiratory-related, tonic, and peak GG activities were also similar between obese and lean rats (P>0.139). There was no reduction in GG activity with mianserin at the hypoglossal motor nucleus, consistent with recent observations of a minimal contribution of endogenous 5-HT to GG activity. These results suggest that despite the upper airway narrowing in obese Zucker rats, these animals have a sufficiently stable airway such that pharyngeal muscle activity is normal across sleep-wake states.

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

“…As shown in Fig. 3C, the actual values of GG activity normalized to percentage of maximum are relatively low in magnitude, in agreement with a previous study using the same normalization (55). These values normalized to percentage of maximum are low, not because the actual levels of GG activity are minimal, e.g., there is clear and appreciable activity, including respiratory modulation (Fig.…”

“…Overall, therefore, maximum GG activity is not a robust reference for these studies. However, when the results of GG activity derived from measurements in arbitrary units have been compared with the results obtained from the percentage of maximum, the results and conclusions are the same (6,55,56), and this also applies to the present study (see RESULTS). Nevertheless, given that 1) maximum respiratory activity cannot be standardized in these behaving preparations (see above), 2) each animal serves as its own control in a repeated-measures design with the electrodes in place throughout the study, and 3) the order of vehicle or drug studies was randomized to account for any potential time-dependent changes in muscle-electrode coupling, the quantification of GG activity in arbitrary units is suitably robust and appropriate.…”

Rodent models of sleep apnea

“…They report evidence of a progressive decrease in inspiratory airflow despite increasing inspiratory effort, which is suggestive of inspiratory flow limitation. In contrast, obese rats did not exhibit any increase in genioglossus muscle activity, despite a narrower airway, compared to lean rats, and their upper airway remained stable even during REM sleep (Sood et al, 2007). Taken together, obese rodents have imaging suggestive of airway narrowing and can secrete adipokines that impact upper airway collapsibility, but it remains inconclusive whether obesity induces functional obstruction or airflow limitation in rodents.…”

Neural Control of the Upper Airway: Integrative Physiological Mechanisms and Relevance for Sleep Disordered Breathing

“…In vitro evidence shows that a major component of the raphé inputs to hypoglossal motoneurons are glutamatergic with 5-HT inhibiting the release of this excitatory neurotransmitter via presynaptic effects (56). Therefore, 5-HT may actually suppress excitatory inputs to hypoglossal motoneurons via presynaptic inhibition (510,511), which may explain the increase (rather than the expected decrease) in GG activity following 5-HT receptor antagonism at the hypoglossal motor nucleus in conscious rats (521,523).…”

“…This anchoring by fixed bony structures and cartilage (rather than via a web of soft tissue) provides for more structural stability, less mobility, and diminished capacity for vocalization, and these are likely some of the major reasons for the lack of airway obstructions in animals other than humans. Even obese mice (69) and rats (521), and massively obese Vietnamese pot-bellied pigs have remarkably stable upper airspaces and do not have obstructive sleep apnea (570)(571)(572). The English bulldog, which has arisen as a product of selective breeding rather than natural selection exhibits occasional obstructive apneas and hypopneas but these are largely confined to REM sleep (194).…”