Microdialysis perfusion of 5‐HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep‐wake states in rats

Abstract

The genioglossus (GG) muscle of the tongue contributes to effective lung ventilation by maintaining an open pharyngeal airway. Decreased GG activity in sleep, especially REM sleep (Sauerland & Harper, 1976) can lead to airway narrowing, increased upper airway resistance and hypoventilation (Henke et al. 1992). In individuals with already anatomically narrow upper airways, such GG suppression can produce airway occlusion and obstructive sleep apnoea (Remmers et al. 1978), a serious sleep-related breathing disorder affecting approximately 4 % of adults (Young et al. 1993). However, despite increased knowledge of the major effects of sleep on GG activity, it is still not known which brainstem neural circuits and neurotransmitters modulate hypoglossal (XII) motor output to GG muscle in wakefulness and natural sleep.In vitro studies using neonatal tissue slices have shown that 5-HT depolarizes and increases the excitability of XII motoneurons (Berger et al. 1992). 5-HT also facilitates XII motoneurons in decerebrate cats (Kubin et al. 1992;Douse & White, 1996). Medullary raphe neurons provide the 5-HT inputs to XII motor nucleus (Manaker & Tischler, 1993) and show decreasing discharge from wakefulness to non-REM and REM sleep (Jacobs & Azmitia, 1992). There is also decreased discharge of medullary raphe neurons projecting to XII motor nucleus in a pharmacological model of REM sleep evoked by carbachol microinjection into the pontine reticular formation of decerebrate cats (Woch et al. 1996). This pharmacological REM-like state in decerebrate cats is also associated with reduced 5-HT at the XII motor nucleus (Kubin et al. 1994). 1. Serotonin (5-hydroxytryptamine, 5-HT) excites hypoglossal (XII) motoneurons in reduced preparations, and it has been suggested that withdrawal of 5-HT may underlie reduced genioglossus (GG) muscle activity in sleep. However, systemic administration of 5-HT agents in humans has limited effects on GG activity. Whether 5-HT applied directly to the XII motor nucleus increases GG activity in an intact preparation either awake or asleep has not been tested.2. The aim of this study was to develop a novel freely behaving animal model for in vivo microdialysis of the XII motor nucleus across sleep-wake states, and test the hypothesis that 5-HT application will increase GG activity.3. Eighteen rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the XII motor nucleus and perfused with artificial cerebrospinal fluid (ACSF) or 10 mM 5-HT.4. Normal decreases in GG activity occurred from wakefulness to non-rapid eye movement (non-REM) and REM sleep with ACSF (P < 0.01). Compared to ACSF, 5-HT caused marked GG activation across all sleep-wake states (increases of 91-251 %, P < 0.015). Importantly, 5-HT increased sleeping GG activity to normal waking levels for as long as 5-HT was applied (3-5 h). Despite tonic stimulation by 5-HT, periods of phasic GG ...

Changes in Inhibitory Amino Acid Release Linked to Pontine-Induced Atonia: AnIn VivoMicrodialysis Study

“…Our previous study showed a reduction of norepinephrine and serotonin release in both the spinal ventral horn and hypoglossal (XII) nucleus during PIA stimulation in the decerebrate cat (Lai et al, 2001). This result combined with other studies that showed a facilitatory effect of these monoamines on motoneurons (Takahashi and Berger, 1990;Parkis et al, 1995;Jelev et al, 2001) indicates that disfacilitation plays an important role in muscle tone suppression.…”

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

“…It was not until 2001 that the central neurotransmitter systems underlying the modulation of a respiratory motoneuron pool began to be investigated across states of wakefulness and natural sleep following the development of appropriate freely behaving animal models (Jelev et al 2001). Studies using such a model were initially focused on the hypoglossal motor nucleus, as illustrated in figure 3.…”

Polymorphisms in the 5-HTR2A gene related to obstructive sleep apnea syndrome

“…Changes in the serotonergic system have been implied in several human diseases such as depression, headaches, epilepsy, obsessive-compulsive behaviors, temporomandibular dysfunction, and affective disorders. [6][7][8][9] Serotonin also has a relevant role in upper airway patency, as it excites airway motor neurons and intrinsically excites the motor neurons in the brainstem. The activity of neurons that provide 5-HT to motor neurons declines with sleep; most of the functional studies have shown that 5-HT and serotonergic neurons exert a significant excitatory effect on respiratory motor neurons in vivo and in vitro.…”

“…6 The genioglossus muscle is innervated by neurons that originate in the hypoglossal nucleus within the brainstem; contractions of this muscle during inspiration help ventilate the lungs and keep upper airways open during wakefulness and sleep. 7,8 Groups of serotonergic and noradrenergic cells may generate parallel patterns by stimulating directly the motor cells of the hypoglossal nerve, thereby regulating these dilating muscles. Thus, activation of these cell groups increases the activity of the genioglossus muscle.…”

“…Thus, activation of these cell groups increases the activity of the genioglossus muscle. [7][8][9] It is evident that serotonin (5-hydroxytryptamine or 5-HT), a central nervous system neurotransmitter, is involved in regulating several visceral and physiologic functions such as sleep, appetite, thermoregulation, pain perception, hormone secretion, and sexual behavior. Changes in the serotonergic system have been implied in several human diseases such as depression, headaches, epilepsy, obsessive-compulsive behaviors, temporomandibular dysfunction, and affective disorders.…”