Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus

Abstract

Rationale: Patients with obstructive sleep apnea (OSA) adapt to the anatomical vulnerability of their upper airway by generating increased activity in upper airway-dilating muscles during wakefulness. Norepinephrine (NE) and serotonin (5-HT) mediate, through a 1 -adrenergic and 5-HT 2A receptors, a wake-related excitatory drive to upper airway motoneurons. In patients with OSA, this drive is necessary to maintain their upper airway open. We tested whether chronic intermittent hypoxia (CIH), a major pathogenic factor of OSA, affects aminergic innervation of XII motoneurons that innervate tongue-protruding muscles in a manner that could alter their airway-dilatory action. Objectives: To determine the impact of CIH on neurochemical markers of NE and 5-HT innervation of the XII nucleus. Methods: NE and 5-HT terminal varicosities and a 1 -adrenergic and 5-HT 2A receptors were immunohistochemically visualized and quantified in the XII nucleus in adult rats exposed to CIH or room air exchanges for 10 h/d for 34 to 40 days. Measurements and Main Results: CIH-exposed rats had approximately 40% higher density of NE terminals and approximately 20% higher density of 5-HT terminals in the ventromedial quadrant of the XII nucleus, the region that controls tongue protruder muscles, than sham-treated rats. XII motoneurons expressing a 1 -adrenoceptors were also approximately 10% more numerous in CIH rats, whereas 5-HT 2A receptor density tended to be lower in CIH rats. Conclusions: CIH-elicited increase of NE and 5-HT terminal density and increased expression of a 1 -adrenoceptors in the XII nucleus may lead to augmentation of endogenous aminergic excitatory drives to XII motoneurons, thereby contributing to the increased upper airway motor tone in patients with OSA.Keywords: chronic-intermittent hypoxia; hypoglossal motoneurons; obstructive sleep apnea; norepinephrine; serotonin Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal episodes of upper airway narrowing or collapse, which lead to reduced ventilation or apnea, blood oxygen (O 2 ) desaturations, and sleep fragmentation (1, 2). Subjects with OSA adapt to the anatomical vulnerability of their upper airway by generating a higher level of activity in their upper airway-dilating muscles during wakefulness than healthy subjects (3-5). This allows them to maintain airway patency, but the mechanisms underlying this adaptation are unknown.Hypoglossal (XII) motoneurons innervate the genioglossus and other muscles of the tongue whose active contraction is important for the maintenance of upper airway patency in patients with OSA (2, 6). Sleep-related decrements of lingual muscle activity facilitate the occurrence of sleep-related upper airway obstructions (6-8). Data from healthy animals show that endogenous excitation mediated by norepinephrine (NE) and serotonin (5-HT) is an important contributor to the maintenance of upper airway muscle tone during wakefulness (9-13). This drive is derived from pontomedullary NE and 5-HT cells (14-16) that have state-depende...

Effect of chronic intermittent hypoxia on noradrenergic activation of hypoglossal motoneurons

“…Rats subjected to a CIH protocol similar to that used in the present study exhibit a prominent increase of noradrenergic terminal density and increased ␣ 1 -adrenoceptor immunoreactivity in the XII nucleus (41). These findings suggest that CIH may also functionally alter noradrenergic effects on XII motoneurons.…”

“…The exposures lasted ϳ35 (range 33-37) days. O 2 levels oscillated between 24% and 7% with 180-s period for 10 h/day (7 AM-5 PM) (41). During the remaining time, all chambers were continuously ventilated with room air to prevent CO 2 accumulation.…”

“…The drugs were injected by application of pressure to the fluid in the pipette, while the movement of the meniscus was monitored with a calibrated microscope with 1-nl resolution. For PE injections, the pipette was inserted into the ventral region of the caudal half of the right XII nucleus, 0.3 mm lateral to the midline, 0.15 mm rostral to the obex, and 1.15 mm below the dorsal medullary surface, because this region contains XII motoneurons that innervate the base of the tongue, including the genioglossus muscle, has the most dense noradrenergic innervation, and sends motor axons in the medial branch of the XII nerve (6,41). After recording of baseline XIIa, the animals received up to three (1.8 on average) PE injections, 10 nl each, separated by Ն15-min intervals.…”

“…A recent neuroanatomic study demonstrated that noradrenergic terminal density and the excitatory ␣ 1 -adrenoceptor immunoreactivity are increased in the XII nucleus in rats exposed to CIH (41). This suggested that exposure to CIH may lead to increased sensitivity of XII motoneurons to noradrenergic inputs and, by implication, that CIH is one of the factors responsible for hyperactivity of upper airway muscles in OSA patients.…”

Effects of obstructive sleep apnoea on heart rhythm

“…However, this mechanism also results in maladaptive changes, such as an increase in the noradrenergic pathways within the brainstem, thereby activating the medullary region [17]. Both the activation of the medullary region, and the direct stimulation of the carotid bodies by intermittent hypoxia, lead to increased sympathetic nervous system activity and enhance catecholamine secretion from adrenal medullary chromaffin cells [18,19].…”