Activity of Dorsal Medullary Respiratory Neurons in Awake Rats

Sleep disordered breathing (SDB) is a major clinical disorder affecting 2-4% of the middle-aged [Young et al., 1993] and is a major public health problem [Phillipson, 1993]. It is characterized by multiple episodes of collapse of the upper airway (UA) during inspiration when the negative pressure in the UA is not adequately counteracted by contraction of UA dilator muscles (obstructive sleep apnoea, OSA) or more rarely by episodic central hypopnoea or apnoea i.e. reduced neural drive to the respiratory muscles [Deegan and McNicholas, 1995]. This results in sleep fragmentation and asphyxia and is associated with hypersomnolence, impaired cognitive function and increased risk of pulmonary and systemic hypertension, congestive heart failure, cardiac arrhythmias, myocardial infarction, stroke and vehicular accidents [Deegan and McNicholas, 1995; Peter et al., 1995]. OSA is caused by collapse of the UA during sleep because of a reduction in tone of the UA muscles that dilate and stabilize the UA during inspiration [Remmers et al., 1978]. However, the cause of the reduction in UA muscle tone occurring in OSA is not known but there is evidence suggesting that it is due to a withdrawal of serotonergic or noradrenergic facilitation of the hypoglossal motor nucleus (XHn), in the dorsal medulla, that contains the motoneurons to the UA muscles (see Horner, 2000, for review). An understanding of the activity of this nucleus is fondamental to understanding the cause of OSA and opens the possibility of pharmacological intervention to treat or prevent OSA [Horner, 2000]. There is some evidence implicating alterations in this central control of respiration in the pathophysiology of SDB [Horner, 1996; Pack, 1995] and histochemical brainstem abnormalities have been identified in patients who have died of sleep apnoea [Sullivan et ai, 1990]. The Xlln receives crucial inputs from other central areas involved in the integration of responses to chemoreceptors and mechanoreceptors, such as the nucleus tractus solitarius (NTS) [Ono et al., 1994; Peever et al., 2002]. However, little is known about the premotor inputs to the XIIn. During apnoeas, there is systemic hypoxia and hypercapnia and the UA muscle responses to systemic hypoxia and hypercapnia play a crucial role in the prevention of apnoea during sleep normally [Parisi et al., 1987; Brouillette and Thach, 1980; Gleeson et al., 1989; Bowes et al., 1981] and in the termination of apnoeic events in SDB [Parisi et al., 1987; Gleeson et al., 1989].