Sleep-disordered breathing (SDB) is a widespread, serious disease characterized intermittent, repetitive episodes of hypoxia during sleep. In most patients, the respiratory disturbances are worst during rapid eye movement sleep (REMS). We will study the central neural mechanisms of SDB during REMS in English Bulldogs, who have a naturally occurring and usually severe form of this disease, and control dogs (beagles). Based on previous studies and preliminary data, we propose that intermittent respiratory muscle inhibition plays an important role in SDB during REMS. Furthermore, asynchronous inhibition of upper airway and diaphragmatic muscles may lead to obstructive as well as central apneas. The role of intermittent inhibition in SDB will be studied in chronically instrumented, freely moving dogs. The central mechanisms producing intermittent inhibition associated with phasic events such as eye movements will be examined by dissecting the relationship between the startle response and phasic events. A link between the startle and phasic events has been proposed because spontaneous and evoked neurophysiological events during REMS are similar to events evoked by startling stimuli. In chronically instrumented dogs, we will experimentally alter the startle response and then measure the degree of intermittent inhibition during REMS, looking for a parallel or correlated change. We will also examine the development of respiratory muscle inhibition and startle responses in Bulldog pups and controls to determine whether an augmented startle response leads to the development of SDB. We will extend preliminary evidence that sleep deprivation and hypoxia augments startle- induced muscle inhibition during REMS. The result of augmented inhibition (SDB), would thus both reinforce the inhibition and produce a vicious cycle. The proposed studies will also attempt to relieve SDB by intervening, for the first time, in a discrete anatomical region of the CNS. The pathway mediating muscle inhibition during REMS is localized bilaterally in a small region of the pontine tegmentum. Lesions in this area can abolish muscle inhibition and, we propose, relieve SDB by increasing the drive for respiratory muscles during REMS. Finally, we will begin to study, for the first time, the neurochemical changes accompanying SDB studying the pontine region of the Bulldogs and control dogs with quantitative densometry and autoradiography to both localize and quantify specific neurotransmitters. These studies should provide important information relating to the progression, pathophysiology and neurochemistry of SDB.
