BASIC NEUROBIOLOGY OF
SLEEP/WAKE STATE AND BEHAVIOR

Neurobiology of Sleep Apnea in Aging
David W. Carley, Principal Investigator (2R01AG016303-06)
Abstract

Intertrigeminal Region Control of Apnea
Misha Radulovacki, Principal Investigator (5R01HL070870)
Abstract

Neurobiology of Sleep Apnea in Aging
Respiratory pattern generation and motor output integration are strongly influenced by behavioral state. In particular, rapid eye movement (REM) sleep is associated with increased variability of respiratory timing and effort. In extreme cases, the respiratory dysrhythmia permitted or provoked during REM sleep appears to be a pathogenic factor for sleep-related breathing disorders such as sleep apnea syndrome. The neuronal networks and synaptic mechanisms that render respiratory outputs more labile during REM sleep remain poorly defined, but during the first funding cycle of this research program we developed key evidence supporting a discrete respiratory modulating region (RMR) within the pedunculopontine tegmental (PPT) nucleus of the pons. The PPT also is an important region for REM sleep homeostasis. We showed that PPT stimulation produced respiratory dysrhythmia in sleeping and anesthetized animals and this application presents preliminary evidence that PPT lesions reduce apnea expression during REM sleep. During years 6 to 10 we will pursue 3 specific aims to determine the anatomical localization, synaptic regulation, and physiological relevance of neurons in the RMR for state-dependent control of respiratory pattern variability. Aim 1 will employ nanoliter injections of glutamate and polygraphic monitoring to test the hypothesis that the RMR is anatomically distinct from regions within the PPT responsible for regulation of REM sleep and associated phenomena, including: EEG activation, hippocampal theta rhythm, and ponto-geniculo-occipital wave generation. Aim 2 will test the hypothesis that making excitotoxic lesions to the functionally identified RMR will decrease respiratory variability during sleep, and in particular during REM sleep. Defining the characteristic extent of the RMR in Aim 1 will help us to tune the size of these lesions, and we will correlate the extent of cell loss with the respiratory impact. Aim 3 will use injections of agonists and antagonists of, and immunohistochemistry for specific glutamate receptor subtypes to define the synaptic regulation of RMR neurons by glutamate. Extending the progress of the first funding cycle, these aims will provide important insights regarding the state-dependent mechanisms by which the PPT modulates respiratory pattern.

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Intertrigeminal Region Control of Apnea
Sleep apnea syndrome affects at least 3% - 5% of the adult population in this country and available data suggest that significant morbidity and increased mortality result from this disorder. Despite 40 years of intensive investigation, the brainstem mechanisms responsible for, or permissive of, sleep-related apnea remain unknown. Our work to develop and characterize a rodent model of sleep-related breathing disorder makes it feasible to systematically examine the detailed brainstem mechanisms of apnea. A brainstem anatomical pathway recently has been demonstrated in which the intertrigeminal region (ITR) of the lateral pons is posited as a key regulatory site for apneic reflexes. The ITR is innervated by sensory subnuclei of the solitary tract that receive inputs from the ninth and tenth cranial nerves; each of which mediate airway-protective apneic reflexes. Moreover, the ITR sends direct projections to respiratory rhythm generating neurons in the medulla. Although the ITR thus may represent an important airway reflex integrating site, no physiological or pathophysiological role has yet been demonstrated for this region. We present novel preliminary evidence that the ITR dampens vagally-mediated reflex apnea, an effect that appears to be mediated by glutamatergic neurotransmission and may result from short term potentiation. Further, we show that focal lesions of the ITR lead to dramatically increased apnea expression during sleep. The overall goals of this proposal are 1) to identify the neural mechanisms by which the ITR modulates apneic reflexes, 2) to demonstrate the functional role of the ITR in sleep apnea genesis and 3) to establish the impact of sleep/wake state changes on ITR function. To achieve these goals, we will employ pressure microinjections to enhance and impair ITR functional activity and to test the strength of monoaminergic and cholinergic inputs on ITR function. The acute impact of these manipulations on respiratory pattern and apneic reflexes will be tested in anesthetized rats. Sustained effects following focal lesions will be tested by behavioral state and cardiorespiratory monitoring in sleeping rats. The proposed neurochemical manipulations of the ITR provide a systematic approach to define the importance of this region in modulating both reflexive and spontaneous sleep-related apnea and to identify the initial steps in the signaling pathway by which this region modulates apnea expression.

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