Sleep apnea syndrome affects at least 3 percent - 5 percent of the adult population in this country and available data suggest that significant morbidity and mortality result from this disorder. It is now well established that the prevalence of sleep-related apnea is dramatically elevated in the elderly with recent estimates ranging from 28 percent - 67 percent for elderly males and from 20 percent - 54 percent for elderly females. However, the mechanisms underlying the age related increase in apnea genesis remain poorly understood. This uncertainly stems in part from a paucity of appropriate animal models to study spontaneous apneas in all stages of sleep. Rapid eye movement (REM) sleep is associated with apneas, reductions in respiratory and upper airway motor outputs, and increased variability of respiration, heart rate and blood pressure. We present novel preliminary evidence suggesting that increased apnea expression with aging results from dysregulation of brainstem respiratory control systems by brainstem phasic events (BPE) in the elderly. Ponto-geniculo-occipital (PGO) waves are a close marker of BPE and are closely associated with cardio- respiratory changes, including apnea. The overall goals of this proposal are to (i) investigate the neural mechanisms by which BPE influence apnea genesis, and (ii) establish the importance of these mechanisms to the age-related increase in apnea. To achieve these goals, we will combine descriptive and interventional human studies with invasive central nervous system measurements and manipulations in rats using a model of sleep-related respiratory instability which we have characterized. We will focus our attention on the pedunculopontine tegmental nucleus (PPT), the putative site of the burst generator responsible brainstem phasic events detectable as PGO waves. We will manipulate BPE expression in two directions: 1) we will augment expression by acoustic stimulation and sleep deprivation in man and rat and by microinjection of cholinergic agonists into PPT in the rat; and 2) we will reduce expression by electrolytic lesions of the PPT in the rat. These manipulations in old and young patients, controls, and rats will provide a comprehensive approach to define the mechanisms and importance of brainstem phasic event-induced respiratory instability in aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016303-04
Application #
6509768
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Monjan, Andrew A
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$322,202
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Topchiy, Irina; Amodeo, Dionisio A; Ragozzino, Michael E et al. (2014) Acute exacerbation of sleep apnea by hyperoxia impairs cognitive flexibility in Brown-Norway rats. Sleep 37:1851-61
Kalauzi, Aleksandar; Spasic, Sladjana; Petrovic, Jelena et al. (2012) Cortico-pontine theta carrier frequency phase shift across sleep/wake states following monoaminergic lesion in rat. Gen Physiol Biophys 31:163-71
Spasic, Sladjana; Kalauzi, Aleksandar; Kesic, Srdjan et al. (2011) Surrogate data modeling the relationship between high frequency amplitudes and Higuchi fractal dimension of EEG signals in anesthetized rats. J Theor Biol 289:160-6
Topchiy, Irina; Radulovacki, Miodrag; Waxman, Jonathan et al. (2011) Impact of the vagal feedback on cardiorespiratory coupling in anesthetized rats. Respir Physiol Neurobiol 175:375-82
Ċ aponji?, Jasna (2011) [Selective stimulations and lesions of the rat brain nuclei as the models for research of the human sleep pathology mechanisms]. Glas Srp Akad Nauka Med :85-97
Topchiy, Irina; Waxman, Jonathan; Radulovacki, Miodrag et al. (2010) Functional topography of respiratory, cardiovascular and pontine-wave responses to glutamate microstimulation of the pedunculopontine tegmentum of the rat. Respir Physiol Neurobiol 173:64-70
(2009) [Neurobiology of sleep apnea: implication for therapy?]. Glas Srp Akad Nauka Med :37-45
Topchiy, Irina; Radulovacki, Miodrag; Waxman, Jonathan et al. (2009) Cardiorespiratory effects of intertrigeminal area stimulation in vagotomized rats. Brain Res 1250:120-9
Kalauzi, A; Kesic, S; Saponjic, J (2009) Cortico-pontine theta synchronization phase shift following monoaminergic lesion in rat. J Physiol Pharmacol 60:79-84

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