The etiology of OSA remains unclear. Although small airway size is clearly a contributor, it is poorly correlated with symptomatology. Treatment of OSA with CPAP and related airway dilation strategies can normalize respiration during sleep, but successful treatment of the airway obstruction in OSA commonly leaves the patient with continued sleepiness and impaired cognitive function. The theme of this SCOR is that both the etiology and consequences of OSA are linked to neurological damage. Our goal is to determine the nature and cause of this damage and begin to develop treatment strategies. Harper has recently presented the first evidence for gray matter loss in OSA patients in cerebellar, limbic and cortical areas that mediate respiratory and blood pressure control, suggesting that this damage may be causal to apnea, whereas other regions show damage that is likely to be a result of OSA. He will use high resolution volumetric structural MRI and diffusion tensor MRI to define this damage and functional MRI to evaluate the dynamics of activity in these regions in OSA patients in response to autonomic challenge. Gozal will test the hypothesis that chronic intermittent hypoxia (CIH) mediated damage results from an inappropriate downregulation of the expression of monocarboxylate transporter 2. He will test this hypothesis using biochemical and transgenic approaches. Siegel will test the hypothesis that CIH interacts with the sleep disruption resulting from OSA to produce oxidative stress. He will explore the role of glutamate and serotonin mediated excitotoxicity and will test strategies for preventing this damage. Chase will study the interaction of sleep state and hypoxia using intracellular recording and iontophoresis to compare CA1 and CA3 responses, investigate the role of glutamate, hypocretin and nitric oxide production in these responses and describe the anatomical consequences of these changes. McGinty will test the hypothesis that CIH and sleep disruption effects on cognitive function in OSA are mediated by disruption of neurogenesis. He will examine the role of brain temperature and serotonin in this effect. Szymusiak will test the hypothesis that CIH causes persistent sleepiness in treated OSA patients due to dysregulation among sleep-and arousal regulatory systems in the preoptic area and posterior hypothalamus. He will use fos protein immunoreactivity and double labeling for neurotransmitter markers to identify affected neurons responsible for increased sleepiness.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL060296-09
Application #
7128210
Study Section
Special Emphasis Panel (ZHL1-CSR-S (M1))
Program Officer
Twery, Michael
Project Start
1998-09-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
9
Fiscal Year
2006
Total Cost
$1,532,312
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Macey, Paul M; Kumar, Rajesh; Yan-Go, Frisca L et al. (2012) Sex differences in white matter alterations accompanying obstructive sleep apnea. Sleep 35:1603-13
Wang, Yang; Guo, Shang Z; Bonen, Arend et al. (2011) Monocarboxylate transporter 2 and stroke severity in a rodent model of sleep apnea. J Neurosci 31:10241-8
Yamuy, Jack; Fung, Simon J; Xi, Mingchu et al. (2010) State-dependent control of lumbar motoneurons by the hypocretinergic system. Exp Neurol 221:335-45
Macey, Paul M; Woo, Mary A; Kumar, Rajesh et al. (2010) Relationship between obstructive sleep apnea severity and sleep, depression and anxiety symptoms in newly-diagnosed patients. PLoS One 5:e10211
Engelhardt, John K; Silveira, Valentina; Morales, Francisco R et al. (2010) Serotoninergic control of glycinergic inhibitory postsynaptic currents in rat hypoglossal motoneurons. Brain Res 1345:1-8
Vespa, P M; McArthur, D L; Xu, Y et al. (2010) Nonconvulsive seizures after traumatic brain injury are associated with hippocampal atrophy. Neurology 75:792-8
Ramanathan, Lalini; Hu, Shuxin; Frautschy, Sally A et al. (2010) Short-term total sleep deprivation in the rat increases antioxidant responses in multiple brain regions without impairing spontaneous alternation behavior. Behav Brain Res 207:305-9
Methippara, Melvi; Bashir, Tariq; Suntsova, Natalia et al. (2010) Hippocampal adult neurogenesis is enhanced by chronic eszopiclone treatment in rats. J Sleep Res 19:384-93
Sportiche, N; Suntsova, N; Methippara, M et al. (2010) Sustained sleep fragmentation results in delayed changes in hippocampal-dependent cognitive function associated with reduced dentate gyrus neurogenesis. Neuroscience 170:247-58
Kumar, Rajesh; Woo, Mary A; Birrer, Bramley V X et al. (2009) Mammillary bodies and fornix fibers are injured in heart failure. Neurobiol Dis 33:236-42

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