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The Journal of Neuroscience, September 12, 2007, 27(37):10060-10071; doi:10.1523/JNEUROSCI.0857-07.2007

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Neurobiology of Disease
Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

Yan Zhu,¹ Polina Fenik,¹ Guanxia Zhan,¹ Emilio Mazza,¹ Max Kelz,³ Gary Aston-Jones,³ and Sigrid C. Veasey^1,2

¹Center for Sleep and Neurobiology and Department of Medicine, ²Department of Anesthesia, and ³Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Sigrid C. Veasey, University of Pennsylvania, Translational Research Building, Room 2115, 125 South 31st Street, Philadelphia, PA 19104. Email: Veasey{at}mail.med.upenn.edu

The presence of refractory wake impairments in many individuals with severe sleep apnea led us to hypothesize that the hypoxia/reoxygenation events in sleep apnea permanently damage wake-active neurons. We now confirm that long-term exposure to hypoxia/reoxygenation in adult mice results in irreversible wake impairments. Functionality and injury were next assessed in major wake-active neural groups. Hypoxia/reoxygenation exposure for 8 weeks resulted in vacuolization in the perikarya and dendrites and markedly impaired c-fos activation response to enforced wakefulness in both noradrenergic locus ceruleus and dopaminergic ventral periaqueductal gray wake neurons. In contrast, cholinergic, histaminergic, orexinergic, and serotonergic wake neurons appeared unperturbed. Six month exposure to hypoxia/reoxygenation resulted in a 40% loss of catecholaminergic wake neurons. Having previously identified NADPH oxidase as a major contributor to wake impairments in hypoxia/reoxygenation, the role of NADPH oxidase in catecholaminergic vulnerability was next addressed. NADPH oxidase catalytic and cytosolic subunits were evident in catecholaminergic wake neurons, where hypoxia/reoxygenation resulted in translocation of p67^phox to mitochondria, endoplasmic reticulum, and membranes. Treatment with a NADPH oxidase inhibitor, apocynin, throughout hypoxia/reoxygenation exposures conferred protection of catecholaminergic neurons. Collectively, these data show that select wake neurons, specifically the two catecholaminergic groups, can be rendered persistently impaired after long-term exposure to hypoxia/reoxygenation, modeling sleep apnea; wake impairments are irreversible; catecholaminergic neurons are lost; and neuronal NADPH oxidase contributes to this injury. It is anticipated that severe obstructive sleep apnea in humans destroys catecholaminergic wake neurons.

Key words: sleep; apnea; oxidative injury; noradrenergic; dopaminergic; wake; NADPH oxidase

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Received Feb. 26, 2007; revised July 31, 2007; accepted July 31, 2007.

Correspondence should be addressed to Dr. Sigrid C. Veasey, University of Pennsylvania, Translational Research Building, Room 2115, 125 South 31st Street, Philadelphia, PA 19104. Email: Veasey{at}mail.med.upenn.edu

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