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

Abstract

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.

Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus

“…We found that NE cell counts in these cell groups were similar to those in untreated rats (16,19) and did not differ between CIH-and sham-exposed rats of the present study. This is consistent with qualitative observations in mice suggesting that only the locus coeruleus, but not other brainstem NE cell groups, is susceptible to CIH-induced damage (39). The absence of changes in relevant cell numbers in our CIH rats further supports our interpretation that CIH elicited sprouting of NE terminals.…”

“…It has been reported that, in mice, prolonged exposure to CIH elicits cellular changes characteristic of neuronal damage in NE neurons of the locus coeruleus (39). If this effect also occurred in our CIH-exposed rats and involved those brainstem NE neurons that have axonal projections to the XII nucleus, a decrease, rather than an increase, of NE terminals would be expected.…”

Eif-2a Protects Brainstem Motoneurons in a Murine Model of Sleep Apnea

“…Long-term intermittent hypoxia (LTIH) across the sleep-predominant period of a circadian period is an established model of sleep apnea oxygenation (Gozal et al, 2001;Decker et al, 2003;Veasey et al, 2004a,b;Kheirandish et al, 2005;Zhan et al, 2005;Polotsky et al, 2006). An automated nitrogen/oxygen gas delivery system (Oxycycler model A84XOV; Biospherix, Redfield, NY) was used to deliver hypoxia/reoxygenation, using our previously described protocol (Veasey et al, 2004a,b;Zhu et al, 2007). Briefly, this system produces reductions in ambient oxygen level from 21 to 10% for 5 s every 90 s for LTIH and from 21 to 20% for 5 s every 90 s for sham LTIH, resulting in fluctuations in oxyhemoglobin saturation from 94 -98% to 76 -84% in LTIH and 96 -98 to 96 -97% in sham LTIH (Veasey et al, 2004).…”

“…Exposure to hypoxia/reoxygenation events in rodents, modeling oxygenation patterns in severe sleep apnea, results in neural injury in select groups of neurons including pyramidal, Purkinje, catecholaminergic wake neurons, and upper airway dilator motoneurons (Gozal et al, 2001;Decker et al, 2003Decker et al, , 2005Veasey et al, 2004a;Kheirandish et al, 2005;Zhan et al, 2005a,b;Zhu et al, 2007). Long-term exposure to hypoxia/reoxygenation impairs hypoglossal whole-nerve responsiveness to both glutamatergic and serotonergic excitation of hypoglossal motoneurons (Veasey et al, 2004b).…”

Alterações cognitivas na SAOS

“…(21) Além disso, foi observado que a hipóxia crônica recorrente induz a lesão irreversível e funcionalmente significativa em grupos neuronais ativos na vigília. (22) A morbidade neurocognitiva na apneia do sono obstrutiva tem sido estudada em roedores submetidos a hipóxia intermitente e/ou a alteração do padrão de sono. Foi demonstrado que os eventos hipóxicos recorrentes prejudicam a memória de trabalho espacial e o aprendizado.…”