Intermittent hypoxia induces transient delay in newborn mice

Title: Intermittent hypoxia induces transient delay in newborn mice

Authors: E. Drand, F. Lofaso, S. Dauger, G. Vardona, C. Gaultier, and J. Gallego

Published; J Appl Physiol 96: 1216-1222, 2004
First Published November 14, 2003; 10.1152/japplphysiol.00802.2003.

Summary:
"We conclude that IH (Intermitten Hypoxia) rapidly and reversibly depressed breathing and delayed arousal in newborn mice. Both effects may be due to hypoxia-induced release of inhibitory neurotransmitters acting concomitantly on both functions."

"Previous studies showed that infants who had survived a life-threatening event with OSAs had abnormal arousal responses to hypoxemia (14) and that infants who subsequently died from sudden infant death syndrome (SIDS) showed fewer spontaneous arousals from sleep than did controls (17). These results suggest that defective arousal responses may be major mechanisms in sleep-disordered breathing (SIDS and OSA) in infantcy."

"A previous experiment in lambs showed that one of the mechanisms that impair the arousal response to hypoxemia in newborns in intermitten hypoxemia (IH) (15). In these experiments, lambs exposed to IH showed depressed arousal and ventilatory responses to hypoxia during active sleep. Similarly, both ventilatory and arousal responses to hypoxia were blunted in adult dogs with experimentally induced OSA over 3-4 mo (22). Several processes may depress arousability during IH. First, ventilatory efforts (the input from mechanoreceptors) are an important stimulus to arousal from sleep (1, 20, 21) that decreases if ventilation is depressed. Second, depression of the arousal response to IH may be due to hapituation. Experiments in adult humans have shown that the arousal respiratory effort threshold during upper airway occlusion is in increased by prior sleep apnea (2, 38). Habituation to repeated tactile stimuli has also been shown to depress arousability in infants (29)."

"Recent results supporting a genetic basis for OSA (34) and SIDS (33,45) provide a promising avenue for the development of mouse models of sleep-disordered breathing."

"The main results of this study are that, in newborn mice, IH: (1) increased the arousal latency to hypoxia and (2) depressed normoxic ventilation, while preserving the ventilatory response to hypoxia. After 2 h of normoxia, the arousal responses to hypoxia recovered fully and baseline breathing returned to prehypoxic levels."

"Previous studies in 4- to 5-day-old lambs exposed to hypoxia showed that the increase in arousal latency was associated with a decrease in arterial O2 saturation value at which arousal occurred(13)."

"Previous studies in humans indicated that respiratory mechanoreceptor input to arousal centers in the brain make a major contribution to the arousal response to hypoxia (1)."

"The increase in arousal latency noted in our study fit in well with the observation that habituation to external stimuli depresses arousal, whatever the nature of these stimuli (7,23,29)."

"Previous studies showed that cortical activity was profoundly altered in 12-day-old piglets exposed to similar levels of IH(43)."

"Hypoxia activates several neurotransmitters (or neuromodulators) such as glutamate, which stimulates breathing, and GABA, opiates, and adenosine, which inhibit breathing (36, 40, 42). The platelet-derived growth factor in the nucleus tractus solitarius exerts a strong inhibitory effect on breathing during hypoxia (10, 11). Several of these neurotransmitters are also pivotal to habituation to external stimuli and sleep induction. In particular, adenosine is endogenous sleep factor this is thought to directly inhibit wakefulness-promoting neurons, such as cholinergic neurons in the basal forebrain(35). GABA is involved in habituation of motor responses to new environments (8). Steroid modulation of the GABA(A) receptor has been reported to mediate habituation of the evoked midbrain response to repetitive acoustic clicks (5), although this may not occur at early stages of development (25). Taken together, these results suggest that the dealyed arousal and decrease in baseline ventilation may be two consequences, relatively independent of each other, of the accumulation of central inhibitory neurotransmitters."

"Arousal impairments induced by IH are potentially hazardous in infants at risk for SIDS, because full behavioral awakening is necessary to inititate withdrawal responses in case of positional asphyxia or apnea. On the other hand, previous studies showed that infants with OSA terminated central and obstructive apneas without arousals (scored according to EEG, submental EMG, and behavioral criteria) (27). This indicates that behavioral arousal is not a necessary condition for OSA termination and that delayed arousal may be a protective mechanism avoiding sleep disruption."