Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat

Abstract

Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups were exposed to either eight trials of hypoxia (3 min 5% O(2) alternating with room air) (group A), or three hypoxia trials as in group A, followed by five trials in which hypoxia was terminated at arousal (group B). In both groups A and B, latency increased over the first four trials of hypoxia, but reversed in group B animals during trials 5-8. Progressive arousal blunting was more pronounced in the older pups. The effects of intermittent hypoxia on heart rate also depended on age. In the older pups, heart rate increased with each hypoxia exposure. In the P5 pups, however, heart rate decreased during hypoxia and did not return to baseline between exposures, resulting in a progressive fall of baseline values over successive hypoxia exposures. In the group B animals, heart rate changes during trials 1-4 also reversed during trials 5-8. We conclude that exposure to repeated episodes of hypoxia can cause progressive blunting of arousal, which is reversible by altering the exposure times to hypoxia and the period of recovery between hypoxia exposures.

Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms

“…47 Pups slept readily in the warmed chamber, and they were judged to be awake, in quiet (QS) or active sleep (AS) through observation and recorded signals. The reliability of this approach has been discussed in detail previously (17). EEGs are unreliable in defining sleep states in young rodents Ͻ P12.…”

“…Both spontaneous and evoked arousals in small mammals, including developing rodents, are characterized by a stereotypical series of events that includes neck extension, retraction of the forelimbs, and in the older pups, head lifting and eye opening (12,(17)(18)(19)54) and are closely correlated with EEG and electromyogram changes (6,12,19). Variably, there is a startle response.…”

“…We and others have shown in newborn and infant rodents (17,18,21), lambs (25,41,42), and piglets (71) that repeated brief exposures to mild hypoxia result in a progressive lengthening of the time to arousal with each successive hypoxia exposure. A similar phenomenon has been described in human infants in response to repeated tactile (55) and auditory (47) stimuli.…”

“…The phenomenon of progressive lengthening of the time to arousal with repeated exposures to hypoxia has been referred to as "habituation" by some investigators and refers to the waning over time of a physiological response to repetitive stimuli. The concept of "habituation" to a hypoxic stimulus has been discussed in detail previously (17).…”

“…We have previously hypothesized that arousal "habituation" could be explained by hypoxia-induced biochemical processes with relatively long time constants, resulting in arousal inhibition, such that with brief alternating periods of hypoxia and normoxia, there is lingering inhibition between exposures resulting in a progressive cumulative inhibitory process (17). Brain levels of GABA, adenosine, glycine, and opiates all increase during hypoxia and are potential candidate inhibitory neuromodulators.…”