Depression of hypoxic arousal response in adolescent mice following antenatal vasoactive intestinal polypeptide blockade

Abstract

Late‐gestation blockade of vasoactive intestinal polypeptide (VIP) activity in pregnant mice produces discrete morphological abnormalities in the somatosensory cortex of offspring. We investigated the functional implications of this lesion on the behavioural arousal response to moderate hypoxia. Pregnant mice received twice‐daily injections of 200 μl saline (control), or saline + 50 μg VIP antagonist (anti‐VIP) on embryonic days 17 and 18. Offspring were studied unrestrained at 6–7 weeks after birth, in a bias‐flow whole‐body plethysmograph during behavioural quiet sleep. Arousal was defined by movement (MVT) lasting >1 s. Hypoxic ventilatory (HVR) and arousal responses were measured during a 5 min exposure to 10 % O2‐3 % CO2 (hypoxia); peripheral chemoreflex drive was estimated by transient hyperoxia administered at rest and end‐hypoxia (Dejours‐type test). MVTs increased in all mice during hypoxia, but in anti‐VIP mice: (a) MVT onset was delayed (174 ± 90 vs. 108 ± 59 s from the start of hypoxia, anti‐VIP vs. control; P= 0.008); and (b) MVTs were less frequent, and total MVT time in hypoxia was less (8 ± 7 vs. 15 ± 9 %; P= 0.03). The HVR, and peripheral drive at rest and end‐hypoxia were comparable in control and anti‐VIP mice. In conclusion, a significant arousal deficit was evident in anti‐VIP mice. This was not associated with obviously deranged peripheral or brainstem‐mediated responses to hypoxia during sleep. This may signal a general deficit in the way hypoxic distress is monitored and processed, and arousal initiated and sustained in these mice.

β2 nicotinic acetylcholine receptor subunit modulates protective responses to stress: A receptor basis for sleep-disordered breathing after nicotine exposure

“…Ventilation was measured by whole-body plethysmography (18). Pairs of mice of the same genotype were studied on alternate days.…”

“…Sleep state was scored by using behavioral criteria; periods of arousal lasting Ն1 s were identified by the pressure artifact associated with sudden movements (18). For the analysis of ventilation, we only used parts of the record where breaths were clearly evident.…”

“…The hypoxic ventilatory response (HVR) was the average V E during the third to fifth and eighth to tenth minute (inclusive) of the first of the two to five challenges administered; respiratory volumes were expressed as absolute values normalized for body weight (microliters per gram), and as a percent of control baseline (ϭ final 3min in air preceding hypoxia). The decline in V E in O 2 (⌬V E ) was the 10-point minimum moving average V E during the initial 20 s of O 2 ; (baseline ϭ 20 s preceding the O 2 switch) (18). Data were analyzed by using a repeated-measures ANOVA (STAT-VIEW 5.0; SAS Institute, Cary, NC), and are presented as group means Ϯ SD in the text and tables, and (for improved clarity) means Ϯ SEM in figures.…”

Ventilatory Response to Hypoxia during Endotoxemia in Young Rats: Role of Nitric Oxide

“…The rats were deemed to be either awake (eyes open with gross body movements, such as crawling or grooming), in quiet sleep (eyes closed, recumbent with limbs adducted, regular and stable respiratory rhythm with minimal or no sighs or periodic breathing and absence of movements except for intermittent brief startles) or in active sleep (recumbent, eyes closed, irregular respiratory pattern, frequent twitches of the whiskers, ears, and extremities). Eye movements were not used since it was difficult to see these through the plethysmograph (20). These observations were made to ensure that the measurements were not obtained during active sleep, which can modify the ventilatory response to hypoxia (19).…”

“…Behavioral states were continuously scored using standard behavioral criteria (20). During circadian cycle, the nonrestrained and undisturbed rats spend most of the daytime in a sleep state, while at night they are awake and active.…”