Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA066

Poster Communications

The effect of chronic inflammation on circadian rhythms in the preterm fetal sheep

V. King1, S. Dhillon1, R. Galinsky2,1, C. Lear1, A. J. Gunn1, L. Bennet1

1. Physiology, The University of Auckland, Auckland, New Zealand. 2. Ritchie Centre, Hudson Research Institute, Melbourne, Victoria, Australia.

Circadian rhythms are important regulators of physiological activity, but little is known about fetal patterns, particularly during preterm life, and the effect of adverse events such as infection. We examined circadian patterns in preterm fetal sheep and the effect of inflammation induced by lipopolysaccharide (LPS). Experiments were approved by the animal ethics committee of Auckland University. Pregnant ewes 98-99d gestation (term=147d) were anaesthetised with propofol (5 mg/kg iv) followed by 2-3% isoflurane in O2. Fetuses were exteriorised, instrumented for fetal heart rate (FHR), mean arterial blood pressure (MAP), and electroencephalographic (EEG) activity measurements and returned to the uterus. Animals recovered from surgery until 104d when fetuses were randomised to receive either a 5d iv saline (n=7) or LPS (n=7) infusion (ramping dose doubled each day from 200ng), followed by 5d of recovery. Ewes were fed ad libitum and acticography showed ewes ate primarily during the day. The housing light period was 06.00-18.00h. Data were evaluated using ANOVA, data are mean±SEM. In controls, FHR fell with age (189.0±2.0 to174.0±1.5bpm, 1st vs. last day, P<0.001). FHR fell primarily between ~22.00-06.00h, with mixed activity from 06.00-12.00h, a rise from 12.00 to19.00h and then plateau. LPS did not affect these patterns. MAP increased with age (34.8±0.5 vs. 40.2±0.7mmHg, P<0.005), primarily during the day, with a plateau ~19.00-02.00h then fall (0.8±0.5mmHg) until 06.00hrs. LPS infusion blunted the rise on days 3-5 (day 5: 36.0±0.8 vs. 38.0±0.8mmHg, P<0.05) without changing circadian patterns. Post-infusion MAP increased continually, and groups were not different on the last day. EEG power increased with age (16.4±0.4 vs. 19.8±1.0dB, P<0.05), primarily during the day with a plateau or fall at night. The rise in EEG was suppressed by LPS on days 3-5 (day 5:17.3±0.6 vs. 18.8±0.4 dB, P<0.05). Post-LPS, EEG increased continually and groups were not different on the last day. Spectral edge frequency (SEF) increased with age until 108d then plateaued and began to decrease. SEF increased only at night, with a daytime plateau or fall. LPS prevented the plateau/fall phase of SEF maturation, with a sustained increase observed throughout (last day 13.0±0.4 vs. 11.1±0.5Hz, P<0.01). Circadian patterns were sustained. Increasing MAP reflects fetal growth, thus our data suggests that fetal growth may occur primarily during the day, consistent with ewe food intake. LPS inhibits growth, and the loss of circadian patterns post-LPS infusion may reflect catch-up growth. Catch-up brain growth may also explain changes in EEG power. Increased SEF at night may reflect neural network development. Maturation of SEF reflects sleep-state development which is delayed by LPS. These data demonstrate time dependent differences in fetal physiology that can be altered by inflammation.

Where applicable, experiments conform with Society ethical requirements