Influence of Repeated Exposure to Neonatal Isoflurane on Sleep Architecture and Neuronal Delta and Theta Oscillations in Adolescent Rats.

Abstract

Background: Normal sleep architecture is important for brain development, and we previously demonstrated that a single exposure to isoflurane during the neonatal period did not induce changes in the sleep architecture and only minimally altered neuronal beta oscillations in adolescent rats. Here, we hypothesized that a more clinically relevant scenario of repeated shorter exposures to isoflurane during brain development may have more profound effects on sleep and wake behavior and associated delta and theta oscillations, respectively.

Methods: Male and female rat pups were exposed to sham anesthesia (30% oxygen) or repeated isoflurane delivery for 2 hours each on 3 consecutive days (total exposure of 6 hours). The rat pups were divided into 2 cohorts. In cohort 1, we evaluated the neurotoxic effects of exposure postanesthesia. In cohort 2, electroencephalogram electrodes were implanted into the rat cortex between postnatal days 21-23, and sleep architecture was classified as wake, nonrapid eye movement (NREM), and rapid-eye movement (REM) sleep. Electroencephalogram power spectra were also measured in adolescent rats over a 72-hour period.

Results: Isoflurane exposure (n = 11) increased neuroapoptosis to 27. 7 ± 6.5 per mm-2 when compared to the sham group (9. 6 ± 3.0 per mm-2, n = 12, P < .001) and disrupted sleep architecture in adolescent rats. Specifically, there was an increase in the total sleep time (light + dark period) from 89. 9 ± 14.2 minutes in sham group (n = 9) to 111. 2 ± 32.2 minutes in the experimental group (n = 11, P < .05). Furthermore, there were fewer transitions during the dark period from 157. 1 ± 43.3 in sham group (n = 9) to 110. 6 ± 52.5 in the experimental group (n = 11, P < .05). The absolute power of delta oscillations was significantly decreased during the light period of NREM from an average 2217 ± 2016 μV2 in the sham group (n = 8) to 791 ± 659 μV2 in the experimental group (n = 11, P < .05). Further, theta oscillations in the wake stage were significantly decreased in the light period from 1579 ± 885 μV2 in sham group (n = 8) to 690 ± 413 μV2 in the experimental group (n = 11, P < .05) and light + dark period from 1390 ± 808 μV2 in sham group (n = 8) to 691 ± 421 μV2 in the experimental group (n = 11, P < .05).

Conclusions: Exposing neonatal rats to isoflurane repeatedly causes significant neurotoxicity, and alters delta and theta thalamocortical oscillations, as well as sleep architecture in adolescence. This contrasts with a single continuous exposure to isoflurane, in which we previously reported no significant effects on sleep-wake architecture and only minimal effect on beta oscillations despite similar acute neurotoxicity.