Neonatal Isoflurane Does Not Affect Sleep Architecture and Minimally Alters Neuronal Beta Oscillations in Adolescent Rats.

Francesca M Manzella,Bethany F Gulvezan,Yogendra H Raol,Stefan Maksimovic,Srdjan M Joksimovic,Vesna Jevtovic-Todorovic,Nemanja Useinovic,Slobodan M Todorovic

doi:10.3389/fnbeh.2021.703859

Abstract

General anesthetics are neurotoxic to the developing rodent and primate brains leading to neurocognitive and socio-affective impairment later in life. In addition, sleep patterns are important predictors of cognitive outcomes. Yet, little is known about how anesthetics affect sleep-wake behaviors and their corresponding oscillations. Here we examine how neonatal general anesthesia affects sleep and wake behavior and associated neuronal oscillations. We exposed male and female rat pups to either 6 h of continuous isoflurane or sham anesthesia (compressed air) at the peak of their brain development (postnatal day 7). One cohort of animals was used to examine neurotoxic insult 2 h post-anesthesia exposure. At weaning age, a second cohort of rats was implanted with cortical electroencephalogram electrodes and allowed to recover. During adolescence, we measured sleep architecture (divided into wake, non-rapid eye movement, and rapid eye movement sleep) and electroencephalogram power spectra over a 24 h period. We found that exposure to neonatal isoflurane caused extensive neurotoxicity but did not disrupt sleep architecture in adolescent rats. However, these animals had a small but significant reduction in beta oscillations, specifically in the 12–20 Hz beta 1 range, associated with wake behavior. Furthermore, beta oscillations play a critical role in cortical development, cognitive processing, and homeostatic sleep drive. We speculate that dysregulation of beta oscillations may be implicated in cognitive and socio-affective outcomes associated with neonatal anesthesia.

Highlights

The use of traditional anesthetics is necessary for life saving interventions in infants and young children
Pups exposed to 1.5% isoflurane for 6 h (51.58 ± 30.66 activated caspase 3 (AC3)+ neurons/mm2) showed a nearly five times increase in neurotoxicity in the ventrobasal thalamus compared to Sham (11.01 ± 5.23 AC3+ neurons/mm2, Figure 2A), Mann-Whitney U = 0, P = 0.0002, Cohen’s D = 1.844
There are few AC3+ neurons depicted in the subiculum of Sham animals 2 h after anesthesia exposure (Figure 2E), but we observed a large increase in apoptosis in the subiculum of Iso exposed pups (Figure 2F)

Summary

Introduction

The use of traditional anesthetics is necessary for life saving interventions in infants and young children. Our previous studies have shown that neonatal exposure to general anesthetics results in changes in plasticity of synaptic and intrinsic ionic currents in the nucleus reticularis (nRT) and the ventrobasal (VB) nucleus of the thalamus in neonatal and juvenile rats (DiGruccio et al, 2015; Joksovic et al, 2015; Woodward et al, 2019). This is important since both VB and nRT nuclei of the thalamus play a major role in the corticothalamic tract regulating slow wave sleep and associated oscillations, such as delta waves (Steriade, 2006)

Methods

Results

Conclusion