Anatomical Substrates of Rapid Eye Movement Sleep Rebound in a Rodent Model of Post-sevoflurane Sleep Disruption.

BACKGROUND: Previous research suggests that sevoflurane anesthesia may prevent the brain from accessing rapid eye movement (REM) sleep. If true, then patterns of neural activity observed in REM-on and REM-off neuronal populations during recovery from sevoflurane should resemble those seen after REM sleep deprivation. In this study, the authors hypothesized that, relative to controls, animals exposed to sevoflurane present with a distinct expression pattern of c-Fos, a marker of neuronal activation, in a cluster of nuclei classically associated with REM sleep, and that such expression in sevoflurane-exposed and REM sleep-deprived animals is largely similar. METHODS: Adult rats and Targeted Recombination in Active Populations mice were implanted with electroencephalographic electrodes for sleep-wake recording and randomized to sevoflurane, REM deprivation, or control conditions. Conventional c-Fos immunohistochemistry and genetically tagged c-Fos labeling were used to quantify activated neurons in a group of REM-associated nuclei in the midbrain and basal forebrain. RESULTS: REM sleep duration increased during recovery from sevoflurane anesthesia relative to controls (157.0 ± 24.8 min vs. 124.2 ± 27.8 min; P = 0.003) and temporally correlated with increased c-Fos expression in the sublaterodorsal nucleus, a region active during REM sleep (176.0 ± 36.6 cells vs. 58.8 ± 8.7; P = 0.014), and decreased c-Fos expression in the ventrolateral periaqueductal gray, a region that is inactive during REM sleep (34.8 ± 5.3 cells vs. 136.2 ± 19.6; P = 0.001). Fos changes similar to those seen in sevoflurane-exposed mice were observed in REM-deprived animals relative to controls (sublaterodorsal nucleus: 85.0 ± 15.5 cells vs. 23.0 ± 1.2, P = 0.004; ventrolateral periaqueductal gray: 652.8 ± 71.7 cells vs. 889.3 ± 66.8, P = 0.042). CONCLUSIONS: In rodents recovering from sevoflurane, REM-on and REM-off neuronal activity maps closely resemble those of REM sleep-deprived animals. These findings provide new evidence in support of the idea that sevoflurane does not substitute for endogenous REM sleep.

Sleep Fragmentation, Electroencephalographic Slowing, and Circadian Disarray in a Mouse Model for Intensive Care Unit Delirium.

BACKGROUND: We aimed to further validate our previously published animal model for delirium by testing the hypothesis that in aged mice, Anesthesia, Surgery and simulated ICU conditions (ASI) induce sleep fragmentation, electroencephalographic (EEG) slowing, and circadian disarray consistent with intensive care unit (ICU) patients with delirium. METHODS: A total of 41 mice were used. Mice were implanted with EEG electrodes and randomized to ASI or control groups. ASI mice received laparotomy, anesthesia, and simulated ICU conditions. Controls did not receive ASI. Sleep was recorded at the end of ICU conditions, and hippocampal tissue was collected on EEG recording. Arousals, EEG dynamics, and circadian gene expression were compared with t tests. Two-way repeated measures analysis of variance (RM ANOVA) was used to assess sleep according to light. RESULTS: ASI mice experienced frequent arousals (36.6 ± 3.2 vs 26.5 ± 3.4; P = .044; 95% confidence interval [CI], 0.29-19.79; difference in mean ± SEM, 10.04 ± 4.62) and EEG slowing (frontal theta ratio, 0.223 ± 0.010 vs 0.272 ± 0.019; P = .026; 95% CI, -0.091 to -0.007; difference in mean ± SEM, -0.05 ± 0.02) relative to controls. In ASI mice with low theta ratio, EEG slowing was associated with a higher percentage of quiet wakefulness (38.2 ± 3.6 vs 13.4 ± 3.8; P = .0002; 95% CI, -35.87 to -13.84; difference in mean ± SEM, -24.86 ± 5.19). ASI mice slept longer during the dark phases of the circadian cycle (nonrapid eye movement [NREM], dark phase 1 [D1]: 138.9 ± 8.1 minutes vs 79.6 ± 9.6 minutes, P = .0003, 95% CI, -95.87 to -22.69, predicted mean difference ± SE: -59.28 ± 13.89; NREM, dark phase 2 (D2): 159.3 ± 7.3 minutes vs 112.6 ± 15.5 minutes, P = .006, 95% CI, -83.25 to -10.07, mean difference ± SE, -46.66 ± 13.89; rapid eye movement (REM), D1: 20.5 ± 2.1 minutes vs 5.8 ± 0.8 minutes, P = .001, 95% CI, -24.60 to -4.71, mean difference ± SE, -14. 65 ± 3.77; REM, D2: 21.0 ± 2.2 minutes vs 10.3 ± 1.4 minutes, P = .029, 95% CI, -20.64 to -0.76, mean difference ± SE, -10.70 ± 3.77). The expression of essential circadian genes was also lower in ASI mice (basic helix-loop-helix ARNT like [BMAL1] : -1.3 fold change; circadian locomotor output cycles protein kaput [CLOCK] : -1.2). CONCLUSIONS: ASI mice experienced EEG and circadian changes mimicking those of delirious ICU patients. These findings support further exploration of this mouse approach to characterize the neurobiology of delirium.

Pan-European phylogeography of the European roe deer (Capreolus capreolus).

To provide the most comprehensive picture of species phylogeny and phylogeography of European roe deer (Capreolus capreolus), we analyzed mtDNA control region (610 bp) of 1469 samples of roe deer from Central and Eastern Europe and included into the analyses additional 1541 mtDNA sequences from GenBank from other regions of the continent. We detected two mtDNA lineages of the species: European and Siberian (an introgression of C. pygargus mtDNA into C. capreolus). The Siberian lineage was most frequent in the eastern part of the continent and declined toward Central Europe. The European lineage contained three clades (Central, Eastern, and Western) composed of several haplogroups, many of which were separated in space. The Western clade appeared to have a discontinuous range from Portugal to Russia. Most of the haplogroups in the Central and the Eastern clades were under expansion during the Weichselian glacial period before the Last Glacial Maximum (LGM), while the expansion time of the Western clade overlapped with the Eemian interglacial. The high genetic diversity of extant roe deer is the result of their survival during the LGM probably in a large, contiguous range spanning from the Iberian Peninsula to the Caucasus Mts and in two northern refugia.

Surgery, Anesthesia and Intensive Care Environment Induce Delirium-Like Behaviors and Impairment of Synaptic Function-Related Gene Expression in Aged Mice.

OBJECTIVE: To establish a clinically relevant mouse model of perioperative delirium. METHODS: Aged C57BL/6J mice were tested at baseline in the Y-maze novel arm preference, buried food, simple discrimination task of the attentional set-shifting test, and open field tests. They were subsequently randomized to insult (anesthesia, surgery, and Intensive Care Unit environment) or control group. Insult-exposed mice received laparotomy under sevoflurane anesthesia, propofol sedation and exposure to intermittent lights, sounds and cage shaking. Controls did not receive anesthesia, surgery, or intensive care environment. All mice were tested in the Y-maze novel arm preference, buried food, attentional, and open field tests at the end of intensive care environment (0 h) and every 6 h up to 24 h. Mouse hippocampi were collected at 24 h for gene expression analyses. RESULTS: Surgery, anesthesia and Intensive Care environment decreased the entries in the Y-maze novel arm at 0 h (P = 0.001), 6 h (P < 0.001), 18 h (P = 0.002), and 24 h (P = 0.029). Insult exposure increased the latency to find a buried cereal reward at 18 h (P = 0.035) and 24 h (P = 0.027), and increased the trials to criterion in the reverse compound discrimination (P = 0.013) and extradimensional shift (P < 0.001) tasks of the attentional test. The overall incidence of delirium was 72% in A/S/I mice. Messenger RNA levels of synuclein alpha (-3.785 fold change relative to controls), Neurotrophic Receptor Tyrosine Kinase1 (-2.267), and syntaxin1a (-1.498) were decreased in the hippocampus of mice 24 h after insult exposure. Protein levels of syntaxin 1a (P = 0.012), Neurotrophic Receptor Tyrosine Kinase1 (P = 0.039), synuclein alpha (P = 0.017), phosphorylated synuclein alpha (P = 0.008), synaptophysin (P = 0.002), postsynaptic density protein 95 (P = 0.003), and microtubule-associated protein 2 (P = 0.013) were also decreased, relative to controls. CONCLUSION: Surgery, anesthesia and Intensive Care environment impaired mouse behaviors that depend on attention, memory, and thought organization. The changes were acute in onset and fluctuating in time. Mice with delirium exhibited decreased expression of key synaptic function-related genes. The behavioral changes induced by anesthesia, surgery, and Intensive Care environment in aged mice are consistent with the clinical features of human delirium, and support the use of this animal model for future mechanistic studies of perioperative delirium.