Loss of Gnas Imprinting Differentially Affects REM/NREM Sleep and Cognition in Mice

It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas. In particular, in mice with loss of imprinting of Gnas, NREM and complex cognitive processes are enhanced while REM and REM–linked behaviors are inhibited. This is the first demonstration that a specific overexpression of an imprinted gene affects sleep states and related complex behavioral traits. Furthermore, in parallel to the Gnas overexpression, we have observed an overexpression of Ucp1 in interscapular brown adipose tissue (BAT) and a significant increase in thermoregulation that may account for the REM/NREM sleep phenotypes. We conclude that there must be significant evolutionary advantages in the monoallelic expression of Gnas for REM sleep and for the consolidation of REM–dependent memories. Conversely, biallelic expression of Gnas reinforces slow wave activity in NREM sleep, and this results in a reduction of uncertainty in temporal decision-making processes

Pharmacological preconditioning in type 2 diabetic rat hearts: the roles of mitochondrial ATP-sensitive potassium channels and the phosphatidylinositol 3-kinase-Akt pathway.

PURPOSE: The authors examined whether olprinone, a phosphodiesterase type 3 inhibitor, or isoflurane, a volatile anesthetic, could protect the heart against myocardial infarction in type 2 diabetic rats and whether the underlying mechanisms involve protein kinase C (PKC), mitochondrial ATP-sensitive potassium (m-K(ATP)) channels, or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. METHODS: All rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Wistar rats received isoflurane or olprinone before ischemia with or without the PKC inhibitor chelerythrine (CHE), the m-K(ATP) channel blocker 5-hydroxydecanoic acid (5HD), or the PI3K-Akt inhibitor LY294002 (LY). Goto-Kakizaki (GK) rats were randomly assigned to receive isoflurane or olprinone. In another group, GK rats received LY before the olprinone. RESULTS: In the Wistar rats, both isoflurane (38 +/- 11%) and olprinone (40 +/- 11%) reduced infarct size as compared to the control group (59 +/- 8%). In the GK rats, olprinone (41 +/- 9%) but not isoflurane (53 +/- 11%) reduced infarct size as compared to the GK control group (58 +/- 14%). The beneficial effects of olprinone were blocked by LY (58 +/- 14%). In the Wistar rats, CHE, 5HD, and LY prevented isoflurane-induced reductions of infarct size. On the other hand, LY but not CHE or 5HD prevented olprinone-induced reductions of infarct size. CONCLUSIONS: Olprinone but not isoflurane protects the heart against myocardial infarction in type 2 diabetic rats. The olprinone-induced cardioprotective effect is mediated by the PI3K-Akt pathway but not PKC or m-K(ATP) channels

cGMP-Dependent Protein Kinase Type I Is Implicated in the Regulation of the Timing and Quality of Sleep and Wakefulness

Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3′,5′-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1–4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep

Bradykinin and adenosine receptors mediate desflurane induced postconditioning in human myocardium: role of reactive oxygen species

BACKGROUND: Desflurane during early reperfusion has been shown to postcondition human myocardium, in vitro. We investigated the role of adenosine and bradykinin receptors, and generation of radical oxygen species in desflurane-induced postconditioning in human myocardium. METHODS: We recorded isometric contraction of human right atrial trabeculae hanged in an oxygenated Tyrode's solution (34 degrees Celsius, stimulation frequency 1 Hz). After a 30-min hypoxic period, desflurane 6% was administered during the first 5 min of reoxygenation. Desflurane was administered alone or with pretreatment of N-mercaptopropionylglycine, a reactive oxygen species scavenger, 8-(p-Sulfophenyl)theophylline, an adenosine receptor antagonist, HOE140, a selective B2 bradykinin receptor antagonist. In separate groups, adenosine and bradykinin were administered during the first minutes of reoxygenation alone or in presence of N-mercaptopropionylglycine. The force of contraction of trabeculae was recorded continuously. Developed force at the end of a 60-min reoxygenation period was compared (mean +/- standard deviation) between the groups by a variance analysis and post hoc test. RESULTS: Desflurane 6% (84 +/- 6% of baseline) enhanced the recovery of force after 60-min of reoxygenation as compared to control group (51 +/- 8% of baseline, P < 0.0001). N-mercaptopropionylglycine (54 +/- 3% of baseline), 8-(p-Sulfophenyl)theophylline (62 +/- 9% of baseline), HOE140 (58 +/- 6% of baseline) abolished desflurane-induced postconditioning. Adenosine (80 +/- 9% of baseline) and bradykinin (83 +/- 4% of baseline) induced postconditioning (P < 0.0001 vs control), N-mercaptopropionylglycine abolished the beneficial effects of adenosine and bradykinin (54 +/- 8 and 58 +/- 5% of baseline, respectively). CONCLUSIONS: In vitro, desflurane-induced postconditioning depends on reactive oxygen species production, activation of adenosine and bradykinin B2 receptors. And, the cardioprotective effect of adenosine and bradykinin administered at the beginning of reoxygenation, was mediated, at least in part, through ROS production

IGFBP3 Colocalizes with and Regulates Hypocretin (Orexin)

Background: The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression. Methodology/Principal Findings: We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and coexpressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decrease

Technologies of sleep research

Sleep is investigated in many different ways, many different species and under many different circumstances. Modern sleep research is a multidisciplinary venture. Therefore, this review cannot give a complete overview of all techniques used in sleep research and sleep medicine. What it will try to do is to give an overview of widely applied techniques and exciting new developments. Electroencephalography has been the backbone of sleep research and sleep medicine since its first application in the 1930s. The electroencephalogram is still used but now combined with many different techniques monitoring body and brain temperature, changes in brain and blood chemistry, or changes in brain functioning. Animal research has been very important for progress in sleep research and sleep medicine. It provides opportunities to investigate the sleeping brain in ways not possible in healthy volunteers. Progress in genomics has brought new insights in sleep regulation, the best example being the discovery of hypocretin/orexin deficiency as the cause of narcolepsy. Gene manipulation holds great promise for the future since it is possible not only to investigate the functions of different genes under normal conditions, but also to mimic human pathology in much greater detail