Thursday, January 19, 2012

Sleep and bones

Sleep duration was recently involved in several systemic condition, like obesity or diabetes. Now also the physiology of bone seems to be affected by the quantity/quality of sleep. 
Beside the intrinsic interest in the data, sleep appear to be definitely a whole body's phenomemenon, and not just for the brain.

Shorter sleep may be a risk factor for impaired bone mass accrual in childhood.:

J Clin Densitom. 2011 Oct-Dec;14(4):453-7
Casazza K, Hanks LJ, Fernandez JR

The purpose of the study was to investigate whether sleep duration during early childhood was associated with fat mass and bone mineral content (BMC). BMC and fat mass were measured by dual-energy X-ray absorptiometry in children (n=336) aged 4-12 yr. Sleep was quantified according to parental report of hours slept at night and napping. The relationship between sleep pattern and body composition was tested using analysis of variance including confounding factors. Based on the sample distribution, children were grouped into tertiles of sleep duration. BMC was greater in children with longer sleep duration (p=0.02). Age was inversely associated with sleep duration; therefore, the sample was analyzed by age category using age 7 yr as a cut-off point. The relationship remained significant only among younger children. Napping was positively associated with BMC (p=0.001). Sleep duration was not associated with fat parameters. Longer sleep duration may allow for optimal energy resource partitioning in which bone is favored. Sleep duration of less than 8h may impair bone mass accrual, particularly during periods of rapid growth.

PMID: 22051093 [PubMed - indexed for MEDLINE]

Emotional sleep

REM sleep is still a mystery. A great amount of evidence is suggesting a link between this stage of sleep and the processing of memory/emotion. 
Interesting data, but still I wonder if this is an effect of sleep, or is what cause it.

Processing of Emotional Reactivity and Emotional Memory over Sleep:

Bengi Baran, Edward F. Pace-Schott, Callie Ericson, and Rebecca M. C. Spencer
The Journal of Neuroscience, January 18, 2012 • 32(3):1035–1042 • 1035

Sleep enhances memories, particularly emotional memories. As such, it has been suggested that sleep deprivation may reduce posttraumatic stress disorder. This presumes that emotional memory consolidation is paralleled by a reduction in emotional reactivity, an association that has not yet been examined. In the present experiment, we used an incidental memory task in humans and obtained valence and arousal ratings during two sessions separated either by 12 h of daytime wake or 12 h including overnight sleep. Recognition accuracy was greater following sleep relative to wake for both negative and neutral pictures. While emotional reactivity to negative pictures was greatly reduced over wake, the negative emotional response was relatively preserved over sleep. Moreover, protection of emotional reactivity was associated with greater time in REM sleep. Recognition accuracy, however, was not associated with REM. Thus, we provide the first evidence that sleep enhances emotional memory while preserving emotional reactivity.

Monday, January 16, 2012

Sleeping without orexin

Orexin is a new hot target in the world of anti-insomnia medication. In this paper, the effects of a dual orexin antagonist is compare with the more common hypnotic Zolpidem. It would seem that ORX antagonism is a "more physiological" approach to sleep-inducing drugs, but still all the possible side effects of an orexinergic blockade (iatrogenic narcolepsy, metabolci syndrome and so on)have to be considered.

Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation, SWS, REM Sleep, and EEG Power Spectra in a Model of Situational Insomnia.:

Neuropsychopharmacology. 2012 Jan 11;

Authors: Bettica P, Squassante L, Groeger JA, Gennery B, Winsky-Sommerer R, Dijk DJ

Orexins have a role in sleep regulation, and orexin receptor antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual orexin receptor antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABA(A) receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p<0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB-6489698 30 mg dose (p<0.001). Latency to persistent sleep was significantly reduced after both doses of SB-6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p< 0.001) and low delta activity (<=1.0 Hz) were increased, and 2.25-11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB-649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p<0.001) after 10 and 30 mg of SB-649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual orexin receptor antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem.Neuropsychopharmacology advance online publication, 11 January 2012; doi:10.1038/npp.2011.310.

PMID: 22237311 [PubMed - as supplied by publisher]

Friday, January 13, 2012

Neonatal Hypoxia and Sleep

cross posted at


Unfortunately this paper does not report any data on sleep. Too bad, it would seem a natural (and interesting) complement to the paper. The Authors show that neonatal hypoxia lead to long lasting vegetative dysregulation,  especially in ventilation and arterial pressure, by mean of DNA methilation. I'm not here discussing the genetic part (very intriguing), but I would like to comment on the physiology used in the paper.

1) To assess to presence of breathing dysregulation in adulthood, animal exposed to hypoxia bout in young age were housed for 2 hours in a whole body plethysmogrphy (from 9:00 to 11:00) . Results: the hypoxia exposed animals have more apnea episodes than the control. Now the interesting question is: were these animal asleep (remember that rats are nocturnal animals, so they sleep during the day)?  Rats spontaneously show episode of central apnea during REM sleep, and it would have been very interesting, especially for the point this paper try to make, to show if the apnea episodes were REM sleep related.

2) Arterial pressure was measured by tail cuff in the same time window (9:00 - 11:00). I am just very curious on what would a 24h telemetric arterial pressure recording have shown. Arterial pressure (and heart rate) is interestingly modulated by sleep, showing different features in different part of the sleep-wake cycle (i.e. dipping vs non-dipping phenotype, or arterial pressure surges in REM sleep) and would have been extremely interesting to see the effects of neonatal hypoxia exposure on such phenomena.

3) No thermoregulatory / metabolic measure. Is the altered chemoreflex somehow affecting also thermoregulation or metabolism? We don't know (yet).

In conclusion, I hope the Authors would continue to analyze this very interesting model, maybe with just a little bit more physiology (that seems to be disappearing from the abundance of genetic / biochemical experiments conducted today) 

Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis.:

Proc Natl Acad Sci U S A. 2012 Jan 9;

Authors: Nanduri J, Makarenko V, Reddy VD, Yuan G, Pawar A, Wang N, Khan SA, Zhang X, Kinsman B, Peng YJ, Kumar GK, Fox AP, Godley LA, Semenza GL, Prabhakar NR

Recurrent apnea with intermittent hypoxia is a major clinical problem in preterm infants. Recent studies, although limited, showed that adults who were born preterm exhibit increased incidence of sleep-disordered breathing and hypertension, suggesting that apnea of prematurity predisposes to autonomic dysfunction in adulthood. Here, we demonstrate that adult rats that were exposed to intermittent hypoxia as neonates exhibit exaggerated responses to hypoxia by the carotid body and adrenal chromaffin cells, which regulate cardio-respiratory function, resulting in irregular breathing with apneas and hypertension. The enhanced hypoxic sensitivity was associated with elevated oxidative stress, decreased expression of genes encoding antioxidant enzymes, and increased expression of pro-oxidant enzymes. Decreased expression of the Sod2 gene, which encodes the antioxidant enzyme superoxide dismutase 2, was associated with DNA hypermethylation of a single CpG dinucleotide close to the transcription start site. Treating neonatal rats with decitabine, an inhibitor of DNA methylation, during intermittent hypoxia exposure prevented oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction. These findings implicate a hitherto uncharacterized role for DNA methylation in mediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.

PMID: 22232674 [PubMed - as supplied by publisher]

Thursday, January 12, 2012

Irisin, the finding of a new hormone targetable for metabolic disease

The finding of a new hormone is not an everyday event.
A paper in Nature shows how Irisin could be an excellent target for a pharmaceutical company in the rush for an effective anti-obesity drug. 
For sure what this new finding shown is that metabolism control is a very intricate system, in which the brain - body interaction is all still the be investigated

A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis:

Nature advance online publication 11 January 2012. doi:10.1038/nature10777

Authors: Pontus Boström, Jun Wu, Mark P. Jedrychowski, Anisha Korde, Li Ye, James C. Lo, Kyle A. Rasbach, Elisabeth Almer Boström, Jang Hyun Choi, Jonathan Z. Long, Shingo Kajimura, Maria Cristina Zingaretti, Birgitte F. Vind, Hua Tu, Saverio Cinti, Kurt Højlund, Steven P. Gygi & Bruce M. Spiegelman

Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise

Monday, January 09, 2012

...and again on Orexin

It seems that Orexin has so many functions that I am so surprise that ORX KO mice seems almost normal to me.
Is this because of redundancy? Other systems take over when ORX is missing, or what?

Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking.:

Int J Neuropsychopharmacol. 2011 Jun;14(5):684-90
Authors: James MH, Charnley JL, Levi EM, Jones E, Yeoh JW, Smith DW, Dayas CV

Orexinergic signalling is critical to drug relapse-like behaviour; however, the CNS sites(s) of action remain unknown. Two candidate brain regions are the paraventricular thalamus (PVT) and ventral tegmental area (VTA). We assessed the effect of intra-PVT or -VTA administration of the orexin-1 receptor (OrxR1) antagonist SB-334867 on discriminative cue-induced cocaine-seeking. Animals received either PVT- or VTA-directed SB-334867 (0, 3 or 6 μg; 0, 1 or 3 μg, respectively) prior to reinstatement testing elicited by presenting cocaine-paired stimuli (S+). The effect of VTA-directed injections of SB-334867 (0 or 3 μg) on locomotor activity was also assessed. Intra-VTA, but not -PVT, SB-334867 dose-dependently attenuated S+-induced reinstatement (3 μg dose, p<0.01). Intra-VTA SB-334867 had no effect on locomotor activity. We conclude that OrxR1 signalling within the VTA, but not the PVT, mediates cue-induced cocaine-seeking behaviour. We hypothesize that blockade of VTA OrxR1 signalling may reduce nucleus accumbens dopamine in response to drug cue presentation.

PMID: 21447232 [PubMed - indexed for MEDLINE]

Orexin for fun

Cerebrospinal fluid hypocretin (orexin) levels are elevated by play but are not raised by exercise and its associated heart rate, blood pressure, respiration or body temperature changes.:

Arch Ital Biol. 2011 Dec;149(4)
Authors: Wu MF, Nienhuis R, Maidment N, Lam HA, Siegel JM

Hypocretin (Hcrt) has been implicated in the control of motor activity and in respiration and cardiovascular changes. Loss of Hcrt in narcolepsy is linked to sleepiness and to cataplexy, a sudden loss of muscle tone which is triggered by sudden strong emotions. In the current study we have compared the effects of treadmill running, to yard play on cerebrospinal fluid (CSF) Hcrt level in normal dogs. We find that treadmill locomotion, at a wide range of speeds, does not increase Hcrt level beyond baseline, whereas yard play produces a substantial increase in Hcrt, even though both activities produce comparable increases in heart rate, respiration and body temperature. We conclude that motor and cardiovascular changes are not sufficient to elevate CSF levels of Hcrt and we hypothesize that the emotional aspects of yard play account for the observed increase in Hcrt.

PMID: 22205595 [PubMed - in process]

Sleep and sympathetic nerve activity, always linked

Sympathetic and angiotensinergic responses mediated by paradoxical sleep loss in rats.:

J Renin Angiotensin Aldosterone Syst. 2011 Sep;12(3):146-52
Authors: Perry JC, Bergamaschi CT, Campos RR, Andersen ML, Montano N, Casarini DE, Tufik S

INTRODUCTION: Recent investigations over the past decade have linked the development of hypertension to sleep loss, although the mechanisms underlying this association are still under scrutiny. To determine the relationship between sleep deprivation and cardiovascular dysfunction, we examined the effects of paradoxical sleep deprivation on heart rate, blood pressure, sympathetic nerve activity (SNA) and their consequences in the blood renin-angiotensin system.
MATERIALS AND METHODS: Wistar-Hannover male rats were randomly assigned to three experimental groups: 1) control, 2) paradoxical sleep deprivation for 24 h and 3) paradoxical sleep deprivation for 96 h. Blood pressure and heart rate were recorded in awake, freely moving rats.
RESULTS: Heart rate was higher in the 96 h paradoxical sleep deprivation group compared with the control group. Renal SNA was increased in all deprived groups. However, no significant statistical differences were observed in blood pressure or splanchnic SNA among groups. Paradoxical sleep deprivation (24 and 96 h) reduced plasma angiotensin II (Ang II) concentrations.
CONCLUSIONS: The results suggest that selective sleep deprivation produces an increase in SNA, preferentially in the kidney. Thus, alterations in the sympathetic system in response to sleep loss may be an important pathway through which hypertension develops.

PMID: 21398399 [PubMed - indexed for MEDLINE]

Sleep and longevity, always linked

Pan-neuronal knockdown of the c-Jun N-terminal Kinase (JNK) results in a reduction in sleep and longevity in Drosophila.:

Biochem Biophys Res Commun. 2011 Dec 16;
Authors: Takahama K, Tomita J, Ueno T, Yamazaki M, Kume S, Kume K

Sleep is a unique behavioral state that is conserved between species, and sleep regulation is closely associated to metabolism and aging. The fruit fly, Drosophila melanogaster has been used to study the molecular mechanism underlying these physiological processes. Here we show that the c-Jun N-terminal Kinase (JNK) gene, known as basket (bsk) in Drosophila, functions in neurons to regulate both sleep and longevity in Drosophila. Pan-neuronal knockdown of JNK mRNA expression by RNA interference resulted in a decrease in both sleep and longevity. A heterozygous knockout of JNK showed similar effects, indicating the molecular specificity. The JNK knockdown showed a normal arousal threshold and sleep rebound, suggesting that the basic sleep mechanism was not affected. JNK is known to be involved in the insulin pathway, which regulates metabolism and longevity. A JNK knockdown in insulin-producing neurons in the pars intercerebralis had slight effects on sleep. However, knocking down JNK in the mushroom body had a significant effect on sleep. These data suggest a unique sleep regulating pathway for JNK.

PMID: 22197814 [PubMed - as supplied by publisher]

Are sleep and metabolism the two faces of Giano?

Increased food intake and changes in metabolic hormones in response to chronic sleep restriction alternated with short periods of sleep allowance:

Rodent models for sleep restriction have good face validity when examining food intake and related regulatory metabolic hormones. However, in contrast to epidemiological studies in which sleep restriction is associated with body weight gain, sleep-restricted rats show a decrease in body weight. This difference with the human situation might be caused by the alternation between periods of sleep restriction and sleep allowance that often occur in real life. Therefore, we assessed the metabolic consequences of a chronic sleep restriction protocol that modeled working weeks with restricted sleep time alternated by weekends with sleep allowance. We hypothesized that this protocol could lead to body weight gain. Male Wistar rats were divided into three groups: sleep restriction (SR), forced activity control (FA), and home cage control (HC). SR rats were subjected to chronic sleep restriction by keeping them awake for 20 h per day in slowly rotating drums. To model the human condition, rats were subjected to a 4-wk protocol, with each week consisting of a 5-day period of sleep restriction followed by a 2-day period of sleep allowance. During the first experimental week, SR caused a clear attenuation of growth. In subsequent weeks, two important processes occurred: 1) a remarkable increase in food intake during SR days, 2) an increase in weight gain during the weekends of sleep allowance, even though food intake during those days was comparable to controls. In conclusion, our data revealed that the alternation between periods of sleep restriction and sleep allowance leads to complex changes in food intake and body weight, that prevent the weight loss normally seen in continuous sleep-restricted rats. Therefore, this "week-weekend" protocol may be a better model to study the metabolic consequences of restricted sleep.

Torpor update 3

A Role for the Melatonin-Related Receptor GPR50 in Leptin Signaling, Adaptive Thermogenesis, and Torpor.:

Curr Biol. 2011 Dec 20;
Authors: Bechtold DA, Sidibe A, Saer BR, Li J, Hand LE, Ivanova EA, Darras VM, Dam J, Jockers R, Luckman SM, Loudon AS

The ability of mammals to maintain a constant body temperature has proven to be a profound evolutionary advantage, allowing members of this class to thrive in most environments on earth. Intriguingly, some mammals employ bouts of deep hypothermia (torpor) to cope with reduced food supply and harsh climates [1, 2]. During torpor, physiological processes such as respiration, cardiac function, and metabolic rate are severely depressed, yet the neural mechanisms that regulate torpor remain unclear [3]. Hypothalamic responses to energy signals, such as leptin, influence the expression of torpor [4-7]. We show that the orphan receptor GPR50 plays an important role in adaptive thermogenesis and torpor. Unlike wild-type mice, Gpr50(-/-) mice readily enter torpor in response to fasting and 2-deoxyglucose administration. Decreased thermogenesis in Gpr50(-/-) mice is not due to a deficit in brown adipose tissue, the principal site of nonshivering thermogenesis in mice [8]. GPR50 is highly expressed in the hypothalamus of several species, including man [9, 10]. In line with this, altered thermoregulation in Gpr50(-/-) mice is associated with attenuated responses to leptin and a suppression of thyrotropin-releasing hormone. Thus, our findings identify hypothalamic circuits involved in torpor and reveal GPR50 to be a novel component of adaptive thermogenesis in mammals.

PMID: 22197240 [PubMed - as supplied by publisher]

Torpor update 2

Increased thermogenic capacity of brown adipose tissue under low temperature and its contribution to arousal from hibernation in Syrian hamsters:

Brown adipose tissue (BAT) is thought to play a significant physiological role during arousal when body temperature rises from the extremely low body temperature that occurs during hibernation. The dominant pathway of BAT thermogenesis occurs through the β3-adrenergic receptor. In this study, we investigated the role of the β3-adrenergic system in BAT thermogenesis during arousal from hibernation both in vitro and in vivo. Syrian hamsters in the hibernation group contained BAT that was significantly greater in overall mass, total protein, and thermogenic uncoupling protein-1 than BAT from the warm-acclimated group. Although the ability of the β3-agonist CL316,243 to induce BAT thermogenesis at 36°C was no different between the hibernation and warm-acclimated groups, its maximum ratio over the basal value at 12°C in the hibernation group was significantly larger than that in the warm-acclimated group. Forskolin stimulation at 12°C produced equivalent BAT responses in these two groups. In vivo thermogenesis was assessed with the arousal time determined by the time course of BAT temperature or heart rate. Stimulation of BAT by CL316,243 significantly shortened the time of arousal from hibernation compared with that induced by vehicle alone, and it also induced arousal in deep hibernating animals. The β3-antagonist SR59230A inhibited arousal from hibernation either in part or completely. These results suggest that BAT in hibernating animals has potent thermogenic activity with a highly effective β3-receptor mechanism at lower temperatures.

Torpor update

Mitochondrial metabolic suppression and reactive oxygen species production in liver and skeletal muscle of hibernating thirteen-lined ground squirrels:

During hibernation, animals cycle between periods of torpor, during which body temperature (Tb) and metabolic rate (MR) are suppressed for days, and interbout euthermia (IBE), during which Tb and MR return to resting levels for several hours. In this study, we measured respiration rates, membrane potentials, and reactive oxygen species (ROS) production of liver and skeletal muscle mitochondria isolated from ground squirrels (Ictidomys tridecemlineatus) during torpor and IBE to determine how mitochondrial metabolism is suppressed during torpor and how this suppression affects oxidative stress. In liver and skeletal muscle, state 3 respiration measured at 37°C with succinate was 70% and 30% lower, respectively, during torpor. In liver, this suppression was achieved largely via inhibition of substrate oxidation, likely at succinate dehydrogenase. In both tissues, respiration by torpid mitochondria further declined up to 88% when mitochondria were cooled to 10°C, close to torpid Tb. In liver, this passive thermal effect on respiration rate reflected reduced activity of all components of oxidative phosphorylation (substrate oxidation, phosphorylation, and proton leak). With glutamate + malate and succinate, mitochondrial free radical leak (FRL; proportion of electrons leading to ROS production) was higher in torpor than IBE, but only in liver. With succinate, higher FRL likely resulted from increased reduction state of complex III during torpor. With glutamate + malate, higher FRL resulted from active suppression of complex I ROS production during IBE, which may limit ROS production during arousal. In both tissues, ROS production and FRL declined with temperature, suggesting ROS production is also reduced during torpor by passive thermal effects.

CB(1) and Orexin, things are getting even more complicated

Heteromultimerization of cannabinoid CB(1) receptor and orexin OX(1) receptor generates a unique complex in which both protomers are regulated by orexin A.:

J Biol Chem. 2011 Oct 28;286(43):37414-28
Ward RJ, Pediani JD, Milligan G

Agonist-induced internalization was observed for both inducible and constitutively expressed forms of the cannabinoid CB(1) receptor. These were also internalized by the peptide orexin A, which has no direct affinity for the cannabinoid CB(1) receptor, but only when the orexin OX(1) receptor was co-expressed along with the cannabinoid CB(1) receptor. This effect of orexin A was concentration-dependent and blocked by OX(1) receptor antagonists. Moreover, the ability of orexin A to internalize the CB(1) receptor was also blocked by CB(1) receptor antagonists. Remarkably, orexin A was substantially more potent in producing internalization of the CB(1) receptor than in causing internalization of the bulk OX(1) receptor population, and this was true in cells in which the CB(1) receptor was maintained at a constant level, whereas levels of OX(1) could be varied and vice versa. Both co-immunoprecipitation and cell surface, homogenous time-resolved fluorescence resonance energy transfer based on covalent labeling of N-terminal "SNAP" and "CLIP" tags present in the extracellular N-terminal domain of the receptors confirmed the capacity of these two receptors to heteromultimerize. These studies confirm the capacity of the CB(1) and OX(1) receptors to interact directly and demonstrate that this complex has unique regulatory characteristics. The higher potency of the agonist orexin A to regulate the CB(1)-OX(1) heteromer compared with the OX(1)-OX(1) homomer present in the same cells and the effects of CB(1) receptor antagonists on the function of orexin A suggest an interplay between these two systems that may modulate appetite, feeding, and wakefulness.

PMID: 21908614 [PubMed - indexed for MEDLINE]