Modulation Of Circadian Rhythms Research Articles

Attenuation of hepatocellular carcinoma by naringenin is associated with modulation of circadian rhythms of redox status in rats

We evaluated the effect of naringenin on the circadian rhythms of circulatory lipid peroxidation and antioxidant status during N-Nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. The characteristics of circadian rhythms (acrophase, amplitude and mesor) of lipid peroxidation products thiobarbituric acid reactive substances (TBARS) and antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST)) were markedly altered in NDEA-treated rats when compared to other groups. Pre- and post-treatment of naringenin to NDEA treated animals significantly increased the mesor and alter amplitude values of antioxidants and significantly decreased the mesor values of TBARS. Further delays in acrophase in NDEA-treated rats were reversed by naringenin administration. Our findings suggest that naringenin could alter the circadian characteristics of lipid peroxidation and antioxidant status, and further research is in process on the chronotherapeutic efficacy of naringenin.

Simultaneous effect of melatonin on supraoesophageal ganglion spontaneous electrical activity and photoreceptor electroretinogram amplitude in crayfish

In crayfish, the supraoesophageal ganglion and the retina are neuronal structures whose electrical activities follow a circadian rhythm. The hormone melatonin (MEL) is an indoleamine, conserved from unicellular organisms to mammals, that is released rhythmically with a peak occurring in the darkness period. In vertebrates, MEL acts on numerous central and peripheral structures and participates in the modulation of circadian rhythms. The main purpose of this study was to present evidence of the role of MEL in crayfish circadian physiology, simultaneously recording the electrical activity of both the supraoesophageal ganglion and the retina under the free-running condition. We found that at circadian time (CT) 2, when the concentration of endogenous MEL is low, injection of this indoleamine into intact animals elicited a decrease in the level of spontaneous electrical activity recorded from the supraoesophageal ganglion and enhancement of electroretinogram amplitude. The MEL-induced effect mimics the level of these activities that was observed when the endogenous MEL concentration is high. These results suggest that MEL acts, simultaneously on both central and peripheral circadian oscillators, as a mediator to maintain the crayfish circadian system organization under the free-running condition.

Brain Renin–Angiotensin System in Hypertension, Cardiac Hypertrophy, and Heart Failure

Brain renin–angiotensin system (RAS) is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. Furthermore, the brain RAS modulates the cardiovascular and fluid–electrolyte homeostasis not only by interacting with the autonomic nervous system but also by modulating hypothalamic–pituitary axis and vasopressin release. The brain RAS is also involved in the modulation of circadian rhythms of arterial pressure, contributing to non-dipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert in diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as renin or angiotensin converting enzyme inhibitors or receptor blockers having increased brain penetrability could be of advantage.

Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels

Attention-deficit hyperactivity disorder (ADHD) in adults is associated with impaired sleep, and it has been postulated that this impairment may contribute to the psychopathology of this common condition. One key driver of sleep/wake cycles is the circadian system, which at the molecular level consists of a series of transcriptional feedback loops of clock genes, which in turn produce endocrine, physiological and behavioural outputs with a near 24 h periodicity. We set out to examine circadian rhythms at the behavioural, endocrine and molecular levels in ADHD. Adults with ADHD as well as age- and sex-matched controls were recruited. Circadian rhythms were measured by means of actigraphy for the determination of gross motor patterns, by self-sampling of oral mucosa for assessment of rhythmic expression of the clock genes BMAL1 and PER2, and by estimation of salivary cortisol and melatonin levels. Actigraphic analysis revealed significant diurnal and nocturnal hyperactivity in the ADHD group, as well as a significant shorter period of best fit for the locomotor circadian rhythm in ADHD. BMAL1 and PER2 showed circadian rhythmicity in controls with this being lost in the ADHD group. Cortisol rhythms were significantly phase delayed in the ADHD group. These findings indicate that adult ADHD is accompanied by significant changes in the circadian system, which in turn may lead to decreased sleep duration and quality in the condition. Further, modulation of circadian rhythms may represent a novel therapeutic avenue in the management of ADHD.

The noradrenaline reuptake inhibitor atomoxetine phase-shifts the circadian clock in mice

Circadian rhythms are recurring cycles in physiology and behaviour that repeat with periods of near 24 h and are driven by an endogenous circadian timekeeping system with a master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Atomoxetine is a specific noradrenaline reuptake inhibitor that is used in the clinical management of attention-deficit/hyperactivity disorder (ADHD). In the current study we examined the effects of atomoxetine on circadian rhythms in mice. Atomoxetine (i.p.; 3 mg/kg) treatment of mice free-running in constant light (LL) at circadian time (CT) 6 induced large phase delays that were significantly different to saline controls. Treatment of animals with atomoxetine at CT13 or CT18 did not elicit any significant phase shifts. We also examined the effects of atomoxetine treatment of animals free-running in constant darkness (DD). Atomoxetine treatment at CT6 in these animals leads to more modest, but significant, phase advances, whereas treatment at CT18 did not elicit significant phase shifts. The effects of atomoxetine in LL were attenuated by pretreatment with the α-1 adrenoreceptor antagonist prazosin and were mimicked by another noradrenaline reuptake inhibitor, reboxetine. Further, atomoxetine treatment at CT6 induced a downregulation of c-Fos and CLOCK in the SCN, but did not alter the expression of PER2 and BMAL1. Atomoxetine during the night phase did not alter any of these factors. Atomoxetine treatment preceding a light pulse at CT15 enhanced the magnitude of the photic-phase shift, whereas it altered photic induction of the immediate early gene products c-Fos and ARC in the SCN. These data indicate that atomoxetine can reset the circadian clock and indicate that part of the therapeutic profile of atomoxetine may be through circadian rhythm modulation.

Peroxisome proliferator-activated receptor α (PPARα) activation advances locomotor activity and feeding daily rhythms in mice

Peroxisome proliferator-activated receptors (PPARs) are key mediators of energy homeostasis, and lipid and glucose metabolism that exhibit circadian expression. PPAR activating drugs are used clinically as lipid and glucose-lowering drugs. We evaluated the effect of long-term (11 weeks) PPARα and PPARγ activation using bezafibrate and rosiglitazone, respectively, on metabolism, locomotor activity and feeding rhythms of non-obese mice. We found that bezafibrate, but not rosiglitazone, led to no weight gain and a slight weight loss with reduced epididymal fat pads. Although rosiglitazone had a minor effect on 24-h food intake rhythm, bezafibrate treatment was accompanied by increased amplitude and an advanced acrophase of the 24-h feeding rhythm. Similarly, unlike rosiglitazone, bezafibrate treatment was accompanied by a significantly advanced acrophase of locomotor activity rhythm under constant darkness conditions. As disrupted circadian rhythms lead to obesity, PPARα activation can serve as a clinical target for the modulation of both circadian rhythms and metabolism.

Induction of Per1 expression following an experimentally induced epilepsy in the mouse hippocampus

The Period1 (Per1) is a clock-oscillating gene product that plays an essential role in the generation and modulation of circadian rhythm in the suprachiasmatic nucleus (SCN) of hypothalamus. However, Per1 is also expressed in many other brain regions including cerebral cortex, hippocampus, and amygdala, suggesting that Per1 may be involved in the broader cellular functions in addition to the rhythm regulation. In this study, we found that chemical or electrical seizure-inducing stimulations regulate Per1 expression. Treatments with electric convulsive shock (ECS) or kainic acid (KA) robustly up-regulated the expressions of per1 mRNA and protein in the hippocampal formation and cerebral cortex. In consistent, we found that neuronal depolarization or KA treatment increased per1 mRNA expression in cultured primary cortical neurons. Because it has been demonstrated that Per family molecules contribute to the regulation of stress-induced cell death, we also explored the effect of Per1 overexpression on the survival of cultured neurons. However, neither basal, staurosporine- nor KA-induced neuronal death was affected by forced expression of Per1. Collectively, these results suggest that the Per1 expression is neuronal activity- and epileptogen-dependent, although its functional significance is remained to be explored.

FC26-06 - Development of interneurons expressing serotonin 3A subtype receptor and sleep regulation

IntroductionSerotonin (5-HT) is known to play a key role in a number of psychiatric disorders. The effects of abnormal 5-HT neurotransmission on the modulation of circadian rhythm have been proposed to be one of the mechanisms underlying these disorders.Objectives and aimsHere we describe developmental characteristics of interneurones (IN) expressing 5-HT type 3A receptor (5-HT3AR) in mice. This receptor is a ligand-gated ion channel which activation leads to a rapid excitatory response in neurons.The expression of 5-HT3AR during embryonic development in mice is mainly restricted to caudal ganglionic eminence (CGE) and entopedoncular area (EPA). We hypothesized that these regions are those specifically involved in the neurogenesis of the IN expressing 5-HT3AR.MethodsTo assess this hypothesis, we used homochronic in utero grafts. Cells were collected from CGE and EPA regions of transgenic mice embryos expressing Green Fluorescent Protein under the control of 5-HT3AR gene promoter. After in utero transplantation in non transgenic embryo, we examined at adult age the location of the grafted cells, as well as their morphological properties.ResultsWe observed that CGE-derived cells gave rise to IN that mostly populated the neocortex and the hippocampus, whereas EPA-derived cells integrated the amygdala, the pyriform cortex and the Ventro-Lateral Pre-Optic (VLPO) nucleus. Moreover, the VLPO EPA-derived cells are similar to “sleep active cells” found in this region and responsible of sleep induction.ConclusionThese results lead to the better understanding of the IN expressing 5HT3AR development. Its activation is possibly implicated in triggering sleep mechanismes.

High-Throughput Chemical Screen Identifies a Novel Potent Modulator of Cellular Circadian Rhythms and Reveals CKIα as a Clock Regulatory Kinase

Author SummaryMost organisms show daily rhythms in physiology, behavior, and metabolism, which may be advantageous because they anticipate environmental changes thus optimize energy metabolism. These rhythms are controlled by the circadian clock, which produces cyclic expression of thousands of output genes. More than a dozen components of the circadian clock are called clock genes, and the proteins they encode form a transcription factor network that generates rhythmic gene expression. In this study, we set out to control the function of the circadian clock and to identify new clock proteins by means of chemical tools. We tested the effects on the clock in human cells of around 120,000 uncharacterized compounds. Here we describe identification of a novel compound “longdaysin” that markedly slows the circadian clock both in cultured mammalian cells and in living zebrafish. By using longdaysin as a chemical probe, we found new proteins that modulate clock function. Because defects of clock function have been linked to numerous diseases, longdaysin may form the basis for therapeutic strategies directed towards circadian rhythm-related disorders, shift-work fatigue, and jet lag.

Glial cell modulation of circadian rhythms

Studies of Drosophila and mammals have documented circadian changes in the morphology and biochemistry of glial cells. In addition, it is known that astrocytes of flies and mammals contain evolutionarily conserved circadian molecular oscillators that are similar to neuronal oscillators. In several sections of this review, I summarize the morphological and biochemical rhythms of glia that may contribute to circadian control. I also discuss the evidence suggesting that glia-neuron interactions may be critical for circadian timing in both flies and mammals. Throughout the review, I attempt to compare and contrast findings from these invertebrate and vertebrate models so as to provide a synthesis of current knowledge and indicate potential research avenues that may be useful for better understanding the roles of glial cells in the circadian system.

Histamine in the CNS

The source of histamine in the CNS is the tuberomammillary nucleus (TMN) of the hypothalamus, which provides widespread innervation to the forebrain, brainstem, and spinal cord. Histamine, acting via H1, H2, and H3 receptors, controls neuronal excitability, synaptic transmission, and synaptic plasticity, both directly and via interactions with other neurotransmitter systems. Histaminergic TMN neurons are active during wakefulness and exert multiple functions. Studies on knockout mice indicate that histamine has a major role in maintenance of arousal and contributes to modulation of circadian rhythms, homeostasis, motor behavior, and cognition. The histaminergic system is involved in narcolepsy and may also contribute to the manifestations of Alzheimer disease (AD), Parkinson disease (PD), Tourette syndrome, and other neurologic disorders. Drugs that affect histamine receptors have therapeutic potential for sleep disorders, pain, epilepsy, and cognitive disorders. These subjects have been recently reviewed.1,–,5 ### Tuberomammillary nucleus and its targets. The TMN of the hypothalamus is the sole source of histaminergic innervation of the CNS1,–,3,6,7 (figure 1). Varicose axons of TMN neurons provide widespread input to all areas of the CNS via 2 ascending pathways that innervate the hypothalamus, basal forebrain, basal ganglia, amygdala, hippocampus, and cerebral cortex; there is one descending pathway that innervates the brainstem, including the cholinergic and monoaminergic nuclei, cerebellum, and spinal cord.2 The most densely innervated target of histaminergic fibers is the hypothalamus. In humans, there is a well-organized network of histaminergic varicose fibers in the cerebral cortex, particularly in lamina I, where the fibers extend parallel to the pial surface.2 Figure 1 The brain histaminergic system The tuberomammillary nucleus (TMN) of the hypothalamus is the sole source of histaminergic innervation of the CNS. Varicose axons of TMN neurons provide widespread input to all areas of the CNS via 2 ascending pathways that innervate the hypothalamus, basal …

Positive and negative modulation of circadian activity rhythms by mGluR5 and mGluR2/3 metabotropic glutamate receptors

Glutamate released from retinal ganglion cells conveys information about the daily light:dark cycle to master circadian pacemaker neurons within the suprachiasmatic nucleus that then synchronize internal circadian rhythms with the external day-length. Glutamate activation of ionotropic glutamate receptors in the suprachiasmatic nucleus is well established, but the function of the metabotropic glutamate receptors that are also located in this nucleus is not known. Therefore, in this study we evaluated agonists and antagonists acting at orthosteric or allosteric sites for mGluR5 and mGluR2/3 metabotropic glutamate receptors for their ability to modulate light-induced phase advances and delays of hamster circadian activity rhythms. mGluR5 allosteric antagonists fenobam, MPEP and MTEP, each 10 mg/kg, potentiated light-induced phase advances of hamster circadian activity rhythms, while the mGluR5 agonists CHPG, (S)-3,5-DHPG or positive allosteric modulator CDPPB had no effect. Neither mGluR5 agonists nor antagonists had any effect on light-induced phase delays of activity rhythms. The competitive mGluR2/3 antagonist LY341495, 10 mg/kg, also potentiated light-induced phase advances, but inhibited light-induced phase delays. The mGluR2/3 agonists LY354740 and LY404039 were without effect on phase advances while a third agonist LY379268, 10 mg/kg, inhibited both light-induced advances and delays. Finally, mGluR2/3 agonists LY379268 and LY404039 also inhibited light-induced phase delays of activity rhythms. These results suggest that during light-induced phase advances, mGluR2/3 and mGluR5 receptors act to negatively modulate the effects of light on the circadian pacemaker or its output(s). mGluR5 receptors do not appear to be involved during light-induced phase delays. In contrast, the role for mGluR2/3 receptors during phase delays is more complicated as both agonists and antagonists inhibit light-induced phase delays. Dysfunctions in human circadian rhythms have been implicated in some forms of depression, and metabotropic glutamate receptor ligands, which are also being evaluated for antidepressant activity, are shown here to be capable of modifying light-induced phase shifts of circadian activity rhythms.

Serotonin and circadian rhythms.

All mammal behaviors and functions exhibit synchronization with environmental rhythms. This is accomplished through an internal mechanism that generates and modulates biological rhythms. The circadian timing system, responsible for this process, is formed by connected neural structures. Pathways receive and transmit environmental cues to the central oscillator, the hypothalamic suprachiasmatic nucleus, which mediates physiological and behavioral alterations. The suprachiasmatic nucleus has three major inputs: the retinohypothalamic tract (a direct projection from the retina), the geniculohypothalamic tract (an indirect photic projection originating in the intergeniculate leaflet), and a dense serotonergic plexus from the raphe nuclei. The serotonergic pathway, a source of non-photic cues to the suprachiasmatic nucleus, modulates its activity. The importance of raphe nuclei in circadian rhythms, especially in photic responses, has been demonstrated in many studies. Serotonin is the raphe neurotransmitter that triggers phase shifts, inhibits light-induced phase-shifts, and plays a role in controlling the sleep-wake cycle. All data to date have demonstrated the importance of the raphe, through serotonergic afferents, in adjusting circadian rhythms and must therefore be considered a component of the circadian timing system. The aim of this paper is to review the literature addressing the involvement of serotonin in the modulation of circadian rhythm.

A computational model of Suprachiasmatic Nucleus (SCN) for circadian rhythm modulation based on ion channel conductance and calcium dynamics

The suprachiasmatic nucleus (SCN), the master biological clock of circadian rhythms, has been highly interested for biological rhythms in animals. Physiological and molecular biological studies [1-3] and computational modeling approach [4] have investigated channels contributing to circadian rhythms of spike firing frequency. The aim of this study was to investigate possible contribution of each channel to circadian rhythms using Hodgkin-Huxley-type model containing BK channel, potassium channel, sodium channel, and calcium concentration oscillation. We found that the change in channel conductance modulated firing rates from high regular firing to low irregular firing with high sensitivity of the channel. In agreement with experimental data, the persistent sodium currents also highly contributed to modulation in spike firing frequency. The leak potassium currents and fast delayed rectifier currents exhibited to restrict the circadian firing range and regulation of interspike intervals. Most interestingly, the sinusoidal shape of the diurnal change in the channel conductance reproduced the change in diurnal firing rates. The calcium concentration oscillation and BK channel activity were examined to determine the synchronized circadian oscillation and phase shifting of firing rate in the neural network models structured by graph theory. We suggest that the model may be a guidance of channel properties in experimental conditions and be helpful to explain the circadian behaviors of SCN neurons. Figure 1 Minimum & Maximum firing rates with varied conductance values of calcium and sodium channels. Figure 2 Firing rate distributions with change in sodium and potassium channel conductances

Photoperiodic modulation of circadian rhythms in the silk gland protein profiles of Bombyx mori and its influence on the silk productivity and quality

Circadian rhythms in the silk gland protein profiles of Bombyx mori were analyzed under 12 h light and 12 h dark cycle (LD), continuous light (LL) and continuous dark (DD) conditions. The phase response curves of protein rhythms indicate the prevalence of a series of silk cycles, each comprising three phases; transcription, translation and consolidation of silk proteins. In the 24h- protein rhythm, the silk cycle repeats every 3h, 42 m under LD, 2h, 36m under LL and 3h under DD. The light and dark conditions advanced the rhythm of each silk cycle by 48m and 24m respectively. As a result the silk gland completes 7 rounds of protein synthesis under LD, 9 rounds under LL and 8 rounds under DD during the 24h-free running time of the rhythm. The light-induced clock-shift in the protein rhythm caused significant gains in economic parameters of sericulture with positive signals for enhancing silk productivity and quality.

Circadian Amplitude of Cryptochrome 1 Is Modulated by mRNA Stability Regulation via Cytoplasmic hnRNP D Oscillation

The mammalian circadian rhythm is observed not only at the suprachiasmatic nucleus, a master pacemaker, but also throughout the peripheral tissues. Its conserved molecular basis has been thought to consist of intracellular transcriptional feedback loops of key clock genes. However, little is known about posttranscriptional regulation of these genes. In the present study, we investigated the role of the 3'-untranslated region (3'UTR) of the mouse cryptochrome 1 (mcry1) gene at the posttranscriptional level. Mature mcry1 mRNA has a 610-nucleotide 3'UTR and mediates its own degradation. The middle part of the 3'UTR contains a destabilizing cis-acting element. The deletion of this element led to a dramatic increase in mRNA stability, and heterogeneous nuclear ribonucleoprotein D (hnRNP D) was identified as an RNA binding protein responsible for this effect. Cytoplasmic hnRNP D levels displayed a pattern that was reciprocal to the mcry1 oscillation. Knockdown of hnRNP D stabilized mcry1 mRNA and resulted in enhancement of the oscillation amplitude and a slight delay of the phase. Our results suggest that hnRNP D plays a role as a fine regulator contributing to the mcry1 mRNA turnover rate and the modulation of circadian rhythm.

234 EXPRESSION OF NUCLEAR AND MEMBRANE MELATONIN RECEPTORS GENES AND THE CLOCK GENES IN RAT OOCYTES: PRELIMINARY RESULTS

There is evidence that melatonin acts directly on the regulation of ovary function. This action is probably attributed in part to melatonin receptors, which are known to be present in granulosa and cumulus cells (Kang J-T et al. 2009 J. Pineal Res. 46, 22–28). Melatonin is also known to be associated with the modulation of circadian rhythms and the regulation of seasonal reproductive function (Arendt J 1998 Rev. Reprod. 3, 13–22). Circadian rhythms and clock genes appear to be involved in reproductive processes (Dolatshad H et al. 2009 Repro. Fertil. Dev. 21, 1–9). However, the presence of melatonin receptor genes and the clock genes has not been so widely studied or has never been reported to exist in mammalian oocytes.The aim of this study was to investigate the presence of nuclear (Rorα) and membrane (Mt1 and Mt2) melatonin receptors genes and the clock genes (Clock, Bmal1, Cry1, Cry21, Per1, Per2) in rat oocytes by reverse RT-PCR. Twenty-seven-day-old Wistar female rats were treated with 20 UI of pregnant mares serum gonadotropin for induction of follicular development and slaughtered 48 h later. All the procedures involving animals were approved by the Animal Care Committee of the Institute of Biomedical Sciences. The ovaries were removed and placed in TCM-199 supplemented with 100 UI mL-1 penicillin, 100 μg mL-1 streptomycin, and 0.1% polyvinyl alcohol (H-199 medium). Germinal vesicle-intact oocytes, isolated from the ovarian follicles, were denuded from cumulus cells by vortexing for 5 to 8 min. The denuded oocytes were incubated for 5 min in H-199 medium with 0.1% pronase for removal of the zona pellucida. Pools of 80 oocytes per cDNA sample were used.As an internal control for the sample integrity, additional primers for RPL37a were included in each PCR reaction. All the 3 control PCR replicates showed a repeatable amplification. Polymerase chain reaction amplifications of cDNA yielded Rorα, Clock, Bmal1, and Cry1 products in 2 of 3 replicates. No expression of the MT1 and MT2 mRNA was observed. The preliminary results suggest the presence of a nuclear melatonin receptor gene and some clock genes in rat oocytes. However, additional studies are necessary to confirm this hypothesis. This research was supported by FAPESP.

Evidence for genetic association of RORB with bipolar disorder

BackgroundBipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB.MethodsWe genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching.ResultsWe report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs.ConclusionOur findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.

Telomerase reconstitution contributes to resetting of circadian rhythm in fibroblasts

The synchronization of the circadian signals to external or suprachiasmatic nucleus stimulation in the peripheral clocks is essential for maintaining the usual function of human body. However, aging will disrupt the synchronization of peripheral circadian rhythms, thus leading to some age-associated diseases. Up to now, little is known about the modification of the oscillatory rhythms in aged cells. A recent report showed that cell senescence in vascular human smooth muscle cells (HSMCs) altered circadian rhythms by a dysregulation of rhythmic gene expression. Furthermore, this alteration could be reversed by telomerase reconstitution. To test whether telomerase reconstitution can restore disrupted circadian rhythm in other types of senescent cells, we used fibroblasts as cell models to profoundly investigate the relationship between cell senescence and circadian rhythm modulation. We found that the response of rhythmic gene expression to serum stimulation was markedly attenuated in senescent fibroblasts, telomerase-reconstituted fibroblasts reset the circadian oscillation of rhythmic gene expression, and the activation of pERK-CREB and p38-CREB pathways might be involved in the circadian rhythm resetting. These findings suggested that telomerase reconstitution might be a good way to reset synchronization of peripheral circadian rhythms disrupted in senescent tissues.

Sex differences in energetic costs explain sexual dimorphism in the circadian rhythm modulation of the electrocommunication signal of the gymnotiform fishBrachyhypopomus pinnicaudatus

To understand the evolution of sexually dimorphic communication signals, we must quantify their costs, including their energetic costs, the regulation of these costs, and the difference between the costs for the sexes. Here, we provide the first direct measurements of the relative energy expended on electric signals and show for the focal species Brachyhypopomus pinnicaudatus that males spend a significantly greater proportion of their total energy budget on signal generation (11-22%) compared with females (3%). Both sexes significantly reduce the energy spent on electric signals during daylight hours through circadian modulation of the amplitude, duration and repetition rate of the electric signal, but this effect is more marked in males. Male body condition predicted the energy spent on electric signals (R(2)=0.75). The oxygen consumed by males for signal production closely paralleled the product of the electric signal's waveform area (R(2)=0.99) and the discharge rate (R(2)=0.59), two signal parameters that can be assessed directly by conspecifics. Thus the electric communication signal of males carries the information to reveal their body condition to prospective mates and competing males. Because the electric signal constitutes a significant fraction of the energy budget, energy savings, along with predation avoidance, provides an adaptive basis for the production of circadian rhythms in electric signals.