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Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal–clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N -methyl- D -aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal–retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40–85 Hz, p =0.006) and reduced low-frequency oscillations (delta band at 1–5 Hz, p <0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal–retardation symptoms experienced during ketamine administration ( p =0.02). Ketamine also reduced gating of the theta-alpha (5–12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the human liver transcriptome but their role in hepatitis B virus infection is largely unknown. Here, Zhuang et al. show that REV-ERB regulates hepatitis B virus entry and BMAL1 directly binds HBV DNA and activates viral genome transcription.

We used electroencephalography (EEG) together with psychopharmacological stimulation to investigate the role of dopamine in neural oscillations during working memory (WM). Following a within-subjects design, healthy humans either received the dopamine precursor l-Dopa (150mg) or a placebo before they performed a Sternberg WM paradigm. Here, sequences of sample images had to be memorized for a delay of 5s in three different load conditions (two, four or six items). On the next day, long-term memory (LTM) for the images was tested. Behaviorally, l-Dopa improved WM and LTM performance as a function of WM load. More precisely, there was a specific drug effect in the four-load condition with faster reaction times to the probe in the WM task and higher corrected hit-rates in the LTM task. During the maintenance period, there was a linear and quadratic effect of WM load on power in the high theta (5–8Hz) and alpha (9–14Hz) frequency range at frontal sensors. Importantly, a drug by load interaction – mimicking the behavioral results – was found only in low theta power (2–4Hz). As such, our results indicate a specific link between prefrontal low theta oscillations, dopaminergic neuromodulation during WM and subsequent LTM performance. •Dopaminergic stimulation improved WM and LTM performance as a function of WM load.•This behavioral effect was accompanied by increased power in low theta (2–4Hz).•High theta (5–8Hz) and alpha power (9–14Hz) were modulated by WM load but not drug.•Together, our data indicate functional interactions between WM and LTM systems.•Low vs. high theta and alpha oscillations serve different roles in WM maintenance.

Introduction Melatonin and light treatment are recommended for hastening adaptation to time zone change. We evaluated an afternoon regimen of 3 mg sustained release (SR) melatonin with and without next morning green light treatment for circadian phase advance. Effects of melatonin and light were tested separately and then combined to determine if the total phase change is additive or synergistic. Material and methods For each condition (melatonin, placebo, light, melatonin plus light), 11 subjects spent from Tuesday evening until Friday afternoon in the laboratory. For all four conditions, the following sleep schedule was maintained: night 1, 2345 to 0630 hours, night 2, 1600 to 0530 hours, and night 3, 2345 to 0700 hours. For the light-only condition, light treatment was administered between 0700 and 0800 hours on Thursday. For melatonin-only or placebo conditions, capsules were administered at 1600 hours on Wednesday. For the combined condition, melatonin was administered at 1600 hours on Wednesday with light treatment between 0600 and 0700 hours on Thursday. Circadian phase was assessed by calculating dim light melatonin onset (DLMO) from salivary melatonin, using a mean baseline +2 standard deviations (BL + 2 SD) threshold. For all four conditions, pre-treatment and post-treatment DLMO assessments were on Tuesday and Thursday evenings, respectively. Results Phase advances were: melatonin at 1600 hours, 0.72 h p  < 0.005, light treatment from 0700 to 0800 hours, 0.31 h, non-significant, and the combined treatment, 1.04 h p  < 0.0002. Conclusion The phase advance from the combination of afternoon melatonin with next morning light is additive.

Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases. Synthetic REV-ERB agonists can alter the circadian expression of core clock genes in the hypothalami of mice, which changes the expression of metabolic genes in liver, skeletal muscle and adipose tissue, and results in increased energy expenditure. Adjusting the metabolic clock Metabolic processes need to run like clockwork to prevent disease. Core clock proteins drive these rhythms, and the nuclear receptors REV-ERB-α and REV-ERB-β have a central role in regulating the expression of clock genes. Solt et al . report the identification of potent synthetic REV-ERB agonists, termed SR9011 and SR9009, which can alter the circadian expression of core clock genes in the hypothalami of mice. This is shown to alter the expression of metabolic genes in liver, skeletal-muscle and adipose tissue, and results in increased energy expenditure by the mice. The REV-ERB agonists reduce fat mass in diet-induced obese mice and improve dyslipidaemia and hyperglycaemia. These results suggest that synthetic REV-ERB ligands are promising candidates for the treatment of metabolic diseases. Cho et al . present genetic evidence that REV-ERB-α and REV-ERB-β are indispensible for the coordination of circadian rhythm and metabolism. Mice without REV-ERBs show disrupted expression of clock and lipid homeostatic gene networks. They have altered circadian wheel-running behaviour and deregulated lipid metabolism. These data ally REV-ERB-α and REV-ERB-β with PER, CRY and other components of the principal feedback loop that drives circadian expression.

Introduction Melatonin is recommended for hastening adaptation to phase shift, but there is little information on appropriate formulations. Materials and methods We evaluated the efficacy of three melatonin formulations for circadian phase advance and delay: (a) 3 mg regular release (RR), (b) 3 mg sustained release (SR), and (c) 3 mg surge-sustained release (SSR; consisting of 1 mg RR and 2 mg SR). Circadian phase was assessed by salivary melatonin dim light melatonin onset (DLMO) or offset (MelOff) using thresholds of (1) 1.0 pg/ml and (2) mean baseline + 2 standard deviations (BL + 2SD). Subjects spent from Tuesday evenings until Thursday in the laboratory. Melatonin (or placebo) was administered at 1600 hours (phase advance) Wednesday, with DLMO assessment on Tuesday and Thursday and at 0600 hours (phase delay) Wednesday, with DLMO assessment Tuesday, Wednesday, and MelOff Thursday morning. Phase advances using the 1.0 pg/ml DLMO were as follows: placebo, 0.73 h; RR, 1.23 h ( p  < 0.003); SR, 1.44 h ( p  < 0.0002); SSR, 1.16 h ( p  < 0.012), with no difference between formulations. Results and discussion Similar but smaller phase advances were found with BL + 2SD. Using MelOff, posttreatment phase position for the RR formulation was delayed compared to placebo by 1.12 h ( p  < 0.012), 1.0 pg/ml, and 0.75 h ( p  < 0.036), BL+2SD. Phase shifts for the SR and SSR conditions could not be determined due to persistent high melatonin levels during sampling times. Similar phase advances were induced by all formulations, and slow clearance of slow release preparations impeded the determination of phase delays. Conclusion Appropriately timed 0.5 mg melatonin doses may avoid these problems.

Renin–angiotensin system (RAS) inhibitors may be useful in preventing the occurrence of paroxysmal atrial fibrillation (PAF). However, evaluation of such effect is difficult because many PAF episodes are asymptomatic and not all episodes are detected by intermittent electrocardiographic monitoring. A pacemaker has been developed with dedicated functions for AF detection and electrocardiogram storage. Accordingly, we examined the effect of losartan, an angiotensin receptor blocker on PAF occurrence using this new modality. We enrolled 70 consecutive patients who had undergone dual-chamber pacemaker implantation for sick sinus syndrome. Finally, 62 patients participated in the study. Thirty patients were randomized to the losartan group (mean 43 ± 12 mg/day) and 32 patients to the control group. They were followed up for 3 months. The frequency, the maximum duration and the total duration of PAF recorded by the stored electrocardiograms for the last 1 month during the observation period and study period were compared between the two groups. The change in the frequency of PAF from the observation period in the losartan and control groups was similar (−35 ± 25 vs. −67 ± 62 times; NS). However, the change in the maximum duration and the total duration of PAF was significantly shorter in the losartan group than in the control group (−493 ± 158 vs. −10 ± 69 min; p  < 0.05, and −4007 ± 2334 vs. 1119 ± 714 min; p  < 0.05, respectively). Losartan suppressed the maximum duration and the total duration of PAF in patients with sick sinus syndrome without hemodynamic changes. This is the first study to show the effect of a renin–angiotensin system inhibitor on the secondary prevention of PAF using the dedicated functions of a pacemaker for PAF detection and electrocardiogram storage.

Sinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current (If) is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. Here, we used the AP-clamp technique to quantify If during the cardiac cycle in mouse SAMs. We found that If is persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of −30 mV. Despite operating at only 2 to 5% of its maximal conductance, If carries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that β-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by If, consistent with a contribution of If to the fight-or-flight increase in heart rate. These properties were confirmed by heterologously expressed HCN4 channels and by mathematical models of If. Modeling further suggested that the slow rates of activation and deactivation of the HCN4 isoform underlie the persistent activity of If during the sinoatrial AP. These results establish a new conceptual framework for the role of If in pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions.

It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node. The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses.

The nuclear receptors REV-ERB-α and REV-ERB-β are indispensible for the coordination of circadian rhythm and metabolism; mice without these nuclear receptors show disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. Adjusting the metabolic clock Metabolic processes need to run like clockwork to prevent disease. Core clock proteins drive these rhythms, and the nuclear receptors REV-ERB-α and REV-ERB-β have a central role in regulating the expression of clock genes. Solt et al . report the identification of potent synthetic REV-ERB agonists, termed SR9011 and SR9009, which can alter the circadian expression of core clock genes in the hypothalami of mice. This is shown to alter the expression of metabolic genes in liver, skeletal-muscle and adipose tissue, and results in increased energy expenditure by the mice. The REV-ERB agonists reduce fat mass in diet-induced obese mice and improve dyslipidaemia and hyperglycaemia. These results suggest that synthetic REV-ERB ligands are promising candidates for the treatment of metabolic diseases. Cho et al . present genetic evidence that REV-ERB-α and REV-ERB-β are indispensible for the coordination of circadian rhythm and metabolism. Mice without REV-ERBs show disrupted expression of clock and lipid homeostatic gene networks. They have altered circadian wheel-running behaviour and deregulated lipid metabolism. These data ally REV-ERB-α and REV-ERB-β with PER, CRY and other components of the principal feedback loop that drives circadian expression. The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK–BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-α and REV-ERB-β have been proposed to form an accessory feedback loop that contributes to clock function 1 , 2 , their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis -acting targets (cistromes) of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1. Although REV-ERB-α has been shown to regulate Bmal1 expression directly 1 , 2 , our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-α and REV-ERB-β genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-α and REV-ERB-β cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-α and Rev-erb-β function by creating double-knockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice show markedly altered circadian wheel-running behaviour and deregulated lipid metabolism. These data now unite REV-ERB-α and REV-ERB-β with PER, CRY and other components of the principal feedback loop that drives circadian expression and indicate a more integral mechanism for the coordination of circadian rhythm and metabolism.