Central Clock Research Articles

Circadian clock factors regulate the first condensation reaction of fatty acid synthesis in Arabidopsis

The circadian clock regulates temporal metabolic activities, but how it affects lipid metabolism is poorly understood. Here, we show that the central clock regulators LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) regulate the initial step of fatty acid (FA) biosynthesis in Arabidopsis. Triacylglycerol (TAG) accumulation in seeds was increased in LHY-overexpressing (LHY-OE) and decreased in lhycca1 plants. Metabolic tracking of lipids in developing seeds indicated that LHY enhanced FA synthesis. Transcript analysis revealed that the expression of genes involved in FA synthesis, including the one encoding β-ketoacyl-ACP synthase III (KASIII), was oppositely changed in developing seeds of LHY/CCA1-OEs and lhycca1. Chromatin immunoprecipitation, electrophoretic mobility shift, and transactivation assays indicated that LHY bound and activated the promoter of KASIII. Furthermore, phosphatidic acid, a metabolic precursor to TAG, inhibited LHY binding to KASIII promoter elements. Our data show a regulatory mechanism for plant lipid biosynthesis by the molecular clock.

Internal circadian misallignment in a mouse model of chemotherapy induced fatigue

BackgroundCancer survivors can experience long lasting fatigue resulting in a lower quality of life. How chemotherapy treatment contributes to this fatigue is poorly understood. Previously we have shown in a mouse model of cancer related fatigue that doxorubicin treatment induces fatigue-like symptoms related to disturbed circadian rhythms. However, the specific components of the circadian regulatory circuitry affected by doxorubicin treatment remained unclear. Therefore we investigated the role of the central circadian clock, the suprachiasmatic nucleus (SCN), in chemotherapy-induced fatigue. MethodsWe measured circadian controlled behavior and multiunit neuronal activity in the SCN in freely moving mice exhibiting fatigue-like behavior after doxorubicin treatment under both light–dark (LD) and constant dark (DD) conditions. Additionally, we assessed the expression of inflammation related genes in spleen and kidney as potential inducers of CRF. ResultsDoxorubicin treatment significantly reduced both the running wheel activity and time spent using the running wheel for over five weeks after treatment. In contrast to the pronounced effects on behavior and neuronal activity of doxorubicin on circadian rhythms, peripheral inflammation markers only showed minor differences, five weeks after the last treatment. Surprisingly, the circadian SCN neuronal activity under both LD and DD conditions was not affected. However, the circadian timing of neuronal activity in peri-SCN areas (the brain areas surrounding SCN) and circadian rest-activity behavior was strongly affected by doxorubicin, suggesting that the output of the SCN was altered. The reduced correlation between the SCN neuronal activity and behavioral activity after doxorubicin treatment, suggests that the information flow from the SCN to the periphery was disturbed. ConclusionOur preclinical study suggests that chemotherapy-induced fatigue disrupts the circadian rhythms in peripheral brain areas and behavior downstream from the SCN, potentially leading to fatigue like symptoms. Our data suggest that peripheral inflammation responses are less important for the maintenance of fatigue. Chronotherapy that realigns circadian rhythms could represent a non-invasive way to improve patient outcomes following chemotherapy.

What factors influence individual differences in vulnerability/resilience to sleep loss and/or circadian misalignment?

Daily rhythms are primarily synchronized by the suprachiasmatic nucleus (SCN) in the hypothalamus, the body’s central circadian clock. The SCN aligns whole-body cellular, behavioral and phenomenological processes with the Earth’s 24-hour day/night rhythm. When disruptions to the SCN’s perceptual system occur (e.g., “jet-lag,” prolonged waking, chronic exposure to light at night or habit change as the result of becoming a parent), disrupted melatonin and glucocorticoid secretion can lead to widespread dysregulation of sleep and circadian cycling. The effects of circadian disruptions are often compounded by the homeostatic sleep drive, wherein sleep pressure accumulates with protracted wakefulness to affect mood, cognition, health and well-being.

Alterations in Per2, Bcl2 gene expression, and oxidative status in aged rats liver after light pulse at night.

The aging process is characterized by circadian rhythm disruption, in physiology and behavior, which could result from weak entrainment. Light is the most potent cue that entrains the central circadian clock, which in turn synchronizes peripheral clocks in animal tissues. Period 2 (Per2) is one of the clock genes that respond to light. Moreover, oxidative stress could entrain the clock. Therefore, the present work aimed to investigate the role of light when applied late at night on the Per2, B cell lymphoma 2 (Bcl2) gene expression, and oxidative status in aged rats. Aged rats were divided into a control group and a group exposed to a 30-min light pulse applied daily during the subjective night at 5 am (ZT 22) for 4weeks. Per2 and Bcl2 gene expression were quantified in liver tissue. To evaluate oxidative status, Glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) were estimated. The light pulse reduced the expression levels of Per2 and Bcl2 mRNA. Although it diminished the levels of malondialdehyde (MDA), nitric oxide (NO) levels were elevated and the glutathione (GSH) levels were declined. In conclusion, the light pulse late at night abolished Per2 mRNA circadian rhythm and reduced its expression in the liver of the aged rat. Similarly, it diminished the anti-apoptotic gene expression, Bcl2. Moreover, it might attenuate oxidative stress through the reduction in MDA levels.

Communication Efficient Curvature Aided Primal-Dual Algorithms for Decentralized Optimization

This paper presents a family of algorithms for decentralized convex composite problems. We consider the setting of a network of agents that cooperatively minimize a global objective function composed of a sum of local functions plus a regularizer. Through the use of intermediate consensus variables, we remove the need for inner communication loops between agents when computing curvature-guided updates. A general scheme is presented which unifies the analysis for a plethora of computing choices, including gradient descent, Newton updates, and BFGS updates. Our analysis establishes sublinear convergence rates under convex objective functions with Lipschitz continuous gradients, as well as linear convergence rates when the local functions are further assumed to be strongly convex. Moreover, we explicitly characterize the acceleration due to curvature information. Last but not the least, we present an asynchronous implementation for the proposed algorithms, which removes the need for a central clock, with linear convergence rates established in expectation under strongly convex objectives. We ascertain the effectiveness of the proposed methods with numerical experiments on benchmark datasets.

O030 GABAA Receptor Expression in the Suprachiasmatic Nucleus under Different Light Conditions

Abstract Our research group has made inroads investigating the phase shifting effects of general anaesthesia (GA) on the circadian clock. Most clinical anaesthetics function by potentiating the effect of GABA on the GABA type A receptor (GABAARs). While the precise role of GABA in the suprachiasmatic nucleus (SCN) is still not fully understood, it has been implicated in circadian functions including photic entrainment and clock coupling. However, we have discovered that the expression of GABAARs in the central circadian clock remains poorly understood. To address this gap in knowledge, we examined the expression of GABAAR subunits α1, α5, β3, and γ2 in male (n = 80) and female (n = 82) C57Bl/6 mice under light-dark (LD) and constant darkness (DD) conditions (male, n = 95). Analysis of GABAAR subunit expression in the SCN was quantified by immunohistochemical analysis. Additionally, we investigated the time-dependent effects of isoflurane GA and light on GABAAR subunit expression in the SCN (male, n = 60). Our findings revealed rhythmic expression of GABAAR subunits in the mouse SCN under LD conditions which differed by sex, suggesting environmental light conditions may regulate GABAAR expression in the circadian clock in a sex-specific manner. In the SCN, γ2 subunit expression was increased following light and GA treatment compared to light-alone, while α1 subunit expression was increased at times of large behavioural phase delays. We conclude that the expression of GABAAR’s in the SCN is phase-dependent and may contribute to the time-dependent relationship between light and GA on the clock.

THU611 Circadian Misalignment Of Melatonin Secretion In Adrenal Insufficiency (AI)

Abstract Disclosure: M. Darji: None. S. Pannain: None. S. Sam: None. E. Van Cauter: None. E.C. Hanlon: None. Background: Despite glucocorticoid replacement, the mortality risk of AI remains markedly elevated. Under normal conditions, the circadian rhythm of endogenous cortisol levels is a major internal synchronizing signal between central and peripheral circadian clocks. There is increasing evidence indicating that circadian misalignment has a host of adverse effects, including increased cardio-metabolic risk. The present study aimed to assess circadian function in AI patients, as compared to individually-matched healthy subjects, under controlled laboratory conditions. The 24-h profile of melatonin, normally secreted exclusively at night, was used as the marker of central circadian timing. The 24-h profile of leptin was used as a marker of peripheral circadian function. Methods: Plasma cortisol, melatonin, and leptin were measured over a 24-h period every 30-60 minutes under controlled light-dark, sleep-wake and dietary conditions. A best-fit curve was calculated for each individual hormonal profile using a locally weighted nonlinear regression procedure with a window of 4 hours. The peak and the nadir were defined as the maximum and minimum of the best-fit curve, respectively. The amplitude was defined as half of the difference between the peak and the nadir. Sleep was polygraphically recorded. During daytime hours, the participants completed validated questionnaires assessing Vigor, Mood and Sleepiness. Results: Complete data sets were obtained in 15 AI patients (12 women; age: 47.9 ±12.5 years, BMI: 26.6 ± 12.5 kg/m2; mean ± SD). Twelve AI patients were on hydrocortisone treatment (total dose range: 20 to 40mg/day, number of doses: 1-5 /day) and 3 were on prednisone treatment. Controls (n=15, 12 women) were aged 48.5 ±14.5 years with BMI of 26.5 ± 5.4 kg/m2. The amplitude of the cortisol profile was wider in AI patients, relative to controls, with a higher morning peak and an extended and lower nocturnal nadir. Unexpectedly, we observed a marked difference in the melatonin profile in AI patients as compared to controls. A daytime phase of elevated melatonin levels, culminating prior to lights off while the patients were awake, was detected in 9 of the 15 AI patients. The nocturnal elevation persisted with a similar amplitude to that observed in controls but was advanced by 1-2 hours. The 24-h leptin profile was similar in the two groups. The presence of a daytime melatonin peak in AI patients was associated with lower ratings of vigor and mood, and higher ratings of sleepiness. Conclusion: Glucocorticoid treatment to replace the endogenous levels and circadian rhythmicity of cortisol in AI may impact central circadian timing, resulting in daytime, in addition to nighttime, release of melatonin. This finding suggests that exogenous cortisol replacement that does not mimic a normal 24-h rhythm, may cause central circadian dysfunction and contribute to alterations in mood, vigor and sleepiness. Presentation: Thursday, June 15, 2023

Developing oral chronotherapy for cortisol replacement in congenital adrenal hyperplasia.

The sun imposes a 24-h periodicity to life and circadian rhythms have evolved to maintain homoeostasis through the day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which is paralleled metabolically by a fast/feed cycle. The clock maintains homoeostasis by synchronising metabolism to the time of feeding. Loss of synchrony between the clock and hormonal rhythms results in loss of homoeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Cortisol has a distinct circadian rhythm; peaking on waking and low at sleep onset. Loss of this rhythm in adrenal insufficiency is associated with a poor quality of life and increased mortality. To replace the cortisol rhythm requires chronotherapy and for this you need to define the key parameters of the target rhythm, create a formulation to replicate that rhythm, and then prove clinical benefit. The physiology of hormones is more complex than that of nonnative drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically-based pharmacokinetic models, and tested various oral delayed and sustained formulations of hydrocortisone (development name, Chronocort) in clinical trials. The outcome from this work was the manufacture of modified-release hydrocortisone hard capsules (tradename Efmody, Diurnal Ltd), that replicate the cortisol diurnal rhythm and improve the disease control of congenital adrenal hyperplasia the commonest hereditary form of adrenal insufficiency.

Inferring circadian gene regulatory relationships from gene expression data with a hybrid framework

BackgroundThe central biological clock governs numerous facets of mammalian physiology, including sleep, metabolism, and immune system regulation. Understanding gene regulatory relationships is crucial for unravelling the mechanisms that underlie various cellular biological processes. While it is possible to infer circadian gene regulatory relationships from time-series gene expression data, relying solely on correlation-based inference may not provide sufficient information about causation. Moreover, gene expression data often have high dimensions but a limited number of observations, posing challenges in their analysis.MethodsIn this paper, we introduce a new hybrid framework, referred to as Circadian Gene Regulatory Framework (CGRF), to infer circadian gene regulatory relationships from gene expression data of rats. The framework addresses the challenges of high-dimensional data by combining the fuzzy C-means clustering algorithm with dynamic time warping distance. Through this approach, we efficiently identify the clusters of genes related to the target gene. To determine the significance of genes within a specific cluster, we employ the Wilcoxon signed-rank test. Subsequently, we use a dynamic vector autoregressive method to analyze the selected significant gene expression profiles and reveal directed causal regulatory relationships based on partial correlation.ConclusionThe proposed CGRF framework offers a comprehensive and efficient solution for understanding circadian gene regulation. Circadian gene regulatory relationships are inferred from the gene expression data of rats based on the Aanat target gene. The results show that genes Pde10a, Atp7b, Prok2, Per1, Rhobtb3 and Dclk1 stand out, which have been known to be essential for the regulation of circadian activity. The potential relationships between genes Tspan15, Eprs, Eml5 and Fsbp with a circadian rhythm need further experimental research.

The Role of the Circadian Rhythm in Dyslipidaemia and Vascular Inflammation Leading to Atherosclerosis.

Cardiovascular diseases (CVD) are among the leading causes of death worldwide. Many lines of evidence suggest that the disturbances in circadian rhythm are responsible for the development of CVDs; however, circadian misalignment is not yet a treatable trait in clinical practice. The circadian rhythm is controlled by the central clock located in the suprachiasmatic nucleus and clock genes (molecular clock) located in all cells. Dyslipidaemia and vascular inflammation are two hallmarks of atherosclerosis and numerous experimental studies conclude that they are under direct influence by both central and molecular clocks. This review will summarise the results of experimental studies on lipid metabolism, vascular inflammation and circadian rhythm, and translate them into the pathophysiology of atherosclerosis and cardiovascular disease. We discuss the effect of time-respected administration of medications in cardiovascular medicine. We review the evidence on the effect of bright light and melatonin on cardiovascular health, lipid metabolism and vascular inflammation. Finally, we suggest an agenda for future research and recommend on clinical practice.

Timing Matters: The Interplay between Early Mealtime, Circadian Rhythms, Gene Expression, Circadian Hormones, and Metabolism-A Narrative Review.

Achieving synchronization between the central and peripheral body clocks is essential for ensuring optimal metabolic function. Meal timing is an emerging field of research that investigates the influence of eating patterns on our circadian rhythm, metabolism, and overall health. This narrative review examines the relationship between meal timing, circadian rhythm, clock genes, circadian hormones, and metabolic function. It analyzes the existing literature and experimental data to explore the connection between mealtime, circadian rhythms, and metabolic processes. The available evidence highlights the importance of aligning mealtime with the body's natural rhythms to promote metabolic health and prevent metabolic disorders. Specifically, studies show that consuming meals later in the day is associated with an elevated prevalence of metabolic disorders, while early time-restricted eating, such as having an early breakfast and an earlier dinner, improves levels of glucose in the blood and substrate oxidation. Circadian hormones, including cortisol and melatonin, interact with mealtimes and play vital roles in regulating metabolic processes. Cortisol, aligned with dawn in diurnal mammals, activates energy reserves, stimulates appetite, influences clock gene expression, and synchronizes peripheral clocks. Consuming meals during periods of elevated melatonin levels, specifically during the circadian night, has been correlated with potential implications for glucose tolerance. Understanding the mechanisms of central and peripheral clock synchronization, including genetics, interactions with chronotype, sleep duration, and hormonal changes, provides valuable insights for optimizing dietary strategies and timing. This knowledge contributes to improved overall health and well-being by aligning mealtime with the body's natural circadian rhythm.

A minimal model of peripheral clocks reveals differential circadian re-entrainment in aging.

The mammalian circadian system comprises a network of endogenous oscillators, spanning from the central clock in the brain to peripheral clocks in other organs. These clocks are tightly coordinated to orchestrate rhythmic physiological and behavioral functions. Dysregulation of these rhythms is a hallmark of aging, yet it remains unclear how age-related changes lead to more easily disrupted circadian rhythms. Using a two-population model of coupled oscillators that integrates the central clock and the peripheral clocks, we derive simple mean-field equations that can capture many aspects of the rich behavior found in the mammalian circadian system. We focus on three age-associated effects that have been posited to contribute to circadian misalignment: attenuated input from the sympathetic pathway, reduced responsiveness to light, and a decline in the expression of neurotransmitters. We find that the first two factors can significantly impede re-entrainment of the clocks following perturbation, while a weaker coupling within the central clock does not affect the recovery rate. Moreover, using our minimal model, we demonstrate the potential of using the feed-fast cycle as an effective intervention to accelerate circadian re-entrainment. These results highlight the importance of peripheral clocks in regulating the circadian rhythm and provide fresh insights into the complex interplay between aging and the resilience of the circadian system.

On the Synchronous Ethernet for a Massive Networking Deployment: Insight Into a Tailored Cosimulated Testbed

Digital communications have a minimum synchronization requirement: the end user of a telecommunication system has to lock into the right bit rhythm sent by the other connection partner. Nevertheless, synchronization in the telecommunication context turns out to be broader than two connection partners locally linked: the suitable feed of a standard time, within many telecommunication domains, has vital importance for many applications to properly handle the demanded network functionalities. The time feed in multidomain scenarios makes a time path, which becomes a nested built-in network. Generally, the data distribution follows the time path in many telecommunication systems. However, the data path may not follow the time path for all scenarios and could partially follow some network branches, usually at the network border. To ensure efficient and controllable synchronization, we focus on the study of time paths. This article provides a first insight into a tailored cosimulated testbed, implemented to determine the time path behavior in terms of jitter and to supervise the drift from the primary reference clock (PRC) with more than 20 cascaded nodes, the maximum achievable cascaded depth within the current G.8262 standard. This cascading must meet the requirements of the International Telecommunication Union (ITU-T) standards G.8262/G.8261 in terms of long-term jitter (wander) and short-term jitter (jitter) to ensure a tolerable drift compared with the central clock. In particular, for Synchronous Ethernet (SyncE), the standard does not provide possible limits for the jitter beyond 20 synchronized nodes. The numerical results, with the extended number of nodes, show that this scenario remains feasible, the parameters being below the masks proposed by the standards.

Presenilin 2 N141I Mutation Induces Hyperimmunity by Immune Cell-specific Suppression of REV-ERBα without Altering Central Circadian Rhythm.

Circadian rhythm is a 24-hour cycle of behavioral and physiological changes. Disrupted sleep-wake patterns and circadian dysfunction are common in patients of Alzheimer Disease (AD) and are closely related with neuroinflammation. However, it is not well known how circadian rhythm of immune cells is altered during the progress of AD. Previously, we found presenilin 2 (Psen2) N141I mutation, one of familial AD (FAD) risk genes, induces hyperimmunity through the epigenetic repression of REV-ERBα expression in microglia and bone marrow-derived macrophage (BMDM) cells. Here, we investigated whether repression of REV-ERBα is associated with dysfunction of immune cell-endogenous or central circadian rhythm by analyses of clock genes expression and cytokine secretion, bioluminescence recording of rhythmic PER2::LUC expression, and monitoring of animal behavioral rhythm. Psen2 N141I mutation down-regulated REV-ERBα and induced selective over-production of IL-6 (a well-known clock-dependent cytokine) following the treatment of toll-like receptor (TLR) ligands in microglia, astrocytes, and BMDM. Psen2 N141I mutation also lowered amplitude of intrinsic daily oscillation in these immune cells representatives of brain and periphery. Of interest, however, the period of daily rhythm remained intact in immune cells. Furthermore, analyses of the central clock and animal behavioral rhythms revealed that central clock remained normal without down-regulation of REV-ERBα. These results suggest that Psen2 N141I mutation induces hyperimmunity mainly through the suppression of REV-ERBα in immune cells, which have lowered amplitude but normal period of rhythmic oscillation. Furthermore, our data reveal that central circadian clock is not affected by Psen2 N141I mutation.

Research progress on circadian rhythm-related Alzheimer's disease and Cancer

Endogenous oscillators include circadian oscillators, which control 24-hour physiological and behavioral processes. Nowadays, 7–16% of people with circadian sleep disorders are young adults or adolescents. On the other hand, there are in excess of six million Alzheimer's patients in the United States. By 2050, it is predicted that the population will nearly triple to 13 million. Numerous facets of mammals biology, such as the coordination of sleep and the immune respond are influenced by the central circadian clock. Unusual sleep-wake cycles and disrupted circadian rhythms are frequent symptoms of Alzheimer's disease (AD), which are typically seen as late effects of the neurodegenerative processes. Additionally, it appears that the amyloid-beta peptide, which is linked to AD, is regulated by the sleep-wake cycle and that altering sleep has a variety of effects on AD pathology in mouse models. Forthemore, cancer's pathophysiology has been clarified by new studies on circadian rhythms and the disease. The connections between irregularities in human circadian clocks and sleep disorders is disscused firstly in this paper. The most recent studies on the possible impact of sleep and circadian rhythms on AD pathogenesis and cancer are introduced. This article reviews the fundamentals of circadian rhythms before moving on to various forms of sleep disorders, cancer, and Alzheimer's disease. This review is significant because it compiles recent research on illnesses connected to the circadian rhythm, including Alzheimer's disease, cancer, and sleep disorders.

Diurnal Variation of L-Arginine and the Cardiovascular Risk Markers Asymmetric and Symmetric Dimethylarginine and Homoarginine in Rotating Night Shift Workers and Controls.

Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) interfere with nitric oxide (NO) formation from L-arginine via different mechanisms. ADMA is a biomarker of cardiovascular disease and mortality, whilst SDMA is a biomarker of mortality after ischemic stroke. Homoarginine, another L-arginine-derived amino acid, is associated with stroke and congestive heart failure. Acute ischemic events like myocardial infarction show a time-of-day variation in the timing of their onset, as do NO-mediated vascular function and blood pressure. We studied whether the plasma concentrations of L-arginine-related amino acid metabolites show diurnal variation in a clinical study comparing 12 non-night shift workers with 60 rotating night shift workers. The plasma concentrations of L-arginine-related biomarkers, melatonin, and cortisol were measured every 3 h during a 24-h period. In addition, 24-h blood pressure recordings were performed. In non-night shift workers, L-arginine and homoarginine plasma concentrations showed diurnal variation with a 12-h period, which were both attenuated in night shift workers. ADMA and SDMA showed a 24-h rhythmicity with no significant differences in phase between night shift and non-night shift workers. The plasma profiles of melatonin and cortisol were not significantly different between both groups, suggesting that the rotating night shift work does not have a major influence on central suprachiasmatic nuclei clock timing. In addition, systolic and diastolic blood pressure patterns were similar between both groups. Our data show diurnal variation of dimethylarginines with the timing of their acrophases corresponding to the published timing of the peak incidence of cardiac ischemic events.

Research progresses on the effects of heavy metals on the circadian clock system.

Environmental pollution with heavy metals is widespread, thus increasing attention has been paid to their toxic effects. Recent studies have suggested that heavy metals may influence the expression of circadian clock genes. Almost all organs and tissues exhibit circadian rhythms. The normal circadian rhythm of an organism is maintained by the central and peripheral circadian clock. Thus, circadian rhythm disorders perturb normal physiological processes. Here, we review the effects of heavy metals, including manganese, copper, cadmium, and lead, on four core circadian clock genes, i.e.,ARNTL, CLOCK, PER, and CRY genes.

Aripiprazole disrupts cellular synchrony in the suprachiasmatic nucleus and enhances entrainment to environmental light-dark cycles in mice.

Many patients with psychiatric conditions, such as bipolar disorder and major depressive disorder, frequently experience disruptions in their sleep-wake cycles. Several case studies and clinical trials have shown that the administration of aripiprazole, a commonly prescribed antipsychotic drug, alleviates the symptoms of circadian sleep disorders in these patients. This improvement may be attributed to the effects of aripiprazole on the circadian central clock, specifically the hypothalamic suprachiasmatic nucleus (SCN), which regulates various circadian physiological rhythms, including the sleep-wake cycle, in mammals. To examine whether aripiprazole facilitates adaptation to changes in the light-dark cycle, we orally administered aripiprazole to mice and subjected them to jet-lag experiments. Mice receiving aripiprazole were more rapidly entrained to 6 h advanced light-dark cycles. Moreover, we examined the effect of aripiprazole on the cellular rhythms of SCN slice cultures and found that aripiprazole disrupted cellular synchronization in the SCN, thereby accelerating the damping of the SCN rhythm at the population level. Adenosine 3'5' monophosphate (cAMP) assay using a bioluminescence indicator revealed that intracellular cAMP level in the SCN increased following aripiprazole treatment. However, this increase was blocked by pre-treatment with the serotonin 1A receptor (5-HT1AR) antagonist. Based on these findings, we propose that aripiprazole modulates intracellular signaling, including 5-HT1AR-mediated cAMP signaling, and desynchronizes SCN neurons, ultimately leading to enhanced entrainment to phase advanced light-dark cycles in mice. These findings indicate that the improvement in sleep symptoms reported in patients with psychiatric disorders receiving aripiprazole may be due to modulation of the circadian clock. Our study provides novel insights into the potential clinical applications of aripiprazole in patients with various circadian sleep disorders.

The genomic basis of temporal niche evolution in a diurnal rodent

Patterns of diel activity-how animals allocate their activity throughout the 24-h daily cycle-play key roles in shaping the internal physiology of an animal and its relationship with the external environment.1,2,3,4,5 Although shifts in diel activity patterns have occurred numerous times over the course of vertebrate evolution,6 the genomic correlates of such transitions remain unknown. Here, we use the African striped mouse (Rhabdomys pumilio), a species that transitioned from the ancestrally nocturnal diel niche of its close relatives to a diurnal one,7,8,9,10,11 to define patterns of naturally occurring molecular variation in diel niche traits. First, to facilitate genomic analyses, we generate a chromosome-level genome assembly of the striped mouse. Next, using transcriptomics, we show that the switch to daytime activity in this species is associated with a realignment of daily rhythms in peripheral tissues with respect to the light:dark cycle and the central circadian clock. To uncover selection pressures associated with this temporal niche shift, we perform comparative genomic analyses with closely related rodent species and find evidence of relaxation of purifying selection on striped mouse genes in the rod phototransduction pathway. In agreement with this, electroretinogram measurements demonstrate that striped mice have functional differences in dim-light visual responses compared with nocturnal rodents. Taken together, our results show that striped mice have undergone a drastic change in circadian organization and provide evidence that the visual system has been a major target of selection as this species transitioned to a novel temporal niche.

Dim artificial light at night alters immediate early gene expression throughout the avian brain.

Artificial light at night (ALAN) is a pervasive pollutant that alters physiology and behavior. However, the underlying mechanisms triggering these alterations are unknown, as previous work shows that dim levels of ALAN may have a masking effect, bypassing the central clock. Light stimulates neuronal activity in numerous brain regions which could in turn activate downstream effectors regulating physiological response. In the present study, taking advantage of immediate early gene (IEG) expression as a proxy for neuronal activity, we determined the brain regions activated in response to ALAN. We exposed zebra finches to dim ALAN (1.5 lux) and analyzed 24 regions throughout the brain. We found that the overall expression of two different IEGs, cFos and ZENK, in birds exposed to ALAN were significantly different from birds inactive at night. Additionally, we found that ALAN-exposed birds had significantly different IEG expression from birds inactive at night and active during the day in several brain areas associated with vision, movement, learning and memory, pain processing, and hormone regulation. These results give insight into the mechanistic pathways responding to ALAN that underlie downstream, well-documented behavioral and physiological changes.