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Cocaine- and amphetamine- regulated transcript (CART) and Neuropeptide Y (NPY) primarily regulate energy homeostasis. Anurans exhibit diurnal behavioral rhythm, but the response of central neuropeptides to the Day-Night cycle is not elucidated. In this study, we have examined the profile of CART and NPY in the brain of Euphlyctis cyanophlyctis from 6:00 h to 24:00 h. Although expressions of CART and NPY changed with time of the day, circadian oscillation was observed only in expression of CART in anteroventral tegmentum (AV). CART exhibited a single peak in preoptic area (POA), Edinger-Westphal nucleus (EW), nucleus isthmus (NI) and raphe nucleus (Ra); two peaks in ventral hypothamalus (vHy), habenula (Hb) and torus semicircularis (TS). NPY exhibited single peak in TS and suprachiasmatic nucleus (SCN); two peaks in POA, vHy, AV and EW. The daily modulations of these neuropeptides may contribute to their physiological activities and are evolutionarily conserved. [ABSTRACT FROM AUTHOR]

Stable and entrainable physiological circadian rhythms are crucial for overall health and well-being. The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, consists of diverse neuron types that collectively generate a circadian profile of electrical activity. However, the mechanisms underlying the regulation of endogenous neuronal excitability in the SCN remain unclear. Two-pore domain potassium channels (K2P), including TASK-3, are known to play a significant role in maintaining SCN diurnal homeostasis by inhibiting neuronal activity at night. In this study, we investigated the role of TASK-3 in SCN circadian neuronal regulation and behavioural photoentrainment using a TASK-3 global knockout mouse model. Our findings demonstrate the importance of TASK-3 in maintaining SCN hyperpolarization during the night and establishing SCN sensitivity to glutamate. Specifically, we observed that TASK-3 knockout mice lacked diurnal variation in resting membrane potential and exhibited altered glutamate sensitivity both in vivo and in vitro. Interestingly, despite these changes, the mice lacking TASK-3 were still able to maintain relatively normal circadian behaviour. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the delay tolerance for stochastic complex networks (SCNs, in short) under Lyapunov conditions. Based on global Lipschitz coefficients, we show that when the SCN without delay is pth moment exponentially stable, the system with small delays is still pth moment exponentially stable. In addition, we also give the explicit delay bounds. An example is provided to demonstrate the obtained results. [ABSTRACT FROM AUTHOR]

The article discusses the physiological process of torpor and hibernation in endothermic animals, including mice. Torpor is a hypoactive metabolic state that animals enter during periods of low temperatures and food scarcity to conserve energy. The central nervous system, particularly the hypothalamus, plays a crucial role in regulating torpor. The article presents recent findings on the neural circuits involved in torpor regulation, specifically focusing on the antero-preoptic area, medial preoptic area, and dorsomedial hypothalamus. The article also highlights the need for further research to understand the mechanisms underlying torpor and hibernation in different animal species, including humans. [Extracted from the article]

Reaction of Mn(OAc)2·4H2O with pentaerythritol (H4peol) in the presence of NaSCN leads to formation of a 1-D coordination polymer (CP) based on Mn(II), [Mn(SCN)2(peol)]n (1, SCN− = thiocyanate), under solvothermal conditions. EA, FTIR, PXRD, SCXRD and TGA analyses were used to study the composition and phase purity of the Mn(II) coordination polymer. The degradation of alizarin was investigated using organic framework substances as degradation agents. The results showed that the maximum degradation value of 86.12% was achieved at 50 min. This study not only promotes the preparation of organic frameworks, but also provides a feasible solution for the effective degradation of alizarin. [ABSTRACT FROM AUTHOR]

Circadian rhythms play a pivotal role in governing various physiological processes, including physical performance. However, in individuals deprived of light perception, such as the blind, these circadian rhythms face disruption. This study aimed to explore the influence of disturbed circadian rhythms on short-term maximal physical performance in children and adolescents with visual impairment. Forty-five volunteers participated in this study, comprising 17 blind, 13 visually impaired, and 15 sighted participants. The participants underwent a series of tests assessing maximal isometric strength performance across two days. To mitigate the influence of morning session fatigue on the evening results, each participant group performed in two separate testing sessions (i.e. in the morning (7:00 h) and in the evening (17:00 h)) on non-consecutive days in a randomized and counterbalanced setting, with approximately 36 h of recovery time between sessions. To mitigate the impact of inter-individual differences on mean values and to account for the influence of age and sex on the studied variables, data were normalized. The outcomes revealed a significant diurnal variation in maximal isometric strength performance among sighted individuals, with peak performance observed in the evening. This pattern aligns with their well-entrained circadian rhythm. In contrast, blind and visually impaired individuals did not display significant diurnal variation, signaling disrupted circadian rhythms due to the absence of light perception. These findings emphasize the crucial consideration of circadian rhythms in assessments of physical performance, especially among participants with visual impairments. [ABSTRACT FROM AUTHOR]

Circadian rhythmicity has been shown to contribute to the regulation of key physiological and cognitive processes related to performance. The period homolog 3 (PER3) is expressed in a circadian pattern in the suprachiasmatic nucleus. Therefore, in this study, we aimed to evaluate the role of the variable tandem repeat (VNTR) variant of the PER3 gene in athletic performance in the Turkish population. This study included 223 subjects, which consisted of 123 athletes and 100 sedentary controls. Blood samples were drawn from all subjects. DNA was extracted from whole-blood samples. The PER3 VNTR variant was genotyped using the polymerase chain reaction-restriction method (PCR). The results of the analyses were evaluated for statistical significance. The mean ages of athletes and controls were 22 ± 2.814 and 23 ± 3.561, respectively. Endurance athletes in the group were 21.1%, and sprint athletes were 78.9%. There was no statistical significance in terms of PER3 VNTR genotype distribution or allele frequency. In the recessive model, a statistically significant association was observed when the athletes were compared with the controls according to 4/4 + 4/5 versus 5/5 genotype (p = 0.020). In this case-control study, for the first time in our country, we obtained findings suggesting that the PER3 VNTR variant may affect sports performance in the Turkish population. Results need to be replicated in different ethnic and larger samples. [ABSTRACT FROM AUTHOR]

Supply chain resilience (SCRES) refers to the ability of a supply chain (SC) to both resist disruptions and recover its operational capability after disruptions. This paper presents a simulation model that includes network structural properties in the analysis of SCRES. This simulation model extends an existing graph model to consider operational behaviours in order to capture disruption-recovery dynamics. Through structural analysis of a supply chain network (SCN), mitigation strategies are designed to build redundancy, while contingency strategies are developed to prioritise recovery of the affected SCN. SCRES indexes are proposed by sampling SC performance measures of disruption for each plant and aggregating the measures based on the criticality of the plants in the SCN. The applicability of this simulation model is demonstrated in a real-world case study of different disruption scenarios. The application of mitigation and contingency strategies is shown to both improve recovery and reduce the total costs associated with disruptions. Through such simulation-based analysis, firms can gain insight into the SCRES of their existing SCNs and identify suitable strategies to improve SCRES by considering recovery time and costs. [ABSTRACT FROM AUTHOR]

Circadian rhythms originate from molecular feedback loops. In mammals, the transcription factors CLOCK and BMAL1 act on regulatory elements (i.e. E-boxes) to shape biological functions in a rhythmic manner. The EPHA4 receptor and its ligands Ephrins (EFN) are cell adhesion molecules regulating neurotransmission and neuronal morphology. Previous studies showed the presence of E-boxes in the genes of EphA4 and specific Ephrins, and that EphA4 knockout mice have an altered circadian rhythm of locomotor activity. We thus hypothesized that the core clock machinery regulates the gene expression of EphA4, EfnB2 and EfnA3. CLOCK and BMAL1 (or NPAS2 and BMAL2) were found to have transcriptional activity on distal and proximal regions of EphA4, EfnB2 and EfnA3 putative promoters. A constitutively active form of glycogen synthase kinase 3β (GSK3β; a negative regulator of CLOCK and BMAL1) blocked the transcriptional induction. Mutating the E-boxes of EphA4 distal promoter sequence reduced transcriptional induction. EPHA4 and EFNB2 protein levels did not show circadian variations in the mouse suprachiasmatic nucleus or prefrontal cortex. The findings uncover that core circadian transcription factors can regulate the gene expression of elements of the Eph/Ephrin system, which might contribute to circadian rhythmicity in biological processes in the brain or peripheral tissues. [ABSTRACT FROM AUTHOR]

Circadian rhythms of physiology, behavior, and metabolism have an endogenous 24 h period that synchronizes with environmental cycles of light/dark and food availability. Alterations in light cycles are stressful and disrupt such diurnal oscillations. Recently, we witnessed a sudden rise in studies describing the mechanisms behind the interaction between the key characteristics of mitochondrial functions, peripheral clocks, and stress responses. To our knowledge, there is no study in the suprachiasmatic nuclei (SCN) describing the dysregulated mitochondrial bioenergetics under abnormal lighting conditions, which is common in today's modern world. Thus, we aimed to investigate the existence of daily changes in mitochondrial bioenergetics (respiratory control rate, RCR), mitochondrial abundance (mtDNA/nDNA), plasma corticosterone, and to test whether disturbances in the lighting conditions might influence such rhythms. To confirm this, mice were sacrificed, mitochondria were isolated from the suprachiasmatic nuclei in the brain and blood was collected, every 3 h at various time points zeitgeber time/circadian time, (0, 3, 6, 9, 12, 15, 18, 21, and 24 h) under 12:12 h light-dark (LD, 150 lux L: 0 lux D) cycle and chronic artificial dim lighting (LL, 5 lux: 5lux) conditions, of a 24 h period, respectively. Our results demonstrate the existence of robust daily rhythmicity in RCR, mtDNA/nDNA and plasma CORT under a normal LD cycle. However, these rhythms were significantly disrupted and clock genes expressions were dysregulated under chronic dim LL. Furthermore, mitochondrial abundance was significantly reduced during LL compared to their numbers under LD cycle. Our data demonstrate that the circadian clock regulates mitochondrial functions (RCR, number), essential for accomplishing daily energy demands and supply by the SCN neurons. Abnormal light exposure dysregulates mitochondrial functions in the SCN and may alter metabolism, resulting in obesity, diabetes, and other metabolic disorders. Therefore, properly designing lighting conditions in workplaces is essential to mitigate the adverse consequences of light on humans. [ABSTRACT FROM AUTHOR]

Circadian rhythms and sleep homeostasis constitute the two-process model for daily sleep regulation. However, evidence for circadian control of sleep-wake cycles has been relatively short since clock-less animals often show sleep behaviors quantitatively comparable to wild-type. Here we examine Drosophila sleep behaviors under different light-dark regimes and demonstrate that circadian clocks gate light-induced arousal. Genetic excitation of tyrosine decarboxylase 2 (TDC2)-expressing neurons suppressed sleep more evidently at night, causing nocturnal activity. The arousal effects were likely mediated in part by glutamate transmission from the octopaminergic neurons and substantially masked by light. Application of T12 cycles (6-h light: 6-h dark) further showed that the light-sensitive effects of TDC2 neurons depended on the time of the day. In particular, light-sensing via visual input pathway led to strong sleep suppression at subjective night, and such an effect disappeared in clock-less mutants. Transgenic mapping revealed that light-induced arousal and free-running behavioral rhythms require distinct groups of circadian pacemaker neurons. These results provide convincing evidence that circadian control of sleep is mediated by the dedicated clock neurons for light-induced arousal. [ABSTRACT FROM AUTHOR]

Animals possess a circadian central clock in the brain, where circadian behavioural rhythms are generated. In the fruit fly (Drosophila melanogaster), the central clock comprises a network of approximately 150 clock neurons, which is important for the maintenance of a coherent and robust rhythm. Several neuropeptides involved in the network have been identified, including Pigment-dispersing factor (PDF) and CCHamide1 (CCHa1) neuropeptides. PDF signals bidirectionally to CCHa1-positive clock neurons; thus, the clock neuron groups expressing PDF and CCHa1 interact reciprocally. However, the role of these interactions in molecular and behavioural rhythms remains elusive. In this study, we generated Pdf01 and CCHa1SK8 double mutants and examined their locomotor activity-related rhythms. The single mutants of Pdf01 or CCHa1SK8 displayed free-running rhythms under constant dark conditions, whereas approximately 98% of the double mutants were arrhythmic. In light-dark conditions, the evening activity of the double mutants was phase-advanced compared with that of the single mutants. In contrast, both the single and double mutants had diminished morning activity. These results suggest that the effects of the double mutation varied in behavioural parameters. The double and triple mutants of per01, Pdf01, and CCHa1SK8 further revealed that PDF signalling plays a role in the suppression of activity during the daytime under a clock-less background. Our results provide insights into the interactions between PDF and CCHa1 signalling and their roles in activity rhythms. [ABSTRACT FROM AUTHOR]

A key perception of energy homeostasis is the recognition of a mutual regulation between biological clock and cell metabolism. For instance, the regular occurrences of appetite and satiety is not incessant over 24 h, but is instead organized temporally over the 24 h and the light/dark cycle. In mammals, the temporal regulation of metabolism, physiology and behaviour about 24 h is regulated by a complex system of manifold cellular clocks, synchronized via neuronal and hormonal cues by a master clock situated in the suprachiasmatic nuclei of the hypothalamus. Chronic disturbance of circadian rhythms, as seen in human shift-workers (up to 20% of the dynamic populace), has been linked with the advancement of numerous unfavourable mental and metabolic disturbances, suggesting that metabolic processes and biological clock are tightly linked with each other. Comprehension of the functional associations among circadian desynchronization and general health in animal model systems and humans, nevertheless, is still meagre. To sum up, this research topic covers a broad assortment of functional connections amid circadian rhythms and metabolism at molecular, cellular, tissue, organ and organism level. [ABSTRACT FROM AUTHOR]

The role of suprachiasmatic nuclei (SCN) in the anterior hypothalamus as a master ~24 h oscillator (clock) and synchronizer of the circadian regulatory system is reviewed extensively. In contrast, the ample evidence that SCN also exert a circadian-independent impact on homeostasis and metabolism is underappreciated. Therefore, herein we focus on the evidence for SCN participation in homeostatic (non-circadian) mechanisms in regulation of arterial blood pressure and hydro-mineral balance, plasma glucose level, food intake, renin, ACTH/corticosterone, GH, thyroid hormones and melatonin secretion. We conclude that, in addition to their major role in circadian control, SCN also selectively participate in homeostatic control. The evidence supports a model where the ventrolateral region of SCN and especially its vasointestinal polypeptide (VIP)-containing neurons convey the homeostatic influences of SCN to the metabolic regulatory pathways. The precise mechanisms of the rhythmic wisdom of the body, i.e., how SCN circadian clock and the daily behavioral and endocrine rhythms harmonize with the homeostatic regulatory systems defending the relative constancy of the internal milieu, remain to be elucidated. The non-circadian SCN contributions in responses to homeostatic challenges certainly deserve careful consideration in future studies. Abbreviations2-DG: 2-deoxy-D-glucose; AV3V: anteroventral third ventricle region; GRF - growth-hormone-releasing factor; MnPO: median preoptic nucleus; NTS: nucleus of the solitary tract; OVLT: organum vasculosum of the lamina terminalis; PRA: plasma renin activity; SCN: suprachiasmatic nuclei; SD: sleep deprivation; VIP: vasoactive intestinal polypeptide. [ABSTRACT FROM AUTHOR]

It has been proposed for years that physical exercise ameliorates metabolic diseases. Optimal exercise timing in humans and mammals has indicated that circadian clocks play a vital role in exercise and body metabolism. Skeletal muscle metabolism exhibits a robust circadian rhythm under the control of the suprachiasmatic nucleus of the hypothalamus. Clock genes also control the development, differentiation, and function of skeletal muscles. In this review, we aimed to clarify the relationship between exercise, skeletal muscles, and the circadian clock. Health benefits can be attained by the scheduling of exercise at the best circadian time. Exercise therapy for metabolic diseases and cardiovascular health is a key adjuvant method. This review highlights the importance of exercise timing in maintaining healthy metabolism and circadian clocks. [ABSTRACT FROM AUTHOR]

The Earth's rotation generates environmental oscillations (e.g., in light and temperature) that have imposed unique evolutionary pressures over millions of years. Consequently, the circadian clock, a ubiquitously expressed molecular system that aligns cellular function to these environmental cues, has become an integral component of our physiology. The resulting functional rhythms optimize and economize physiological performance: perturbing these rhythms, therefore, is frequently deleterious. This perspective article focuses on circadian rhythms in resistance artery myogenic reactivity, a key mechanism governing tissue perfusion, total peripheral resistance and systemic blood pressure. Emerging evidence suggests that myogenic reactivity rhythms are locally generated in a microvascular bed-specific manner at the level of smooth muscle cells. This implies that there is a distinct interface between the molecular clock and the signalling pathways underlying myogenic reactivity in the microvascular beds of different organs. By understanding the precise nature of these molecular links, it may become possible to therapeutically manipulate microvascular tone in an organ-specific manner. This raises the prospect that interventions for vascular pathologies that are challenging to treat, such as hypertension and brain malperfusion, can be significantly improved. [ABSTRACT FROM AUTHOR]

Temporal coordination of organisms according to the daytime allows a better performance of physiological processes. However, modern lifestyle habits, such as food intake during the rest phase, promote internal desynchronization and compromise homeostasis and health. The hypothalamic suprachiasmatic nucleus (SCN) synchronizes body physiology and behavior with the environmental light–dark cycle by transmitting time information to several integrative hypothalamic nuclei, such as the paraventricular nucleus (PVN), dorsomedial hypothalamic nucleus (DMH) and median preoptic area (MnPO). The SCN receives metabolic information mainly via Neuropeptide Y (NPY) inputs from the intergeniculate nucleus of the thalamus (IGL). Nowadays, there is no evidence of the response of the PVN, DMH and MnPO when the animals are subjected to internal desynchronization by restricting food access to the rest phase of the day. To explore this issue, we compared the circadian activity of the SCN, PVN, DMH and MnPO. In addition, we analyzed the daily activity of the satiety centers of the brainstem, the nucleus of the tractus solitarius (NTS) and area postrema (AP), which send metabolic information to the SCN, directly or via the thalamic intergeniculate leaflet (IGL). For that, male Wistar rats were assigned to three meal protocols: fed during the rest phase (Day Fed); fed during the active phase (Night Fed); free access to food (ad libitum). After 21 d, the daily activity patterns of these nuclei were analyzed by c-Fos immunohistochemistry, as well as NPY immunohistochemistry, in the SCN. The results show that eating during the rest period produces a phase advance in the activity of the SCN, changes the daily activity pattern in the MnPO, NTS and AP and flattens the c-Fos rhythm in the PVN and DMH. Altogether, these results validate previous observations of circadian dysregulation that occurs within the central nervous system when meals are consumed during the rest phase, a behavior that is involved in the metabolic alterations described in the literature. [ABSTRACT FROM AUTHOR]

Graph On June 3, 2020, after long, 3 year battle with dementia Stuart Maxwell Arm-strong, Professor of Chronobiology and friend of many across the globe, passed away. Working with Cassone and Chesworth, Stuart was also to show the SCN dependency of melatonin's chronobiotic effects. Dr Robert Sack describes the importance of Stuart's work and the inspiration derived there from, in the subsequent work that transpired. [Extracted from the article]

The circadian system induces oscillations in most physiological variables, with periods close to 24 hours. Dysfunctions in clock-controlled body functions, such as sleep disorders, as well as deregulation of clock gene expression or glucocorticoid levels have been observed in cancer patients. Moreover, these disorders have been associated with a poor prognosis or worse response to treatment. This work explored the circadian rhythms at behavioral and molecular levels in a murine melanoma model induced by subcutaneous inoculation of B16 tumoral cells. We observed that the presence of the tumors induced a decrease in the robustness of the locomotor activity rhythms and in the amount of nighttime activity, together with a delay in the acrophase and in the activity onset. Moreover, these differences were more marked when the tumor size was larger than in the initial stages of the tumorigenesis protocol. In addition, serum glucocorticoids, which exhibit strong clock-controlled rhythms, lost their circadian patterns. Similarly, the rhythmic expression of the clock genes Bmal1 and Cry1 in the hypothalamic Suprachiasmatic Nuclei (SCN) were also deregulated in mice carrying tumors. Altogether, these results suggest that tumor-secreted molecules could modulate the function of the central circadian pacemaker (SCN). This could account for the worsening of the peripheral biological rhythms such as locomotor activity or serum glucocorticoids. Since disruption of the circadian rhythms might accelerate tumorigenesis, monitoring circadian patterns in cancer patients could offer a new tool to get a better prognosis for this disease. [ABSTRACT FROM AUTHOR]

Circadian clocks are an endogenous internal timekeeping mechanism that drives the rhythmic expression of genes, controlling the 24 h oscillatory pattern in behaviour and physiology. It has been recently shown that post-transcriptional mechanisms are essential for controlling rhythmic gene expression. Controlling the stability of mRNA through poly(A) tail length modulation is one such mechanism. In this study, we show that Cnot1, encoding the scaffold protein of the CCR4-NOT deadenylase complex, is highly expressed in the suprachiasmatic nucleus, the master timekeeper. CNOT1 deficiency in mice results in circadian period lengthening and alterations in the mRNA and protein expression patterns of various clock genes, mainly Per2. Per2 mRNA exhibited a longer poly(A) tail and increased mRNA stability in Cnot1+/- mice. CNOT1 is recruited to Per2 mRNA through BRF1 (ZFP36L1), which itself oscillates in antiphase with Per2 mRNA. Upon Brf1 knockdown, Per2 mRNA is stabilized leading to increased PER2 expression levels. This suggests that CNOT1 plays a role in tuning and regulating the mammalian circadian clock. [ABSTRACT FROM AUTHOR]

Despite major developments in lung cancer investigations and the progress of innovative oncology treatments in recent decades, lung cancer continues to be the predominant cause of cancer-related mortality globally, with over a million deaths each year. This highlights the urgent need to develop a deeper understanding of the current state of cancer care. At the environmental and cellular levels, circadian rhythms are closely associated with living organisms. In humans, the suprachiasmatic nucleus is the principal circadian pacemaker. Circadian gene feedback loops regulate the clock, connecting peripheral tissue metabolism, cell proliferation, DNA repair, and cell death to energy homeostasis, physical activity, and neurohormonal regulation at the organismal level. Endogenous circadian homeostasis has been frequently disturbed in modern civilizations, resulting in a higher risk of many disorders, including lung cancer. Despite major developments in lung cancer investigations and the progress of innovative oncology treatments in recent decades, lung cancer continues to be the predominant cause of cancer-related mortality globally, with over a million deaths each year. This highlights the urgent need to develop a deeper understanding of the current state of cancer care. At the environmental and cellular levels, circadian rhythms are closely associated with living organisms. In humans, the suprachiasmatic nucleus is the principal circadian pacemaker. Circadian gene feedback loops regulate the clock, connecting peripheral tissue metabolism, cell proliferation, DNA repair, and cell death to energy homeostasis, physical activity, and neurohormonal regulation at the organismal level. Endogenous circadian homeostasis has been frequently disturbed in modern civilizations, resulting in a higher risk of many disorders, including lung cancer. The mammalian circadian clock controls metabolism and cell division, and disruption of these processes may lead to cancer pathogenesis. Furthermore, circadian disturbance has recently been identified as a self-regulating cancer risk factor and is listed as a carcinogen. The theory that both somatic and systemic disturbances of circadian rhythms are related to a higher risk of lung cancer development and poor prognosis is addressed in this study. The chronotherapy principles hold much more promise for enhancing the lung cancer care options currently available. Developing a better understanding of the molecular interactions that control the physiological equilibrium between both the circadian rhythm and the cycle of cell division could significantly influence the development of novel treatments for lung cancer and other diseases. [ABSTRACT FROM AUTHOR]

As the largest organ exposed to the outside of mammals, skin has direct photosensitivity. Recent studies have even shown that cutaneous irradiation played a role in local circadian systems. However, whether it can further affect the central clock system is controversial. Here, plasm melatonin rhythm of melatonin-proficient C3H/He mice was assessed, and on this basis, a well-designed segmented lighting method was used to investigate the effects of dorsal skin irradiation on locomotor activity and plasm melatonin content in male C3H/He mice. In brief, mice were separately exposed to cutaneous irradiation, intraocular irradiation or darkness for 60 min at specific moments. The results showed that neither blue nor red cutaneous exposure had obvious effect on central rhythm oscillation while intraocular irradiation could significantly change the central clock of mice, and the effect of blue light was more forceful than red light. It suggests that intraocular nonvisual channels still play a dominant role in rhythmic regulation, which has not been challenged by the discovery of local light entrainment in exposed peripheral tissues. [ABSTRACT FROM AUTHOR]

ِAim: Tryptophan hydroxylase-2 mRNA (TPH, the rate limiting enzyme in 5-HT synthesis) expression levels display circadian variations in the median and dorsal raphe nuclei. This circadian pattern is under the control of the suprachiasmatic nuclei (SCN), the master clock. Photoperiodic cue is encoded by the SCN which convey the seasonal message to target sites. In the present study, we have investigated the effect of photoperiodic changes on the serotonergic neurons of the raphe nuclei. We have assessed the daily expression of TPH2 mRNA in both median and dorsal raphe nuclei of rats housed either under long photoperiod (18 h light/6 h dark cycle, LP18:6) or short photoperiod (SP6:18). ٌ Results: Our results demonstrate that under LP18:6, TPH2 mRNA levels display a progressive decrease during the dark period and a maximal expression is reported at the beginning of the light period. The expression pattern of TPH2 mRNA under SP6:18 remains unchanged during the dark period and increases significantly before the light/dark transition. This latter expression pattern is in line with the daily profiles of TPH2 mRNA reported previously under standard lighting regimen (12 h light/12 h dark cycle). Conclusion: The present results suggest that TPH2 mRNA expression pattern within DR and MR is affected by photoperiod which might in turn affect TPH content and 5‐HT release within the circadian structures, but also in all the serotonergic projection areas of the brain. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes mellitus are major health concerns worldwide. In obese-type 2 diabetic patients, the function of the central brain clock in the hypothalamus, as well as rhythmicity in white adipose tissue (WAT), are reduced. To better understand how peripheral clocks in white adipose tissue (WAT) are synchronized, we assessed the importance of the central brain clock for daily WAT rhythms. We compared gene expression rhythms of core clock genes (Bmal1, Per2, Cry1, Cry2, RevErbα, and DBP) and metabolic genes (SREBP1c, PPARα, PPARγ, FAS, LPL, HSL, CPT1b, Glut4, leptin, adiponectin, visfatin/NAMPT, and resistin) in epididymal and subcutaneous white adipose tissue (eWAT and sWAT) of SCN-lesioned and sham-lesioned rats housed in regular L/D conditions. Despite complete behavioral and hormonal arrhythmicity, SCN lesioning only abolished Cry2 and DBP rhythmicity in WAT, whereas the other clock gene rhythms were significantly reduced, but not completely abolished. We observed no major differences in the effect of SCN lesions between the two WAT depots. In contrast to clock genes, all metabolic genes lost their daily rhythmicity in WAT, with the exception of NAMPT. Interestingly, NAMPT rhythmicity was even less affected by SCN lesioning than the core clock genes, suggesting that it is either strongly coupled to the remaining rhythmicity in clock gene expression, or very sensitive to other external rhythmic factors. The L/D cycle could be such a rhythmic external factor that generates modulating signals by photic masking via the intrinsic photosensitive retinal ganglion cells in combination with the autonomic nervous system. Our findings indicate that in normal weight rats, gene expression rhythms in WAT can be maintained independent of the central brain clock. [ABSTRACT FROM AUTHOR]

Chronotype or diurnal preference is a questionnaire-based measure influenced both by circadian period and by the sleep homeostat. In order to further characterize the biological determinants of these measures, we used a hypothesis-free approach to investigate the association between the score of the morningness-eveningness questionnaire (MEQ) and the Munich chronotype questionnaire (MCTQ), as continuous variables, and volumetric measures of brain regions acquired by magnetic resonance imaging (MRI). Data were collected from the Baependi Heart Study cohort, based in a rural town in South-Eastern Brazil. MEQ and anatomical 1.5-T MRI scan data were available from 410 individuals, and MCTQ scores were available from a subset of 198 of them. The average MEQ (62.2 ± 10.6) and MCTQ (average MSFsc 201 ± 85 min) scores were suggestive of a previously reported strong general tendency toward morningness in this community. Setting the significance threshold at P >.002 to account for multiple comparisons, we observed a significant association between lower MEQ score (eveningness) and greater volume of the left anterior occipital sulcus (β = −0.163, p =.001) of the occipital lobe. No significant associations were observed for MCTQ. This may reflect the smaller dataset for MCTQ, and/or the fact that MEQ, which asks questions about preferred timings, is more trait-like than the MCTQ, which asks questions about actual timings. The association between MEQ and a brain region dedicated to visual information processing is suggestive of the increasingly recognized fluidity in the interaction between visual and nonvisual photoreception and the circadian system, and the possibility that chronotype includes an element of masking. [ABSTRACT FROM AUTHOR]

The present study investigated circadian rhythms and hippocampal-dependent memory in female Fischer brown Norway rats. As in past reports with female Long Evans rats, we hypothesized that six days of exposure to an unentrainable T21 light–dark cycle that occurred during distributed Morris water task training would not impair the retention of the acquired memory. As expected, the rats did not have impaired retention of the place memory acquired in the distributed Morris water task. We next, quantified circadian entrainment two months after exposure to the T21 cycle. As expected, measures of circadian rhythms suggested that the rats exposed to the T21 had since entrained to a 12:12 light–dark cycle. To confirm that the T21 paradigm induces free-running circadian rhythms in female Fischer brown Norway rats, the control animals were subjected to the same T21 paradigm and circadian rhythms were continuously measured. Signs of free-running circadian rhythms were present during T21 exposure such as delayed phase of entrainment, elongated period, and decreased activity during the dark phase of the cycle. To our knowledge, this is one of the first characterization of activity rhythms in Fischer brown Norway rats. [ABSTRACT FROM AUTHOR]

Verapamil is the first-line preventive medication for cluster headache, an excruciating disorder with strong circadian features. Whereas second- and third-line preventives include known circadian modulators, such as melatonin, corticosteroids, and lithium, the circadian effects of verapamil are poorly understood. Here, we characterize the circadian features of verapamil using both in vitro and in vivo models. In Per2::LucSV reporter fibroblasts, treatment with verapamil (0.03–10 µM) showed a dose-dependent period shortening of the reporter rhythm which reached a nadir at 1 µM, and altered core clock gene expression at 10 µM. Mouse wheel-running activity with verapamil (1 mg/mL added to the drinking water) also resulted in significant period shortening and activity reduction in both male and female free-running wild-type C57BL6/J mice. The temporal patterns of activity reduction, however, differ between the two sexes. Importantly, piezo sleep recording revealed sexual dimorphism in the effects of verapamil on sleep timing and bout duration, with more pronounced adverse effects in female mice. We also found altered circadian clock gene expression in the cerebellum, hypothalamus, and trigeminal ganglion of verapamil-treated mice. Verapamil did not affect reporter rhythms in ex vivo suprachiasmatic nucleus (SCN) slices from Per2:Luc reporter mice, perhaps due to the exceptionally tight coupling in the SCN. Thus, verapamil affects both peripheral (trigeminal ganglion) and central (hypothalamus and cerebellum) nervous system structures involved in cluster headache pathophysiology, possibly with network effects instead of isolated SCN effects. These studies suggest that verapamil is a circadian modulator in laboratory models at both molecular and behavioral levels, and sex is an important biological variable for cluster headache medications. These observations highlight the circadian system as a potential convergent target for cluster headache medications with different primary mechanisms of action. [ABSTRACT FROM AUTHOR]

Obesity is a global health threat and a risk factor for several metabolic conditions. Though circadian dysfunction has been considered among the multiple causes of obesity, little work has been done to explore the relationship between obesity, circadian dysfunction, and sexual dimorphism. The Neotomodon alstoni mouse is a suitable model for such research. This study employed N. alstoni mice in a chronobiological analysis to determine whether there is circadian desynchronization of relative PER1 and BMAL1 protein levels in the hypothalamus, liver, visceral white adipose tissue, kidney, and heart. It also compared differences between sexes and lean and obese N. alstoni adult mice, by recording behavior and daily circulating serum melatonin as markers of circadian output. We found that obese mice display reduced locomotor activity. Additionally, Cosinor analyses of the relative expression of PER1 and BMAL1 show differences between lean and obese mice in a sex-linked manner. The PER1 24 h rhythm was absent in all tissues of obese males and significant in the tissues of obese females. The BMAL1 24 h rhythm also was significant in most of the tissues tested in lean males, whereas it was significant and shifted the acrophase (peak time of rhythm) in most of the tissues in obese females. Both lean male and female mice showed a rhythmic 24 h pattern of circulating serum melatonin. This daily profile was not only absent in obese mice of both sexes but showed sexual dimorphism. Obese male mice showed lower circulating levels of melatonin compared to lean male mice, but they were higher in obese females compared to lean females. Our results suggest that obesity in N. alstoni is associated with an internal circadian desynchronization in a sex-dependent manner. Overall, this study reinforces the need for further research on the neuroendocrinology of obesity and circadian rhythms using this biological model. [ABSTRACT FROM AUTHOR]

The sleep requirement of humans varies as a function of the country they live in, and their chronotype, gender, ethnicity, physiological state, and lifestyle. An interaction between the circadian clock (process C) and the sleep-wake homeostasis (process S) regulates sleep in humans. The Suprachiasmatic nuclei (SCN) – the master clock, measures the length of the solar day and through appropriate neuroendocrine mechanisms promotes sleep in the night. In this mini-review, we made an attempt to summarize findings of earlier studies dealing with the distribution pattern of chronotypes, sleep quality, and behavioral sleep patterns in human populations. The review is based on 203 relevant papers that we picked up from the databases, such as PubMed, Scopus, and Google Scholar. The review reveals the paucity of information on sleep behavior in humans in densely populated countries, like China and India. In addition, a clear message emerged from the review of the literature, i.e. the studies on the distribution of chronotypes and their problems associated with sleep quality, the behavioral sleep pattern, and diseases are critically limited and are far from complete. We recommend that this is the area that needs to be investigated extensively and intensively. [ABSTRACT FROM AUTHOR]

Social cues are potent non-photic modulators of the circadian clock and play a vital role in resetting the endogenous clock. Several lines of evidence strongly suggest a functional link between olfactory cues and the circadian clock. However, there is a paucity of information on the effects of social interaction with the conspecifics of the opposite sex on the circadian clock. Hence, we studied the effect of social cues of sexually mature naïve opposite sex of the conspecific on the phase resetting of the circadian clock at various circadian times (CT) and molecular changes at the suprachiasmatic nuclei (SCN) and odor responsive structure in the brain of mice. Sexually naïve adult male and female free-running mice (designated as 'runners') were exposed to the conspecifics of the opposite-sex ('strangers') for 30 min at CT3, CT9, CT15, and CT21. Both male and female 'runners' exhibited a phase advance at CT3, delay at CT21, and no response at CT9. However, at CT15 only the male 'runners' exhibited phase advance but not the female 'runners'. Control mice did not elicit any significant phase shifts at all CTs. Social interactions with conspecifics of the opposite-sex up-regulated c-fos/C-FOS, omp in the olfactory bulb, per-1/PER-1 in the SCN, C-FOS, and PER-1 in the piriform cortex of both male and female runners at CT3. However, at CT15 up-regulation of variables only occurred in male but not in female runners. Together, the present investigation has shown the gender difference in circadian clock responses for social cues with conspecific of the opposite-sex in mice. [ABSTRACT FROM AUTHOR]

Zearalenone (ZEA), a mycotoxin, is known to impair reproductive capability by disrupting the synthesis and secretion of testosterone by Leydig cells (LCs), although the mechanism is unknown. Robust rhythmicity of circadian clock and steroidogenic genes were identified in LCs. The aim of this study was to examine whether ZEA significantly attenuated the transcription of core clock genes (Bmal1, Dbp, Per2, and Nr1d1) as well as steroidogenic genes (StAR, Hsd3b2, and Cyp11a1) in mouse testis Leydig cell line (TM3). Western blotting confirmed declines in BMAL1, NR1D1, and StAR protein levels. ZEA also suppressed secreted testosterone levels. In primary LCs, isolated from PER2::LUCIFERASE reporter gene knock in mice, ZEA diminished the amplitude of PER2::LUC expression, and induced a phase shift and period extension. In primary LCs, ZEA also suppressed the expression levels of core clock and steroidogenic genes, reduced protein levels of BMAL1, and decreased testosterone secretion. In vivo expression of core clock and steroidogenic genes were reduced in testes of mice exposed to ZEA for 1 week leading to decreased serum testosterone levels. In summary, data suggest that ZEA may impair testosterone synthesis through attenuation of the circadian clock in LCs culminating in reproductive dysfunction in male mammals. [ABSTRACT FROM AUTHOR]

The role of the serotonin 7 receptor (5-HT7 receptor) subtype in a number of domains has been widely recognized, but its role in the regulation of changes of the circadian rhythm after anesthesia is still unclear. We used intraperitoneal injection of 5-HT7 receptor agonist LP-211 or antagonist SB-269970 in mice to influence the level of 5-HT7 receptor protein in the SCN and to observe the role of this receptor on circadian rhythm changes after isoflurane anesthesia. Our results show the appropriate dose of SB-269970 significantly alleviated the circadian rhythm disorder induced by isoflurane anesthesia, while LP-211 significantly aggravated it after anesthesia, which is different from the phase shift that can be caused by the administration of LP-211 before anesthesia. These findings may indicate the 5-HT7 receptor plays a complex role in the regulation of circadian rhythm after anesthesia. Our findings may provide some positive significance for alleviating circadian rhythm disorder in patients after anesthesia and ultimately promoting rapid postoperative recovery. [ABSTRACT FROM AUTHOR]

Chronic jet lag has deleterious effects on many physiological parameters. Most simulations of chronic jet lag consist of repeated advances only, while real-life conditions may differ. We compared number of transients, activity (α) and rest (ρ), and robustness of rhythm by autocorrelation in male and female AKR mice; before, during, and after simulated chronic jet lag (CJL); and phase angle of entrainment and accuracy before and after CJL, using alternate 9-h advances and delays of the light-dark schedule. Females exhibited no scalloping. Compared to pre-CJL values, α was significantly more in females post-CJL, indicating α decompression. The levels of activity increased during and after CJL, particularly in females, indicating behavioural feedback on the circadian rhythm. Robustness of rhythm (autocorrelation coefficient, and amplitude) was significantly suppressed during CJL in both males and females. Females took more transients than males to re-entrain to the final LD shift at the end of CJL. More transients were needed to re-entrain at the end of CJL, compared to a single shift. The study suggests that animals undergoing CJL incorporating alternating advances and delays are able to avoid α compression associated with jet lag, and also that females are detrimentally affected more than males. Abbreviations: SCN: Suprachiasmatic Nuclei; CJL: Chronic Jet Lag; LD: Light-dark [ABSTRACT FROM AUTHOR]

The main clock in mammals, located in the suprachiasmatic nucleus (SCN) of hypothalamus, not only regulates the daily rhythms in physiological and behavioral activities, but also plays a key role as one of the control nodes in the brain regulating behavioral activity. As such, it induces scale-invariance in the temporal patterns of behavioral activity and of multi-unit neural activity of the SCN network. In particular, the scale-invariant patterns maintain across multiple time scales from 3 minutes to 10 hours, characterized by a scaling exponent around 1. Thus far, no study found the origin of the scale-invariance of the SCN network. Using the method of correlation-dependent balance estimation of diffusion entropy (cBEDE), we found that scale-invariance also exists in the individual neurons of the SCN, and the scale invariance properties are significantly increased when the neurons are coupled in a network of neurons. Improved scale invariance in the single neurons is, therefore, imposed by the emergent network properties of the SCN network. Our findings show that the scale-invariance of the SCN can already be found at the level of the individual neurons and that the application of a scale invariance measure, such as cBEDE, can help in determining the network status of the SCN. [ABSTRACT FROM AUTHOR]

The avian pineal gland is an independent molecular oscillator that receives external light information that regulates the synthesis and secretion of melatonin. Arylalkylamine N-acetyltransferase plays an important role in the pineal gland by controlling the rhythmic production of melatonin. Previous study showed that monochromatic light influences the secretion of melatonin, which is regulated by the molecular circadian clock genes in chick pineal gland. This study was designed to investigate the effect of monochromatic light on the circadian rhythm of levels of cAanat, clock protein (CLOCK and BMAL1), cCreb, and opsins (cOpnp, Pinopsin; cOpn4-1, Melanopsin-1; cOpn4-2, Melanopsin-2) in chick pineal gland. A total of 240 post-hatching day (P) 0 broiler chickens were reared under white (WL), red (RL), green (GL), and blue light (BL) with light (L)-dark (D) cycle of 12L:12D for 14 d. The results show significant circadian rhythms in the expression of cAanat, CLOCK, BMAL1, cCreb, cOpnp, cOpn4-1, and cOpn4-2, but not for cOpnp under RL. Compared with WL, GL increased the level of cAanat mRNA, while RL decreased it. Meanwhile, CLOCK and BMAL1 proteins were expressed at high levels in GL. Furthermore, the peak of the 24 h pattern of cOpnp mRNA in GL was earlier than that of in WL, RL, and BL. These results demonstrated that monochromatic light affects the daily expression of cAanat in the chick pineal gland via the biological clock. GL activates the transcription of cAanat, while RL suppresses the transcription of cAanat. Meanwhile, GL appears to induce the peak of cOpnp mRNA in advance to affect the transmission of light. Thus, monochromatic light regulates cAanat in the chick pineal gland by affecting the levels of clock regulators via entraining the expression of pineal gland opsins. [ABSTRACT FROM AUTHOR]

We investigated in a preliminarily study the circadian rest-activity rhythm of elderly Japanese community-dwellers according to sarcopenia status based upon the 2019 updated classification criteria of the Asian Working Group for Sarcopenia. A total of 30 participants were recruited from a single rehabilitation center in northern Japan between July and November 2019. The rest-activity rhythm of those with and without sarcopenia was assessed for 7 consecutive 24 h spans by wrist actigraphy in free-living condition and gait performance in the clinic. As group phenomena, the circadian activity rhythm of the sarcopenia cohort (N = 11) was of significantly lower amplitude and more fragmented than the non-sarcopenia cohort (N = 19). The nonparametric circadian rest activity (RAR) parameters of intra-daily variability (IV), relative amplitude (RA), most active 10-h span (M10), and the least active 5-h span (L5), but not interdaily stability (IS), of the sarcopenia group, were all significantly worse than those of the non-sarcopenia group. Gait performance for the sarcopenia group correlated strongly with the fragmentation and altered amplitude of the RAR. These preliminary findings motivated future longitudinal investigation both to improve the detection of sarcopenia in community dwelling elderly and to inform novel preventive or rehabilitative strategies. [ABSTRACT FROM AUTHOR]

The glowing light of cinema, which continues to claim supremacy as a collective site for evolving senses of time, has fundamentally changed since its inception, from exclusively projected light to primarily emitted light. Digital, rather than analog projectors, dominate in personal rather than public spheres. The physiological and behavioral effects of those technologies manipulate our biological clocks, creating an entanglement of time-sensing. Similarly, the art of cinema now relies far more upon energy-intensive materials and methods, from equipment to image manufacturing and data flow. This essay takes the twelve-hour clock as a slanted optic to address those profound shifts, choosing a handful of moving-image artists to feature, including Deborah Stratman, Nikolaus Geyrhalter, and Mikael Kristersson, who are attempting to find alternative temporal modes of depicting the hyperobjectiveness of eternity, ecocrises, dystopias, and deep time on screen. [ABSTRACT FROM AUTHOR]

Circadian clock(s) allow an organism to be in synchrony with the surrounding environment and perform daily and seasonal physiological processes, including hibernation, migration, and reproduction. To cope with adverse environmental conditions, organisms have evolved various strategies. Insects undergo diapause, while some higher animals either migrate or hibernate/aestivate during unfavorable environmental conditions. Hibernation is an energy conservation strategy used to cope with adverse environmental conditions. Limited knowledge is available on the physiology of hibernation in non-mammalian vertebrates. Some studies suggest that metabolism is altered during amphibian hibernation, but nothing is known about the circadian clock. In the present study, we investigated daily oscillation of clock genes in the brain and liver of the terai tree frog (Polypedates teraiensis) during two annual phases of life: breeding and hibernation. Adult male terai tree frogs were procured from their natural habitat on the Mizoram University campus (23°N 92°E) during their breeding and hibernation phases. Body mass and testes weight were recorded. Animals were sacrificed at six time points: ZT1, ZT5, ZT9, ZT13, ZT17, and ZT21 (ZT0, zeitgeber time 0, indicates the sunrise time at the respective time of the year; N = 5 frogs per time point). Quantitative real-time polymerase chain reaction (qPCR) was performed for clock genes (Bmal1, Clock, Per2, and Cry2) in the hypothalamus and liver. Our results showed that body and testes weights decreased during hibernation. Further, the hypothalamus retained daily clock gene oscillations during breeding and hibernation. However, the liver lost this daily oscillation during hibernation. The maintained rhythm in hypothalamus in contrast to other hibernating animals might be the result of the fact that these animals hibernate at a higher temperature and might be more alert. As the animals have no food intake during their hibernation season which might be the reason the animals loose their rhythm in liver clock genes. These results suggest that retaining daily clock gene oscillations in the hypothalamic clock could be important for internal time tracking and post-hibernation emergence. [ABSTRACT FROM AUTHOR]

Objectives: The therapeutic value of the antidepressant agomelatine in the aftermath of traumatic experience and early post-reminder has been questioned. Herein, agomelatine, its vehicle or melatonin agonist were administered either acutely 1 h post-stressor or repeatedly (7 days) after early post-reminder in a post-traumatic stress rat model (PSS) using the scent of predator urine. Methods: Behavioural responses, and brain molecular and morphological changes were evaluated after each treatment procedure in PSS-exposed and unexposed rats. Results: When administered immediately after PSS, agomelatine induced a significant reduction of anxiety-like behaviour as assessed in the elevated-plus-maze and acoustic startle response at 8 days post-administration. Concomitantly, agomelatine significantly decreased Per1/Per2 expression in the CA1/CA3 areas, suprachiasmatic nucleus and basolateral amygdala, thereby partially restoring genes expression overregulated by PSS. Agomelatine further significantly increased cell growth and facilitated dendritic growth and arbour in dentate gyrus (DG) granule and apical CA1 cells and upregulated brain-derived neurotrophic factor protein in the DG and cortex III versus vehicle. When administered early post-reminder over 7 days before testing, agomelatine was ineffective on behavioural responses pattern, molecular and morphological changes induced by PSS. Conclusions: These findings suggest that agomelatine may be a potential agent in the acute aftermath of traumatic stress exposure. [ABSTRACT FROM AUTHOR]

Circadian system is comprised by central circadian pacemaker and several peripheral clocks that receive information from the external environment, synchronizing the circadian clocks. It is widely known that physiology is rhythmic and that the rupture of this rhythmicity can generate serious consequences. Circadian clocks, led by suprachiasmatic nucleus (SCN) in the central nervous system, are the responsible for generating this biological rhythmicity. These clocks are affected by external signals such as light (changes between day and night) and feeding rhythms. In this review, the basic principles of the circadian system and current knowledge of biological clocks are addressed, analyzing the relationship between circadian system, food intake, nutrition, and associated metabolic processes. In addition, the consequences occurring when these systems are not well coordinated with each other, such as the development of cardiovascular and metabolic pathologies, will be thoroughly discussed. [ABSTRACT FROM AUTHOR]

To investigate the relationship between light sensing systems in the eye and circadian oscillators in the hypothalamus of subterranean rodents, we studied subterranean Mandarin voles (Lasiopodomys mandarinus) that spend their entire lives under dark conditions with degenerated eyes, and compared oscillatory expression patterns of clock genes in the hypothalamus and eye between Mandarin voles and their aboveground relatives, Brandt's voles (L. brandtii). Individuals of both vole species were kept under a 12-h light/12-h dark condition or continuous dark condition for 4 weeks. In both species, the expressions of most genes showed significant cosine rhythmicity in the hypothalamus but relatively weak rhythmicity in the eye. The number of rhythmic genes in the eye of Mandarin voles increased under the dark condition, but the opposite trend was observed in the eye of Brandt's voles. The expression levels of most clock genes in the hypothalamus of both vole species did not significantly differ between the two conditions, but unlike in Mandarin voles, these expression levels significantly decreased in the eye of Brandt's voles kept under the dark condition. In both vole species, the peak phase of most clock genes exhibited advanced or invariant change in the hypothalamus under the dark condition, and the peak phase of most clock genes showed consistent changes between the eye and hypothalamus of Mandarin voles. However, most clock genes in the eye showed a delayed phase in Brandt's voles kept under the dark condition. In conclusion, the hypothalamus plays an important role in both vole species irrespective of the light condition. However, the expression patterns of clock genes in the eye differed between the vole species, indicating that each species adapted differently to their environments. [ABSTRACT FROM AUTHOR]

Most of the processes that occur in the mind and body follow natural rhythms. Those with a cycle length of about one day are called circadian rhythms. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues. The circadian system is responsible for regulating a variety of physiological and behavioral processes, including feeding behavior and energy metabolism. Studies revealed that the circadian clock system consists primarily of a set of clock genes. Several genes control the biological clock, including BMAL1, CLOCK (positive regulators), CRY1, CRY2, PER1, PER2, and PER3 (negative regulators) as indicators of the peripheral clock. Circadian has increasingly become an important area of medical research, with hundreds of studies pointing to the body's internal clocks as a factor in both health and disease. Thousands of biochemical processes from sleep and wakefulness to DNA repair are scheduled and dictated by these internal clocks. Cancer is an example of health problems where chronotherapy can be used to improve outcomes and deliver a higher quality of care to patients. In this article, we will discuss knowledge about molecular mechanisms of the circadian clock and the role of clocks in physiology and pathophysiology of concerns. [ABSTRACT FROM AUTHOR]

Endogenous glucocorticoids have diverse physiological effects and are important regulators of metabolism, immunity, cardiovascular function, musculoskeletal health and central nervous system activity. Synthetic glucocorticoids have received widespread attention for their potent anti-inflammatory activity and have become an important class of drugs used to augment endogenous glucocorticoid activity for the treatment of a host of chronic inflammatory conditions. Chronic use of synthetic glucocorticoids is associated with a number of adverse effects as a result of the persistent dysregulation of glucocorticoid sensitive pathways. A failure to consider the pronounced circadian rhythmicity of endogenous glucocorticoids can result in either supraphysiological glucocorticoid exposure or severe suppression of endogenous glucocorticoid secretion, and is thought be a causal factor in the incidence of adverse effects during chronic glucocorticoid therapy. Furthermore, given that synthetic glucocorticoids have potent feedback effects on the hypothalamic-pituitary-adrenal (HPA) axis, physiological factors which can give rise to individual variability in HPA axis activity such as sex, age, and disease state might also have substantial implications for therapy. We use a semi-mechanistic mathematical model of the rodent HPA axis to study how putative sex differences and individual variability in HPA axis regulation can influence the effects of long-term synthetic exposure on endogenous glucocorticoid circadian rhythms. Model simulations suggest that for the same drug exposure, simulated females exhibit less endogenous suppression than males considering differences in adrenal sensitivity and negative feedback to the hypothalamus and pituitary. Simulations reveal that homeostatic regulatory variability and chronic stress-induced regulatory adaptations in the HPA axis network can result in substantial differences in the effects of synthetic exposure on the circadian rhythm of endogenous glucocorticoids. In general, our results provide insight into how the dosage and exposure profile of synthetic glucocorticoids could be manipulated in a personalized manner to preserve the circadian dynamics of endogenous glucocorticoids during chronic therapy, thus potentially minimizing the incidence of adverse effects associated with long-term use of glucocorticoids [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) and Asthma patients exhibit exacerbation of symptoms in night hours and early morning. Temporal variability in airway caliber have been reported in past using peak expiratory flow rate which represents large airways caliber, while in COPD and Asthma, smaller airways are particularly affected. We studied circadian variability of airway caliber using Forced Expiratory Volume in the First Second (FEV1) and Mid Expiratory Flow rate. Methods: Male volunteers (18–26 years), having similar daily routine were recruited. Spirometry was performed at 5: 00, 8:00, 11:00, 14:00, 17:00, 20:00 and 23:00 h. Data from 104 subjects was analyzed for diurnal variability parameters viz., amplitude percent mean and standard deviation percent of mean. For circadian rhythm Cosinor curve was fitted and rhythm characteristics in terms of MESOR, Amplitude and Acrophase were determined. Results: Repeated measures ANOVA revealed significant differences in spirometric parameters measured at different time points during the day. In general, spirometric parameters follow a sinusoidal pattern and exhibit minimum values during night hours and maximum values during day time. FEV1 Cosinor rhythm was significant in 31% of subjects (Zero amplitude test). The distribution of acrophase revealed interindividual differences in chronophenotypes. Variability was minimum for FEV1% and maximum for FEF75 suggesting dynamic interplay of airway geometry and neuro-chemical influences. Conclusion: The presence of different chronophenotypes in normal subjects suggests that the nocturnal asthma may also be a different phenotype. Availability of portable spirometers and home monitoring thus may be required for ascertaining chronophenotype and tailoring chronotherapeutic interventions. [ABSTRACT FROM AUTHOR]

Daily rhythms in light exposure influence the expression of behavior by entraining circadian rhythms and through its acute effects on behavior (i.e., masking). Importantly, these effects of light are dependent on the temporal niche of the organism; for diurnal organisms, light increases activity, whereas for nocturnal organisms, the opposite is true. Here we examined the functional and morphological differences between diurnal and nocturnal rodents in retinorecipient brain regions using Nile grass rats (Arvicanthis niloticus) and Sprague-Dawley (SD) rats (Rattus norvegicus), respectively. We established the presence of circadian rhythmicity in cFOS activation in retinorecipient brain regions in nocturnal and diurnal rodents housed in constant dark conditions to highlight different patterns between the temporal niches. We then assessed masking effects by comparing cFOS activation in constant darkness (DD) to that in a 12:12 light/dark (LD) cycle, confirming light responsiveness of these regions during times when masking occurs in nature. The intergeniculate leaflet (IGL) and olivary pretectal nucleus (OPN) exhibited significant variation among time points in DD of both species, but their expression profiles were not identical, as SD rats had very low expression levels for most timepoints. Light presentation in LD conditions induced clear rhythms in the IGL of SD rats but eliminated them in grass rats. Additionally, grass rats were the only species to demonstrate daily rhythms in LD for the habenula and showed a strong response to light in the superior colliculus. Structurally, we also analyzed the volumes of the visual brain regions using anatomical MRI, and we observed a significant increase in the relative size of several visual regions within diurnal grass rats, including the lateral geniculate nucleus, superior colliculus, and optic tract. Altogether, our results suggest that diurnal grass rats devote greater proportions of brain volume to visual regions than nocturnal rodents, and cFOS activation in these brain regions is dependent on temporal niche and lighting conditions. [ABSTRACT FROM AUTHOR]

Animals have an endogenous circadian clock that temporally regulates 24 hour (h) oscillations in behavior and physiology. This highly conserved mechanism consists of two positive regulators, Bmal and Clock, and two negative regulators, Cry and Per, that run with a 24-h cycle that synchronizes itself with environmental changes in light, food, and temperature. We examined the circadian clock in Chinook salmon (Oncorhynchus tshawytscha), a non-model organism in which the function of the clock has not been studied. Recent studies indicate that clock genes in Chinook salmon play a role in its evolution of local adaptation, possibly by influencing migration timing. We designed real-time quantitative PCR (RT-qPCR) assays to quantify the transcription of components of the clock system, and validated these for PCR efficiency and specificity in detecting Chinook target genes. Chinook salmon tissue samples were collected in 3-h intervals, over the course of 24 h, from five different organs. Our data indicate that the circadian clock functions differently in each of these tissues. In the liver, positive and negative regulators exhibit anti-phasic peaking in the evening and morning, respectively. However, in the heart, these same regulators peak and trough with a different timing, indicating that the liver and heart are not synchronous. The digestive tract displays yet another difference: simultaneous phases in the expression of positive and negative clock regulators, and we do not observe significant rhythms in clock gene expression in the retina. Our data show that there is a functional clock in Chinook salmon tissues, but that this clock behaves in a tissue-specific manner, regardless of the whole animal being exposed to the same environmental cues. These results highlight the adaptive role of the clock in Chinook salmon and that it may have different positive and negative effects depending on tissue function. [ABSTRACT FROM AUTHOR]

Human postmortem studies as well as experimental animal studies indicate profound changes in neuropeptide expression in the suprachiasmatic nucleus (SCN) in several pathological conditions including hypertension. In addition, animal experimental observations show that the SCN peptides, vasopressin (AVP) and vasoactive intestinal peptide (VIP) are essential for adequate rhythmicity. These data prompted us to investigate whether changes in these neuronal populations could be the cause or consequence of hypertension. Changes in blood pressure and levels of neuropeptide expression in the SCN were determined during development of hypertension in spontaneously hypertensive rats (SHR), in 2K1C reno-vascular induced hypertensive animals and their respective controls. During the pre-hypertensive stage (5 weeks of age), the VIP and AVP content was higher and the somatostatin (SOM) content was lower in the SHR SCN. At the onset of hypertension (12 weeks of age), when blood pressure levels had just reached about 140 mmHg, AVP and SOM content in the SCN was not different anymore in SHRs compared to control, but VIP was still higher. After 16 weeks, the AVP content was decreased, but SOM was increased and the overall level of VIP in the SCN was still higher in SHRs compared to controls. None of the aforementioned changes in the SCN was observed after induction of hypertension in the 2K1C model. However, while VIP was increased in the NTS projecting medial region of the SCN in SHR animals only after the establishment of hypertension, VIP was decreased in the same region in the 2K1C induced hypertensive rats. Consequently, the present findings confirm previous studies in human and rat indicating that changes in the SCN are strongly associated with the development of hypertension. In addition, the changes in peptide content in the 2K1C animals indicate that the SCN is also able to respond to increases in blood pressure. [ABSTRACT FROM AUTHOR]

The ability to predict and adjust physiology and behavior to recurring environmental events has been necessary for survival on Earth. Recent discoveries revealed that not only changes in irradiance but also light spectral composition can stimulate the suprachiasmatic nucleus (SCN), ensuring the body's synchronization to the environment. Therefore, using a lighting system that modulates spectral composition during the day using combined red-green-blue (RGB) lights, we evaluated the effect of variations in light spectral composition on the rest-activity rhythm of rodents. Male Wistar rats (n = 17) were gestated and raised under different lighting conditions and exposed to a long photoperiod (16 h light: 8 h dark). The difference between groups was the presence of variations in light spectral composition during the day (RGB-v) to simulate daily changes in natural light, or not (RGB-f). After weaning, spontaneous motor activity was recorded continuously for rhythm evaluation. Our results indicated that animals under RGB-v did not present a reactive peak of activity after the beginning of the light phase, suggesting that this group successfully detected the variations aimed at mimicking daily alterations of natural light. Furthermore, RGB-v animals exhibited an earlier activity acrophase in comparison to animals under RGB-f (RGB-v = 12:16 – "hh:mm", RGB-f = 13:02; p < 0.001), which might have been due to the capability to predict the beginning of the dark phase when exposed to variations in light spectrum. However, this earlier activity acrophase can be also explained by the blue-light peak that occurred in RGB-v. The spectral and waveform analysis of daily patterns of motor activity revealed that rats in the RGB-v group were better entrained to a circadian rhythm throughout the experiment. RGB-v showed higher interdaily stability (IS) values (29.75 ± 6.5, n = 9) than did RGB-f (t(15) = 2.74, p = 0.015). Besides, the highest power content (PC) on the first harmonic (circadian) was reached earlier in the RGB-v group. The circadianity index (CI) of the whole period was higher in the RGB-v group (t(15) = 3.47, p = 0.003). Thus, we could consider that locomotor activity rhythm was entrained to the light-dark cycle in the RGB-v rats earlier compared to the RGB-f rats. Our results provide additional evidence for the effect of variations in light spectral composition on the rest-activity pattern of nocturnal rodents. This suggests that these animals might predict the arrival of the activity phase by its advanced acrophase when exposed to RGB-v, demonstrating a better synchronization to a 24-h rhythm. [ABSTRACT FROM AUTHOR]

Sleep-wake cycle is the predominant example of circadian rhythms. Melatonin is commonly used to treat insomnia and in additional neurodevelopmental disorders in which sleep disturbance is frequent. In mammals, melatonin receptors are present in the membrane and cell nucleus of many tissues and systems where it exhibits various actions, including the regulation of circadian rhythms. The rhythmic pattern of melatonin secretion is imperative since it endows with vital information to the organism concerning time, which permits for alterations of a number of physiological functions consistent with daily and seasonal variations. Melatonin as well has sleep promoting effects demonstrated in changes in brain activation patterns and tiredness generation. The SCN's (suprachiasmatic nuclei) function and melatonin production capability turns down with age consequently depriving the brain from an important time cue and sleep regulator. [ABSTRACT FROM AUTHOR]

Currently, one of the most disputed hypotheses regarding breast cancer (BC) development is exposure to short wavelength artificial light at night (ALAN) as multiple studies suggest a possible link between them. This link is suggested to be mediated by nocturnal melatonin suppression that plays an integral role in circadian regulations including cell division. The objective of the research was to evaluate effects of 1 × 30 min/midnight ALAN (134 µ Wcm−2, 460 nm) with or without nocturnal melatonin supplement on tumor development and epigenetic responses in 4T1 tumor-bearing BALB/c mice. Mice were monitored for body mass (Wb) and tumor volume for 3 weeks and thereafter urine samples were collected at regular intervals for determining daily rhythms of 6-sulfatoxymelatonin (6-SMT). Finally, mice were sacrificed and the tumor, lungs, liver, and spleen were excised for analyzing the total activity of DNA methyltransferases (DNMT) and global DNA methylation (GDM) levels. Mice exposed to ALAN significantly reduced 6-SMT levels and increased Wb, tumor volume, and lung metastasis compared with controls. These effects were diminished by melatonin. The DNMT activity and GDM levels showed tissue-specific response. The enzymatic activity and GDM levels were lower in tumor and liver and higher in spleen and lungs under ALAN compared with controls. Our results suggest that ALAN disrupts the melatonin rhythm and potentially leading to increased BC burden by affecting DNMT activity and GDM levels. These data may also be applicable to early detection and management of BC by monitoring melatonin and GDM levels as early biomarker of ALAN circadian disruption. [ABSTRACT FROM AUTHOR]