The circadian clock in choroid plexus (ChP) controls processes involved in its physiological functions, but the signals that synchronize the clock have been sparsely studied. We found that the ChP clock in the fourthventricle (4V) is more robust than that in the lateral ventricle (LV) and investigated whether both clocks use information about mealtime as a signal to synchronize with the current activity state. Exposure of mPer2Luc mice to a 10-day reverse restricted feeding (rRF) protocol, in which food was provided for 6 h during daytime, advanced the phase of the ChP clock in 4V and LV, as evidenced by shifted (1) PER2-driven bioluminescence rhythms of ChP explants ex vivo and (2) daily profiles in clock gene expression in both ChP tissues in vivo. In contrast, clocks in other brain regions (DMH, ARC, LHb) of the same mice did not shift. The 4V ChP responded more strongly than the LV ChP to rRF by modulating the expression of genes to ensure a decrease in resistance to cerebrospinal fluid drainage and increase the secretory capacity of ChP cells. Mechanistically, rRF affects the ChP clock through food-induced increases in insulin, glucose and temperature levels, as in vitro all three signals significantly shifted the clocks in both ChP tissues, similar to rRF. The effect of glucose was partially blocked by OSMI-1, suggesting involvement of O-linked N-acetylglucosamine posttranslational modification. We identified mechanisms that can signal to the brain the time of feeding and the associated activity state via resetting of the ChP clock.

• Klíčová slova
• Choroid plexus, Circadian clock, Glucose, Insulin, O-GlcNAc, Restricted feeding, Temperature,
• MeSH
• cirkadiánní hodiny * fyziologie   genetika   MeSH
• cirkadiánní proteiny Period metabolismus   genetika   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• plexus chorioideus * metabolismus   fyziologie   MeSH
• regulace genové exprese MeSH
• stravovací zvyklosti * fyziologie   MeSH
• ventriculi laterales metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cirkadiánní proteiny Period MeSH
• Per2 protein, mouse MeSH Prohlížeč

AIM: Exposure to light at night and meal time misaligned with the light/dark (LD) cycle-typical features of daily life in modern 24/7 society-are associated with negative effects on health. To understand the mechanism, we developed a novel protocol of complex chronodisruption (CD) in which we exposed female rats to four weekly cycles consisting of 5-day intervals of constant light and 2-day intervals of food access restricted to the light phase of the 12:12 LD cycle. METHODS: We examined the effects of CD on behavior, estrous cycle, sleep patterns, glucose homeostasis and profiles of clock- and metabolism-related gene expression (using RT qPCR) and liver metabolome and lipidome (using untargeted metabolomic and lipidomic profiling). RESULTS: CD attenuated the rhythmic output of the central clock in the suprachiasmatic nucleus via Prok2 signaling, thereby disrupting locomotor activity, the estrous cycle, sleep patterns, and mutual phase relationship between the central and peripheral clocks. In the periphery, CD abolished Per1,2 expression rhythms in peripheral tissues (liver, pancreas, colon) and worsened glucose homeostasis. In the liver, it impaired the expression of NAD+, lipid, and cholesterol metabolism genes and abolished most of the high-amplitude rhythms of lipids and polar metabolites. Interestingly, CD abolished the circadian rhythm of Cpt1a expression and increased the levels of long-chain acylcarnitines (ACar 18:2, ACar 16:0), indicating enhanced fatty acid oxidation in mitochondria. CONCLUSION: Our data show the widespread effects of CD on metabolism and point to ACars as biomarkers for CD due to misaligned sleep and feeding patterns.

• Klíčová slova
• acylcarnitine, chronodisruption, clock, female, glucose homeostasis, liver, metabolome, pancreas, rat, sleep, suprachiasmatic nucleus,
• MeSH
• cirkadiánní hodiny * fyziologie   MeSH
• cirkadiánní rytmus * fyziologie   MeSH
• fotoperioda MeSH
• játra * metabolismus   MeSH
• karnitin * analogy a deriváty   metabolismus   MeSH
• krysa rodu Rattus MeSH
• metabolom * fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acylcarnitine MeSH Prohlížeč
• karnitin * MeSH

The lifestyle of human society is drifting apart from the natural environmental cycles that have influenced it since its inception. These cycles were fundamental in structuring the daily lives of people in the pre-industrial era, whether they were seasonal or daily. Factors that disrupt the regularity of human behaviour and its alignment with solar cycles, such as late night activities accompanied with food intake, greatly disturb the internal temporal organization in the body. This is believed to contribute to the rise of the so-called diseases of civilization. In this review, we discuss the connection between misalignment in daily (circadian) regulation and its impact on health, with a focus on cardiovascular and metabolic disorders. Our aim is to review selected relevant research findings from laboratory and human studies to assess the extent of evidence for causality between circadian clock disruption and pathology. Keywords: Circadian clock, Chronodisruption, Metabolism, Cardiovascular disorders, Spontaneously hypertensive rat, Human, Social jetlag, Chronotype.

• MeSH
• chronobiologické poruchy patofyziologie   metabolismus   komplikace   MeSH
• cirkadiánní hodiny fyziologie   MeSH
• cirkadiánní rytmus * fyziologie   MeSH
• kardiovaskulární nemoci * metabolismus   etiologie   epidemiologie   patofyziologie   MeSH
• lidé MeSH
• metabolické nemoci * metabolismus   epidemiologie   patofyziologie   etiologie   MeSH
• modely nemocí na zvířatech MeSH
• rizikové faktory MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The activity of the immune system is controlled by circadian clocks present in different immune cells. The brain-resident subtype of immune cells, microglia, exhibits a wide range of functional phenotypes depending on the signaling molecules in their microenvironment. The exact role of microglia in the hypothalamic suprachiasmatic nuclei (SCN), the central circadian clock, has not been known. Therefore, the aim of this study was to determine (1) whether microenvironment-induced changes in microglial polarization affect circadian clocks in these cells and (2) whether the presence of microglia contributes to SCN clock function. Microglial and SCN clocks were monitored using PER2-driven bioluminescence rhythms at the tissue and single-cell levels. We found that polarization of resting microglia to a pro-inflammatory (M1) or anti-inflammatory (M2) state significantly altered the period and amplitude of their molecular circadian clock; importantly, the parameters changed plastically with the repolarization of microglia. This effect was reflected in specific modulations of the expression profiles of individual clock genes in the polarized microglia. Depletion of microglia significantly reduced the amplitude of the SCN clock, and co-cultivation of the SCN explants with M2-polarized microglia specifically improved the amplitude of the SCN clock. These results demonstrate that the presence of M2-polarized microglia has beneficial effects on SCN clock function. Our results provide new insight into the mutual interaction between immune and circadian systems in the brain.

• Klíčová slova
• Circadian clock, Microglia, PLX3397, Polarization, Suprachiasmatic nuclei, mPER2Luc mouse,
• MeSH
• cirkadiánní hodiny * genetika   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• mikroglie MeSH
• mozek MeSH
• myši MeSH
• nucleus suprachiasmaticus metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Misaligned feeding may lead to pancreatic insufficiency, however, whether and how it affects circadian clock in the exocrine pancreas is not known. We exposed rats to a reversed restricted feeding regimen (rRF) for 10 or 20 days and analyzed locomotor activity, daily profiles of hormone levels (insulin, glucagon, and corticosterone) in plasma, and clock gene expression in the liver and endocrine and exocrine pancreas. In addition, we monitored responses of the exocrine pancreatic clock in organotypic explants of mPer2Luc mice in real time to acetylcholine, insulin, and glucocorticoids. rRF phase-reversed the clock in the endocrine pancreas, similar to the clock in the liver, but completely abolished clock gene rhythmicity and significantly downregulated the expression of Cpb1 and Cel in the exocrine pancreas. rRF desynchronized the rhythms of plasma insulin and corticosterone. Daily profiles of their receptor expression differed in the two parts of the pancreas and responded differently to rRF. Additionally, the pancreatic exocrine clock responded differently to treatments with insulin and the glucocorticoid analog dexamethasone in vitro. Mathematical simulation confirmed that the long-term misalignment between these two hormonal signals, as occurred under rRF, may lead to dampening of the exocrine pancreatic clock. In summary, our data suggest that misaligned meals impair the clock in the exocrine part of the pancreas by uncoupling insulin and corticosterone rhythms. These findings suggest a new mechanism by which adverse dietary habits, often associated with shift work in humans, may impair the clock in the exocrine pancreas and potentially contribute to exocrine pancreatic insufficiency.

• Klíčová slova
• Circadian clock, Dexamethasone, Insulin, Misaligned feeding, Pancreas, mPer2Luc mouse,
• MeSH
• cirkadiánní hodiny * fyziologie   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• glukokortikoidy MeSH
• inzulin metabolismus   MeSH
• kortikosteron metabolismus   farmakologie   MeSH
• krysa rodu Rattus MeSH
• myši MeSH
• pankreas exokrinní * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glukokortikoidy MeSH
• inzulin MeSH
• kortikosteron MeSH

Abandoning daylight saving time in Europe raises the topical issue of proper setting of yearlong social time, which needs mapping of various socio-demographic factors, including chronotype, in specific geographic regions. This study represents the first detailed large scale chronotyping in the Czech Republic based on data collected in the complex panel socio-demographic survey in households (total 8760 respondents) and the socio-physiological survey, in which chronotyped participants also provided blood samples (n = 1107). Chronotype assessment based on sleep phase (MCTQ questions and/or time-use diary) correlated with a self-assessed interval of best alertness. The mean chronotype of the Czech population defined as mid sleep phase (MSFsc) was 3.13 ± 0.02 h. Chronotype exhibited significant east-to-westward, north-to-southward, and settlement size-dependent gradients and was associated with age, sex, partnership, and time spent outdoors as previously demonstrated. Moreover, for subjects younger than 40 years, childcare was highly associated with earlier chronotype, while dog care was associated with later chronotype. Body mass index correlated with later chronotype in women whose extreme chronotype was also associated with lower plasma levels of protective HDL cholesterol. Based on the chronotype prevalence the results favour yearlong Standard Time as the best choice for this geographic region.

• MeSH
• časové faktory MeSH
• chronobiologie (obor) statistika a číselné údaje   MeSH
• cirkadiánní hodiny fyziologie   MeSH
• demografie statistika a číselné údaje   MeSH
• dítě MeSH
• dospělí MeSH
• fotoperioda * MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• průzkumy a dotazníky statistika a číselné údaje   MeSH
• sexuální faktory MeSH
• spánek fyziologie   MeSH
• věkové faktory MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

KEY POINTS: In mammals, the mother-offspring interaction is essential for health later in adulthood. The impact of altered timing and quality of maternal care on the offspring's circadian system was assessed using a cross-strain fostering approach. Better maternal care facilitated the development of amplitudes of Bmal1 clock gene expression in the central clock, as well as the clock-driven activity/rest rhythm, and also its entrainment to the external light/dark cycle. Worse maternal care impaired entrainment of the central clock parameters in the Wistar rat during the early developmental stages. Better maternal care remedied the dampened amplitudes of the colonic clock, as well as cardiovascular functions. The results provide compelling evidence that the circadian phenotype of a foster mother may affect the pathological symptoms of the offspring, even if they are genetically programmed. ABSTRACT: In mammals, the mother-offspring interaction is essential for health later in adulthood. Maternal care is determined by the circadian phenotype of the mother. The impact of altered timing and quality of maternal care on the circadian system was assessed using a cross-strain fostering approach, with 'abnormal' (i.e. circadian misaligned) care being represented by spontaneously hypertensive rats (SHR) and 'normal' care by Wistar rats. The SHR mothers worsened synchrony of the central clock in the suprachiasmatic nuclei with the light/dark cycle in Wistar rat pups, although this effect disappeared after weaning. The maternal care provided by Wistar rat mothers to SHR pups facilitated the development of amplitudes of the Bmal1 expression rhythm in the suprachiasmatic nuclei of the hypothalamus, as well as the clock-driven activity/rest rhythm and its entrainment to the external light/dark cycle. The peripheral clocks in the liver and colon responded robustly to cross-strain fostering; the circadian phenotype of the Wistar rat foster mother remedied the dampened amplitudes of the colonic clock in SHR pups and improved their cardiovascular functions. In general, the more intensive maternal care of the Wistar rat mothers improved most of the parameters of the abnormal SHR circadian phenotype in adulthood; conversely, the less frequent maternal care of the SHR mothers worsened these parameters in the Wistar rat during the early developmental stages. Altogether, our data provide compelling evidence that the circadian phenotype of a foster mother may positively and negatively affect the regulatory mechanisms of various physiological parameters, even if the pathological symptoms are genetically programmed.

• Klíčová slova
• circadian clock, colon, development, heart rate, liver, locomotor activity, maternal care, suprachiasmatic nucleus,
• MeSH
• chování zvířat fyziologie   MeSH
• cirkadiánní hodiny fyziologie   MeSH
• druhová specificita MeSH
• fenotyp MeSH
• mateřské chování fyziologie   MeSH
• novorozená zvířata MeSH
• nucleus suprachiasmaticus fyziologie   MeSH
• potkani inbrední SHR MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The McGill-R-Thy1-APP transgenic rat is an animal model of the familial form of Alzheimer's disease (AD). This model mirrors several neuropathological hallmarks of the disease, including the accumulation of beta-amyloid and the formation of amyloid plaques (in homozygous animals only), neuroinflammation and the gradual deterioration of cognitive functions even prior to plaque formation, although it lacks the tauopathy observed in human victims of AD. The goal of the present study was a thorough characterization of the homozygous model with emphasis on its face validity in several domains of behavior known to be affected in AD patients, including cognitive functions, motor coordination, emotionality, sociability, and circadian activity patterns. On the behavioral level, we found normal locomotor activity in spontaneous exploration, but problems with balance and gait coordination, increased anxiety and severely impaired spatial cognition in 4-7 month old homozygous animals. The profile of social behavior and ultrasonic communication was altered in the McGill rats, without a general social withdrawal. McGill rats also exhibited changes in circadian profile, with a shorter free-running period and increased total activity during the subjective night, without signs of sleep disturbances during the inactive phase. Expression of circadian clock gene Bmal1 was found to be increased in the parietal cortex and cerebellum, while Nr1d1 expression was not changed. The clock-controlled gene Prok2 expression was found to be elevated in the parietal cortex and hippocampus, which might have contributed to the observed changes in circadian phenotype. We conclude that the phenotype in the McGill rat model is not restricted to the cognitive domain, but also includes gait problems, changes in emotionality, social behavior, and circadian profiles. Our findings show that the model should be useful for the development of new therapeutic approaches targeting not only memory decline but also other symptoms decreasing the quality of life of AD patients.

• Klíčová slova
• Alzheimer's disease, amyloid precursor protein, circadian system, cognition, rat, social behavior, transgenic,
• Publikační typ
• časopisecké články MeSH

The functional state of the circadian system of spontaneously hypertensive rats (SHR) differs in several characteristics from the functional state of normotensive Wistar rats. Some of these changes might be due to the compromised ability of the central pacemaker to entrain the peripheral clocks. Daily body temperature cycles represent one of the important cues responsible for the integrity of the circadian system, because these cycles are driven by the central pacemaker and are able to entrain the peripheral clocks. This study tested the hypothesis that the aberrant peripheral clock entrainment of SHR results from a compromised peripheral clock sensitivity to the daily temperature cycle resetting. Using cultured Wistar rat and SHR fibroblasts transfected with the circadian luminescence reporter Bmal1-dLuc, we demonstrated that two consecutive square-wave temperature cycles with amplitudes of 2.5 °C are necessary and sufficient to restart the dampened oscillations and entrain the circadian clocks in both Wistar rat and SHR fibroblasts. We also generated a phase response curve to temperature cycles for fibroblasts of both rat strains. Although some of the data suggested a slight resistance of SHR fibroblasts to temperature entrainment, we concluded that the overall effect it too weak to be responsible for the differences between the SHR and Wistar in vivo circadian phenotype.

• MeSH
• cirkadiánní hodiny MeSH
• cirkadiánní rytmus * MeSH
• fibroblasty fyziologie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• potkani inbrední SHR fyziologie   MeSH
• potkani Wistar MeSH
• teplota MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The mammalian timekeeping system generates circadian oscillations that rhythmically drive various functions in the body, including metabolic processes. In the liver, circadian clocks may respond both to actual feeding conditions and to the metabolic state. The temporal restriction of food availability to improper times of day (restricted feeding, RF) leads to the development of food anticipatory activity (FAA) and resets the hepatic clock accordingly. The aim of this study was to assess this response in a rat strain exhibiting complex pathophysiological symptoms involving spontaneous hypertension, an abnormal metabolic state and changes in the circadian system, i.e., in spontaneously hypertensive rats (SHR). The results revealed that SHR were more sensitive to RF compared with control rats, developing earlier and more pronounced FAA. Whereas in control rats, the RF only redistributed the activity profiles into two bouts (one corresponding to FAA and the other corresponding to the dark phase), in SHR the RF completely phase-advanced the locomotor activity according to the time of food presentation. The higher behavioral sensitivity to RF was correlated with larger phase advances of the hepatic clock in response to RF in SHR. Moreover, in contrast to the controls, RF did not suppress the amplitude of the hepatic clock oscillation in SHR. In the colon, no significant differences in response to RF between the two rat strains were detected. The results suggested the possible involvement of the Bmal2 gene in the higher sensitivity of the hepatic clock to RF in SHR because, in contrast to the Wistar rats, the rhythm of Bmal2 expression was advanced similarly to that of Bmal1 under RF. Altogether, the data demonstrate a higher behavioral and circadian responsiveness to RF in the rat strain with a cardiovascular and metabolic pathology and suggest a likely functional role for the Bmal2 gene within the circadian clock.

• MeSH
• cirkadiánní hodiny genetika   fyziologie   MeSH
• cirkadiánní rytmus genetika   fyziologie   MeSH
• exprese genu genetika   MeSH
• játra metabolismus   fyziologie   MeSH
• kolon metabolismus   fyziologie   MeSH
• krysa rodu Rattus MeSH
• pohybová aktivita genetika   fyziologie   MeSH
• potkani inbrední SHR MeSH
• potkani Wistar MeSH
• potraviny MeSH
• proteiny CLOCK genetika   metabolismus   MeSH
• stravovací zvyklosti fyziologie   MeSH
• transkripční faktory ARNTL genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Arntl2 protein, rat MeSH Prohlížeč
• proteiny CLOCK MeSH
• transkripční faktory ARNTL MeSH