Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be elucidated. The aim of our study was to [1] identify rhythmically controlled cellular processes in the mouse ChP and [2] assess the role and nature of signals derived from the master clock in the suprachiasmatic nuclei (SCN) that control ChP rhythms. To accomplish this goal, we used various mouse models (WT, mPer2Luc, ChP-specific Bmal1 knockout) and combined multiple experimental approaches, including surgical lesion of the SCN (SCNx), time-resolved transcriptomics, and single cell luminescence microscopy. In ChP of control (Ctrl) mice collected every 4 h over 2 circadian cycles in darkness, we found that the ChP clock regulates many processes, including the cerebrospinal fluid circadian secretome, precisely times endoplasmic reticulum stress response, and controls genes involved in neurodegenerative diseases (Alzheimer's disease, Huntington's disease, and frontotemporal dementia). In ChP of SCNx mice, the rhythmicity detected in vivo and ex vivo was severely dampened to a comparable extent as in mice with ChP-specific Bmal1 knockout, and the dampened cellular rhythms were restored by daily injections of dexamethasone in mice. Our data demonstrate that the ChP clock controls tissue-specific gene expression and is strongly dependent on the presence of a functional connection with the SCN. The results may contribute to the search for a novel link between ChP clock disruption and impaired brain health.

• MeSH
• cirkadiánní hodiny * fyziologie   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• nucleus suprachiasmaticus * metabolismus   fyziologie   MeSH
• plexus chorioideus * metabolismus   fyziologie   MeSH
• transkripční faktory ARNTL metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The physiological function of the pancreas is controlled by the circadian clock. The aim of this study was to determine whether aging-induced changes in glucose homeostasis affect properties of the circadian clock in the pancreas and/or its sensitivity to disturbances in environmental lighting conditions. mPer2Luc mice aged 24-26 months developed hyperinsulinemic hypoglycaemia, which was likely due to the Pclo-mediated insulin hyper-secretion and Slc2a2-mediated glucose transport impairment in the pancreas, and due to the alterations in Pp1r3c-related glycogen storage and Sgk1-related glucose transport in the liver. In the pancreatic tissue, aging affected clock gene expression only marginally, it upregulated Bmal1 and downregulated Clock expression. Whereas aging significantly impaired the circadian clock in lung explants, which were used as a control tissue, the properties of the pancreatic clock in vitro were not affected. The data suggest a non-circadian role of Bmal1 in changes of pancreatic function that occur during aging. Additionally, the pancreatic clock was more sensitive to exposure of animals to constant light conditions. These findings provide an explanation for the previously demonstrated relationship between disturbances in the circadian system and disordered glucose homeostasis, including diabetes mellitus type 2, in subjects exposed to long-term shift work.

• MeSH
• cirkadiánní hodiny * účinky záření   MeSH
• cirkadiánní proteiny Period metabolismus   MeSH
• glukosa metabolismus   MeSH
• homeostáza * MeSH
• játra metabolismus   MeSH
• kolon metabolismus   MeSH
• myši MeSH
• orgánová specificita genetika   MeSH
• pankreas metabolismus   účinky záření   MeSH
• proteiny CLOCK genetika   metabolismus   MeSH
• regulace genové exprese účinky záření   MeSH
• stárnutí metabolismus   MeSH
• světlo MeSH
• transkripční faktory ARNTL genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIM: The reactivity of the circadian clock in the suprachiasmatic nuclei (SCN) to stressful stimuli has been controversial but most studies have confirmed the resilience of the SCN to stress. We tested the hypothesis that during a critical period shortly after birth, the developing SCN clock is affected by glucocorticoids. METHODS: Mothers of 2 rat strains with different sensitivities to stress, that is Wistar rats and spontaneously hypertensive rats (SHR), and their pups were exposed to stressful stimuli every day from delivery, and clock gene expression profiles were detected in the 4-day-old pups' SCN. Levels of glucocorticoids in plasma were measured by LC-MS/MS. The glucocorticoid receptors antagonist mifepristone was administered to pups to block the effect of the glucocorticoids. RESULTS: The glucocorticoid receptors were detected at the mRNA and protein levels in the SCN of 4-day-old pups. The exposure of mothers to stressful stimuli elevated their plasma glucocorticoid levels. In Wistar rat pups, combination of daily maternal stress with their manipulation increased the plasma glucocorticoid levels and shifted the Bmal1 rhythm in the SCN which was completely blocked by mifepristone. In contrast, in SHR pups, maternal stress on its own caused phase shift of the Bmal1 expression rhythm in the SCN but the effect was mediated via glucocorticoid-independent mechanism. The Per1 and Per2 expression profiles remained phase-locked to the light/dark cycle. CONCLUSION: The results demonstrate that the SCN is sensitive to stressful stimuli early after birth in pups maintained under light/dark conditions and the effect is mediated via glucocorticoid-dependent pathways.

• MeSH
• antagonisté hormonů farmakologie   MeSH
• cirkadiánní hodiny * účinky léků   genetika   MeSH
• druhová specificita MeSH
• fotoperioda MeSH
• glukokortikoidy krev   MeSH
• laktace MeSH
• matka - expozice noxám MeSH
• mifepriston farmakologie   MeSH
• novorozená zvířata MeSH
• nucleus suprachiasmaticus účinky léků   metabolismus   patofyziologie   MeSH
• potkani inbrední SHR MeSH
• potkani Wistar MeSH
• psychický stres genetika   metabolismus   patofyziologie   MeSH
• receptory glukokortikoidů antagonisté a inhibitory   metabolismus   MeSH
• transkripční faktory ARNTL genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

The mammalian circadian system develops gradually during ontogenesis, and after birth, the system is already set to a phase of the mothers. The role of maternal melatonin in the entrainment of fetal circadian clocks has been suggested, but direct evidence is lacking. In our study, intact or pinealectomized pregnant rats were exposed to constant light (LL) throughout pregnancy to suppress the endogenous melatonin and behavioral rhythms. During the last 5 days of gestation, the rats were injected with melatonin or vehicle or were left untreated. After delivery, daily expression profiles of c-fos and Avp in the suprachiasmatic nuclei (SCN), and Per1, Per2, Rev-erbα, and Bmal1 in the liver were measured in 1-day-old pups. Due to the LL exposure, no gene expression rhythms were detected in the SCN of untreated pregnant rats or in the SCN and liver of the pups. The administration of melatonin to pregnant rats entrained the pups' gene expression profiles in the SCN, but not in the liver. Melatonin did not affect the maternal behavior during pregnancy. Vehicle injections also synchronized the gene expression in the SCN but not in the liver. Melatonin and vehicle entrained the gene expression profiles to different phases, demonstrating that the effect of melatonin was apparently not due to the treatment procedure per se. The data demonstrate that in pregnant rats with suppressed endogenous melatonin levels, pharmacological doses of melatonin affect the fetal clock in the SCN but not in the liver.

• MeSH
• arginin vasopresin metabolismus   MeSH
• cirkadiánní hodiny fyziologie   MeSH
• cirkadiánní proteiny Period metabolismus   MeSH
• jaderné receptory - podrodina 1, skupina D, člen 1 metabolismus   MeSH
• játra embryologie   fyziologie   MeSH
• kortikosteron krev   MeSH
• krysa rodu rattus MeSH
• mateřské chování fyziologie   MeSH
• melatonin metabolismus   MeSH
• novorozená zvířata MeSH
• nucleus suprachiasmaticus embryologie   fyziologie   MeSH
• pohybová aktivita fyziologie   MeSH
• potkani Wistar MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• světlo MeSH
• transkripční faktory ARNTL metabolismus   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Under physiological conditions the mammalian circadian system is synchronized to a cyclic environment. The central oscillator in the suprachiasmatic nuclei (SCN) responds predominantly to an external light (L) dark (D) cycle. Peripheral oscillators are more efficiently synchronized by metabolic cues. When the circadian system is exposed to opposing synchronizing cues, peripheral oscillators uncouple from the SCN. To consider influence of phase advances and delays in light regimens mimicking shift work, we analyzed the expression of clock genes (per2, bmal1) and natriuretic peptides (anp, bnp) in the heart of male rats. Experimental groups were exposed to a rotating LD regimen with either 8 h phase advance or delay for 11 weeks. Samples were taken for a 24 h cycle in 4 h intervals. Peripheral oscillators responded to rotating phase advance by decreasing rhythm robustness, while phase delay mostly influenced the phase angle between the acrophase of rhythmic gene expression and the external LD cycle. The expression of anp was arrhythmic in the heart of control rats and was not influenced by rotating LD regimens. The expression of bnp showed a daily rhythm with a nadir during the active phase. The daily rhythm in bnp expression diminished under rotating LD regimen conditions.

• MeSH
• cirkadiánní proteiny Period metabolismus   MeSH
• cirkadiánní rytmus * MeSH
• fotoperioda MeSH
• myokard metabolismus   MeSH
• natriuretické peptidy metabolismus   MeSH
• potkani Wistar MeSH
• transkripční faktory ARNTL metabolismus   MeSH
• zvířata MeSH
• Check Tag
• 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