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Aims: Circadian clocks in the hippocampus (HPC) align memory processing with appropriate time of day. Our study was aimed at ascertaining the specificity of glycogen synthase kinase 3-beta (GSK3β)- and glucocorticoid (GC)-dependent pathways in the entrainment of clocks in individual HPC regions, CA1-3, and dentate gyrus (DG). Methods: The role of GCs was addressed in vivo by comparing the effects of adrenalectomy (ADX) and subsequent dexamethasone (DEX) supplementation on clock gene expression profiles (Per1, Per2, Nr1d1, and Bmal1). In vitro the effects of DEX and the GSK3β inhibitor, CHIR-99021, were assessed from recordings of bioluminescence rhythms in HPC organotypic explants of mPER2Luc mice. Results: Circadian rhythms of clock gene expression in all HPC regions were abolished by ADX, and DEX injections to the rats rescued those rhythms in DG. The DEX treatment of the HPC explants significantly lengthened periods of the bioluminescence rhythms in all HPC regions with the most significant effect in DG. In contrast to DEX, CHIR-99021 significantly shortened the period of bioluminescence rhythm. Again, the effect was most significant in DG which lacks the endogenously inactivated (phosphorylated) form of GSK3β. Co-treatment of the explants with CHIR-99021 and DEX produced the CHIR-99021 response. Therefore, the GSK3β-mediated pathway had dominant effect on the clocks. Conclusion: GSK3β- and GC-dependent pathways entrain the clock in individual HPC regions by modulating their periods in an opposite manner. The results provide novel insights into the mechanisms connecting the arousal state-relevant signals with temporal control of HPC-dependent memory and cognitive functions.

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 mPer2

Acetylcholine is an important modulator of striatal activity, and it is vital to controlling striatal-dependent behaviors, including motor and cognitive functions. Despite this significance, the mechanisms determining how acetylcholine impacts striatal signaling are still not fully understood. In particular, little is known about the role of nAChRs expressed by striatal interneurons. In the present study, we used FISH to determine which neuronal types express the most prevalent beta2 nicotinic subunit in the mouse striatum. Our data support a common view that nAChR expression is mostly restricted to striatal interneurons. Surprisingly though, cholinergic interneurons were identified as a population with the highest expression of beta2 nicotinic subunit. To investigate the functional significance of beta2-containing nAChRs in striatal interneurons, we deleted them by injecting the AAV-Cre vector into the striatum ofbeta2-flox/floxmale mice. The deletion led to alterations in several behavioral domains, namely, to an increased anxiety-like behavior, decrease in sociability ratio, deficit in discrimination learning, and increased amphetamine-induced hyperlocomotion and c-Fos expression in mice with beta2 deletion. Further colocalization analysis showed that the increased c-Fos expression was present in both medium spiny neurons and presumed striatal interneurons. The present study concludes that, despite being relatively rare, beta2-containing nAChRs are primarily expressed in striatal neurons by cholinergic interneurons and play a significant role in behavior.SIGNIFICANCE STATEMENTA large variety of nAChRs are expressed in the striatum, a brain region that is crucial in the control of behavior. The complexity of receptors with different functions is hindering our understanding of mechanisms through which striatal acetylcholine modulates behavior. We focused on the role of a small population of beta2-containing nAChRs. We identified neuronal types expressing these receptors and determined their impact in the control of explorative behavior, anxiety-like behavior, learning, and sensitivity to stimulants. Additional experiments showed that these alterations were associated with an overall increased activity of striatal neurons. Thus, the small population of nicotinic receptors represents an interesting target for a modulation of response to stimulant drugs and other striatal-based behavior.

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a down-regulation (models of Angelman syndrome) vs. Ube3a up-regulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. In contrast to previous reports, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei, the pacemaking circadian brain locus. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.

The suprachiasmatic nuclei (SCN) of the hypothalamus harbor the central clock of the circadian system, which gradually matures during the perinatal period. In this study, time-resolved transcriptomic and proteomic approaches were used to describe fetal SCN tissue-level rhythms before rhythms in clock gene expression develop. Pregnant rats were maintained in constant darkness and had intact SCN, or their SCN were lesioned and behavioral rhythm was imposed by temporal restriction of food availability. Model-selecting tools dryR and CompareRhythms identified sets of genes in the fetal SCN that were rhythmic in the absence of the fetal canonical clock. Subsets of rhythmically expressed genes were assigned to groups of fetuses from mothers with either intact or lesioned SCN, or both groups. Enrichment analysis for GO terms and signaling pathways revealed that neurodevelopment and cell-to-cell signaling were significantly enriched within the subsets of genes that were rhythmic in response to distinct maternal signals. The findings discovered a previously unexpected breadth of rhythmicity in the fetal SCN at a developmental stage when the canonical clock has not yet developed at the tissue level and thus likely represents responses to rhythmic maternal signals.

Modification of the Per2 clock gene in mPer2Luc reporter mice significantly alters circadian function. Behavioral period in constant dark is lengthened, and dissociates into two distinct components in constant light. Rhythms exhibit increased bimodality, enhanced phase resetting to light pulses, and altered entrainment to scheduled feeding. Mechanistic mathematical modelling predicts that enhanced protein interactions with the modified mPER2 C-terminus, combined with differential clock regulation among SCN subregions, can account for effects on circadian behavior via increased Per2 transcript and protein stability. PER2::LUC produces greater suppression of CLOCK:BMAL1 E-box activity than PER2. mPer2Luc carries a 72 bp deletion in exon 23 of Per2, and retains a neomycin resistance cassette that affects rhythm amplitude but not period. The results show that mPer2Luc acts as a circadian clock mutation illustrating a need for detailed assessment of potential impacts of c-terminal tags in genetically modified animal models., Author summary Engineered genes that are modified to express bioluminescent signals can be used to monitor cellular processes by reflecting the actual state of the process in real time. For circadian rhythm studies, a widely used reporter model (mPer2Luc) expresses firefly luciferase under the control of the clock gene Period 2 (Per2), encoding a fusion protein (PER2::LUCIFERASE) which produces rhythms of bioluminescence. We present evidence that the engineered protein produces extensive changes in iconic circadian behavioral patterns in mice. The evidence comes from analysis of long-term recordings of circadian behavior in mPer2Luc mice in constant darkness and constant light, together with responsiveness to light pulses and entrainment to restricted food availability. By integrating a well-established mathematical model of circadian rhythm generation in the suprachiasmatic nuclei with the known functional heterogeneity within the nucleus, we recapitulated the observed locomotor behavioral patterns in WT and mPer2Luc mice. Functional alterations to the stability of PER2 protein predicted from the model were substantiated by increased repression strength of PER2::LUC over WT PER2 on CLOCK:BMAL1 transcriptional activation. Therefore, mPer2Luc is a clock mutation that provides new insights into the functional neuroanatomy of the mammalian circadian system and the critical importance of Per2 regulation in rhythm generation.

Suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock that drives circadian rhythms in physiology and behavior and adjusts their timing to external cues. Neurotransmitter glutamate and glutamatergic receptors sensitive to N-methyl- d -aspartate (NMDA) play a dual role in the SCN by coupling astrocytic and neuronal single cell oscillators and by resetting their phase in response to light. Recent reports suggested that signaling by endogenous cannabinoids (ECs) participates in both of these functions. We have previously shown that ECs, such as 2-arachidonoylglycerol (2-AG), act via CB1 receptors to affect the SCN response to light-mimicking NMDA stimulus in a time-dependent manner. We hypothesized that this ability is linked to the circadian regulation of EC signaling. We demonstrate that circadian clock in the rat SCN regulates expression of 2-AG transport, synthesis and degradation enzymes as well as its receptors. Inhibition of the major 2-AG synthesis enzyme, diacylglycerol lipase, enhanced the phase delay and lowered the amplitude of explanted SCN rhythm in response to NMDAR activation. Using microscopic PER2 bioluminescence imaging, we visualized how individual single cell oscillators in different parts of the SCN respond to the DAGL inhibition/NMDAR activation and shape response of the whole pacemaker. Additionally, we present strong evidence that the zero amplitude behavior of the SCN in response to single NMDA stimulus in the middle of subjective night is the result of a loss of rhythm in individual SCN cells. The paper provides new insights into the modulatory role of endocannabinoid signaling during the light entrainment of the SCN.

During fetal stage, maternal circadian system sets the phase of the developing clock in the suprachiasmatic nuclei (SCN) via complex pathways. We addressed the issue of how impaired maternal signaling due to a disturbed environmental light/dark (LD) cycle affects the fetal SCN. We exposed pregnant Wistar rats to two different challenges – a 6-h phase shift in the LD cycle on gestational day 14, or exposure to constant light (LL) throughout pregnancy – and detected the impact on gene expression profiles in 19-day-old fetuses. The LD phase shift, which changed the maternal SCN into a transient state, caused robust downregulation of expression profiles of clock genes (Per1, Per2, and Nr1d1), clock-controlled (Dbp) genes, as well as genes involved in sensing various signals, such as c-fos and Nr3c1. Removal of the rhythmic maternal signals via exposure of pregnant rats to LL abolished the rhythms in expression of c-fos and Nr3c1 in the fetal SCN. We identified c-fos as the gene primarily responsible for sensing rhythmic maternal signals because its expression profile tracked the shifted or arrhythmic maternal SCN clock. Pathways related to the maternal rhythmic behavioral state were likely not involved in driving the c-fos expression rhythm. Instead, introduction of a behavioral rhythm to LL-exposed mothers via restricted feeding regime strengthened rhythm in Vip expression in the fetal SCN. Our results revealed for the first time that the fetal SCN is highly sensitive in a gene-specific manner to various changes in maternal signaling due to disturbances of environmental cycles related to the modern lifestyle in humans.

Exposure to environmental conditions that disturb the daily rhythms has been shown to enhance the proinflammatory responses of immunostimulant-challenged immune system. However, it is not known whether circadian disturbances may stimulate unchallenged immune responses and thus contribute per se to the development of inflammation-related diseases. Our aim was to ascertain an effect of various conditions threatening the behavioral activity/rest cycle regulation, namely aging with or without melatonin, 6 h advance/delay phase shifts in the light/dark cycle repeated with a 2-day frequency and constant light, on expression of immune markers in the rat colon. The impact of these conditions on parameters of behavioral activity and mRNA levels of selected immune markers in the colonic mucosa of Wistar rats, namely TNFα (Tnf), IL1a (Il1a), IL17RA (Il17ra), STAT3 (Stat3) and Rgs16 (Rsg16), were detected. Our results demonstrate that aging with or without melatonin as well as repeated 6 h advance/delay phase shifts in the light/dark cycle, which increased inactivity as a correlate of sleep during the dark phase of the light/dark cycle (i.e. during the active phase for nocturnal animals), had a minor effect on immune state in the colonic mucosa; all these conditions caused downregulation of gene Rgs16 which is involved in attenuation of the inflammatory response in the colon but did not affect expression of the other immune markers. Interestingly, a long-term absence of melatonin facilitated the aging-induced effect on immune state in the colon. In contrast, exposure to constant light, which perturbed the interval of inactivity (sleep) and led to the complete abolishment of activity/inactivity cycles, activated robustly proinflammatory state in the colon selectively via Stat3-dependent pathway. In spite all these experimental conditions (aging with or without melatonin, shifts in light/dark cycles, constant light) perturbed the activity/rest cycles, none of them induced sleep deprivation. These results provided the first evidence that disruptions in the behavioral activity/inactivity cycles may spontaneously (without immuno-stimulant) induce selective proinflammatory responses in the colonic mucosa. Such effects may take part in the mechanisms of modern lifestyle-induced inflammatory diseases of the gut.B2M: β2-microglobulin; DSS: dextran sodium sulfate; Gapdh: glyceraldehyde-3-phosphate dehydrogenase; Ifng: interferon g; Il1a: interleukin 1a; Il1b: interleukin 1b; Il2: interleukin 2; Il6: interleukin 6; Il17ra: interleukin 17 receptor a; LD: light/dark cycle; LL: constant light; LPS: lipopolysaccharide; Mntr1a: melatonin receptor 1a; PINX: pinealectomy; Rgs16: regulator of G protein signaling 16; RT qPCR: quantitative reverse transcription polymerase chain reaction; Stat3: signal transducer and activator of transcription 3; Th17: type 17 T helper cells; Tnfα: tumor necrosis factor α; Tnfrsf1b: tumor necrosis factor receptor superfamily member 1b.

Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS.

The adult circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is resilient to glucocorticoids (GCs). The fetal rodent SCN resembles that of the adult in its organization of GC-sensitive peripheral tissues. We tested the hypothesis that the fetal SCN clock is sensitive to changes in GC levels. Maternal GCs must pass through the placenta to reach the fetal SCN. We show that the maternal but not the fetal part of the placenta harbors the autonomous circadian clock, which is reset by dexamethasone (DEX) and rhythmically expresses Hsd11b2. The results suggest the presence of a mechanism for rhythmic GC passage through the placental barrier, which is adjusted according to actual GC levels. GC receptors are expressed rhythmically in the laser-dissected fetal SCN samples. We demonstrate that hypothalamic explants containing the SCN of the mPer2Lucmouse prepared at embryonic day (E)15 spontaneously develop rhythmicity within several days of culture, with dynamics varying among fetuses from the same litter. Culturing these explants in media enriched with DEX accelerates the development. At E17, treatment of the explants with DEX induces phase advances and phase delays of the rhythms depending on the timing of treatments, and the shifts are completely blocked by the GC receptor antagonist, mifepristone. The DEX-induced phase-response curve differs from that induced by the vehicle. The fetal SCN is sensitive to GCs in vivo because DEX administration to pregnant rats acutely downregulates c-fos expression specifically in the laser-dissected fetal SCN. Our results provide evidence that the rodent fetal SCN clock may respond to changes in GC levels.

Colonic function is controlled by an endogenous clock that allows the colon to optimize its function on the daytime basis. For the first time, this study provided evidence that the clock is synchronized by rhythmic hormonal signals. In rat colon, adrenalectomy decreased and repeated applications of dexamethasone selectively rescued circadian rhythm in the expression of the clock gene Per1. Dexamethasone entrained the colonic clock in explants from mPer2Luc mice in vitro. In contrast, pinealectomy had no effect on the rat colonic clock, and repeated melatonin injections were not able to rescue the clock in animals maintained in constant light. Additionally, melatonin did not entrain the clock in colonic explants from mPer2Luc mice in vitro. However, melatonin affected rhythmic regulation of Nr1d1 gene expression in vivo. The findings provide novel insight into possible beneficial effects of glucocorticoids in the treatment of digestive tract-related diseases, greatly exceeding their anti-inflammato...

The role of melatonin in maintaining proper function of the circadian system has been proposed but very little evidence for such an effect has been provided. To ascertain the role, the aim of the study was to investigate impact of long-term melatonin absence on regulation of circadian system. The parameters of behavior and circadian clocks of rats which were devoid of the melatonin signal due to pinealectomy (PINX) for more than one year were compared with those of intact age-matched controls. PINX led to a decrease in spontaneous locomotor activity and a shortening of the free-running period of the activity rhythm driven by the central clock in the suprachiasmatic nuclei (SCN) in constant darkness. However, the SCN-driven rhythms in activity and feeding were not affected and remained well entrained in the light/dark cycle. In contrast, in these conditions PINX had a significant effect on amplitudes of the clock gene expression rhythms in the duodenum and also partially in the liver. These results demonstrate the significant impact of long-term melatonin absence on period of the central clock in the SCN and the amplitudes of the peripheral clocks in duodenum and liver and suggest that melatonin might be a redundant but effective endocrine signal for these clocks.

Animals create implicit memories of the time of day that significant events occur then anticipate the recurrence of those conditions at the same time on subsequent days. We tested the hypothesis that implicit time memory for daily encounters relies on the setting of the canonical circadian clockwork in brain areas involved in the formation or expression of context memories. We conditioned mice to avoid locations paired with a mild foot shock at one of two Zeitgeber times set 8 hours apart. Place avoidance was exhibited only when testing time matched the prior training time. The suprachiasmatic nucleus, dorsal striatum, nucleus accumbens, cingulate cortex, hippocampal complex, and amygdala were assessed for clock gene expression. Baseline phase dependent differences in clock gene expression were found in most tissues. Evidence for conditioned resetting of a molecular circadian oscillation was found only in the striatum (dorsal striatum and nucleus accumbens shell), and specifically for Per2 expression. There was no evidence of glucocorticoid stress response in any tissue. The results are consistent with a model where temporal conditioning promotes a selective Per2 response in dopamine-targeted brain regions responsible for sensorimotor integration, without resetting the entire circadian clockwork.

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.

Circadian clocks coordinate physiological and behavioral rhythms that allow the organism to anticipate and adapt to daily changes in environment. The clock-driven cellular oscillations are highly tissue specific to efficiently fine-tune local signaling, manage energy use and segregate incompatible processes. In most peripheral tissues, food acts as the main cue that entrains the oscillations to external time. Food intake and energy balance are under control of endocannabinoid (EC) signaling. Despite this obvious link between the circadian and EC systems, evidence for their interaction started to emerge only recently. We used targeted lipidomics to analyze circadian variations in EC tone in rat plasma, liver and adrenal tissue. The results provide the evidence that ECs, monoacylglycerols, N-acylethanolamines and their precursors oscillate with a tissue-specific circadian phase in plasma and liver. We then identified a set of rhythmically expressed genes likely responsible for the variations in EC tissue tone. In contrast to the liver, EC levels did not oscillate in the adrenal glands. Instead, we revealed that local EC receptor genes are under circadian regulation. To explore the impact of metabolic signals on expression of these genes, we used daytime-restricted feeding schedule. We subsequently showed that daytime feeding strongly suppressed liver-expressed fatty acid binding protein 5 (Fabp5) and adrenal-expressed non-canonical endocannabinoid receptors Gpr55 and Trpv1, whereas it upregulated liver-expressed Trpv1 and glycerophosphodiester phosphodiesterase 1 (Gde1). Our results reveal tissue-specific mechanisms involved in interaction between endocannabinoid signaling, circadian system and metabolism.

The mammalian suprachiasmatic nuclei (SCN) and their intrinsic rhythmicity develop gradually during ontogenesis. In the rat, the SCN forms between embryonic day (E) 14 and E17, with gestation terminating at E21–22. Overt SCN rhythmicity is already present in the late embryonic stage. The aim of the present study was to determine when the fetal SCN clock develops in vivo and whether overt rhythmicity results from a functional fetal clock. To achieve this goal, the prenatal development of rhythmic expression of clock genes was measured with a more sensitive method for detection of the clock gene expression than previously. Fetal SCN were collected at 3 h intervals during the 24 h period on E19 and E21 by laser dissection and expression of clock genes (Per2, Nr1d1 and Bmal1) and genes related to cellular activity (c-fos, Avp and Vip) was measured by qRT PCR. At E19, the expression of canonical clock genes Per2 and Bmal1 was not rhythmic; however, the expression of all other studied genes followed clear circadian rhythms. At E21, Per2 and Bmal1 expression exhibited low amplitude but significant rhythmicity. From E19 to E21, the levels of the non-rhythmic transcripts (Per2 and Bmal1) decreased; however, the levels of the rhythmic transcripts (Nr1d1, c-fos, Avp and Vip) increased. In summary, these data demonstrate that at E19, rhythms in Per2 and Bmal1 expression were absent in the fetal SCN; however, the expression of Nr1d1 and other genes related to cellular activity was driven rhythmically. Therefore, at the early stage in vivo, the developing fetal SCN clock could theoretically be entrained by oscillation of Nr1d1 which may be driven by the maternal rather than fetal circadian system.

In mammals, the circadian system is composed of the central clock in the hypothalamic suprachiasmatic nuclei and of peripheral clocks that are located in other neural structures and in cells of the peripheral tissues and organs. In adults, the system is hierarchically organized so that the central clock provides the other clocks in the body with information about the time of day. This information is needed for the adaptation of their functions to cyclically changing external conditions. During ontogenesis, the system undergoes substantial development and its sensitivity to external signals changes. Perinatally, maternal cues are responsible for setting the phase of the developing clock, while later postnatally, the LD cycle is dominant. The central clock attains its functional properties during a gradual and programmed process. Peripheral clocks begin to exhibit rhythmicity independent of each other at various developmental stages. During the early developmental stages, the peripheral clocks are set or driven by maternal feeding, but later the central clock becomes fully functional and begins to entrain the periphery. During the perinatal period, the central and peripheral clocks seem to be vulnerable to disturbances in external conditions. Further studies are needed to understand the processes of how the circadian system develops and what degree of plasticity and resilience it possesses during ontogenesis. These data may lead to an assessment of the contribution of disturbances of the circadian system during early ontogenesis to the occurrence of circadian diseases in adulthood.

In mammals, the circadian system is composed of the central clock in the hypothalamic suprachiasmatic nuclei and of peripheral clocks that are located in other neural structures and in cells of the peripheral tissues and organs. In adults, the system is hierarchically organized so that the central clock provides the other clocks in the body with information about the time of day. This information is needed for the adaptation of their functions to cyclically changing external conditions. During ontogenesis, the system undergoes substantial development and its sensitivity to external signals changes. Perinatally, maternal cues are responsible for setting the phase of the developing clock, while later postnatally, the LD cycle is dominant. The central clock attains its functional properties during a gradual and programmed process. Peripheral clocks begin to exhibit rhythmicity independent of each other at various developmental stages. During the early developmental stages, the peripheral clocks are set or driven by maternal feeding, but later the central clock becomes fully functional and begins to entrain the periphery. During the perinatal period, the central and peripheral clocks seem to be vulnerable to disturbances in external conditions. Further studies are needed to understand the processes of how the circadian system develops and what degree of plasticity and resilience it possesses during ontogenesis. These data may lead to an assessment of the contribution of disturbances of the circadian system during early ontogenesis to the occurrence of circadian diseases in adulthood.