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Journal of Applied Physiology... Jan 2002Many daily biological rhythms are governed by an innate timekeeping mechanism or clock. Endogenous, temperature-compensated circadian clocks have been localized to... (Review)
Review
Many daily biological rhythms are governed by an innate timekeeping mechanism or clock. Endogenous, temperature-compensated circadian clocks have been localized to discrete sites within the nervous systems of a number of organisms. In mammals, the master circadian pacemaker is the bilaterally paired suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The SCN is composed of multiple single cell oscillators that must synchronize to each other and the environmental light schedule. Other tissues, including those outside the nervous system, have also been shown to express autonomous circadian periodicities. This review examines 1) how intracellular regulatory molecules function in the oscillatory mechanism and in its entrainment to environmental cycles; 2) how individual SCN cells interact to create an integrated tissue pacemaker with coherent metabolic, electrical, and secretory rhythms; and 3) how such clock outputs are converted into temporal programs for the whole organism.
Topics: Animals; Brain; Circadian Rhythm; Humans; Nerve Net; Sleep; Suprachiasmatic Nucleus
PubMed: 11744683
DOI: 10.1152/japplphysiol.00836.2001 -
The Journal of Neuroscience : the... Apr 2011The suprachiasmatic nucleus (SCN) of the hypothalamus is the master mammalian circadian clock. The SCN is highly specialized because it is responsible for generating a...
The suprachiasmatic nucleus (SCN) of the hypothalamus is the master mammalian circadian clock. The SCN is highly specialized because it is responsible for generating a near 24 h rhythm, integrating external cues, and translating the rhythm throughout the body. Currently, our understanding of the developmental origin and genetic program involved in the proper specification and maturation of the SCN is limited. Herein, we provide a detailed analysis of transcription factor (TF) and developmental-gene expression in the SCN from neurogenesis to adulthood in mice (Mus musculus). TF expression within the postmitotic SCN was not static but rather showed specific temporal and spatial changes during prenatal and postnatal development. In addition, we found both global and regional patterns of TF expression extending into the adult. We found that the SCN is derived from a distinct region of the neuroepithelium expressing a combination of developmental genes: Six3, Six6, Fzd5, and transient Rx, allowing us to pinpoint the origin of this region within the broader developing telencephalon/diencephalon. We tested the necessity of two TFs in SCN development, RORα and Six3, which were expressed during SCN development, persisted into adulthood, and showed diurnal rhythmicity. Loss of RORα function had no effect on SCN peptide expression or localization. In marked contrast, the conditional deletion of Six3 from early neural progenitors completely eliminated the formation of the SCN. Our results provide the first description of the involvement of TFs in the specification and maturation of a neural population necessary for circadian behavior.
Topics: Animals; Animals, Newborn; Circadian Rhythm; Eye Proteins; Female; Gene Expression Regulation, Developmental; Homeodomain Proteins; Intermediate Filament Proteins; LIM-Homeodomain Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Nestin; Neuroepithelial Cells; Nuclear Receptor Subfamily 1, Group F, Member 1; RNA, Messenger; Suprachiasmatic Nucleus; Trans-Activators; Transcription Factors; Vasoactive Intestinal Peptide; Homeobox Protein SIX3
PubMed: 21525287
DOI: 10.1523/JNEUROSCI.5385-10.2011 -
Neurobiology of Learning and Memory Sep 2022The circadian system plays an important role in aligning biological processes with the external time of day. A range of physiological functions are governed by the... (Review)
Review
The circadian system plays an important role in aligning biological processes with the external time of day. A range of physiological functions are governed by the circadian cycle, including memory processes, yet little is understood about how the clock interfaces with memory at a molecular level. The molecular circadian clock consists of four key genes/gene families, Period, Clock, Cryptochrome, and Bmal1, that rhythmically cycle in an ongoing transcription-translation negative feedback loop that maintains an approximately 24-hour cycle within cells of the brain and body. In addition to their roles in generating the circadian rhythm within the brain's master pacemaker (the suprachiasmatic nucleus), recent research has suggested that these clock genes may function locally within memory-relevant brain regions to modulate memory across the day/night cycle. This review will discuss how these clock genes function both within the brain's central clock and within memory-relevant brain regions to exert circadian control over memory processes. For each core clock gene, we describe the current research that demonstrates a potential role in memory and outline how these clock genes might interface with cascades known to support long-term memory formation. Together, the research suggests that clock genes function locally within satellite clocks across the brain to exert circadian control over long-term memory formation and possibly other biological processes. Understanding how clock genes might interface with local molecular cascades in the hippocampus and other brain regions is a critical step toward developing treatments for the myriad disorders marked by dysfunction of both the circadian system and cognitive processes.
Topics: Brain; Circadian Clocks; Circadian Rhythm; Learning; Suprachiasmatic Nucleus
PubMed: 35697314
DOI: 10.1016/j.nlm.2022.107651 -
Neural Plasticity 2017Circadian rhythm disturbances are a common symptom among individuals with mood disorders. The suprachiasmatic nucleus (SCN), in the ventral part of the anterior... (Review)
Review
Circadian rhythm disturbances are a common symptom among individuals with mood disorders. The suprachiasmatic nucleus (SCN), in the ventral part of the anterior hypothalamus, orchestrates physiological and behavioral circadian rhythms. The SCN consists of self-sustaining oscillators and receives photic and nonphotic cues, which entrain the SCN to the external environment. In turn, through synaptic and hormonal mechanisms, the SCN can drive and synchronize circadian rhythms in extra-SCN brain regions and peripheral tissues. Thus, genetic or environmental perturbations of SCN rhythms could disrupt brain regions more closely related to mood regulation and cause mood disturbances. Here, we review clinical and preclinical studies that provide evidence both for and against a causal role for the SCN in mood disorders.
Topics: Animals; Circadian Rhythm; Humans; Mood Disorders; Neural Pathways; Suprachiasmatic Nucleus
PubMed: 29230328
DOI: 10.1155/2017/1504507 -
Endocrinology Dec 2007Circadian rhythms in physiology and behavior are regulated by a master clock resident in the suprachiasmatic nucleus (SCN) of the hypothalamus, and dysfunctions in the... (Review)
Review
Circadian rhythms in physiology and behavior are regulated by a master clock resident in the suprachiasmatic nucleus (SCN) of the hypothalamus, and dysfunctions in the circadian system can lead to serious health effects. This paper reviews the organization of the SCN as the brain clock, how it regulates gonadal hormone secretion, and how androgens modulate aspects of circadian behavior known to be regulated by the SCN. We show that androgen receptors are restricted to a core SCN region that receives photic input as well as afferents from arousal systems in the brain. We suggest that androgens modulate circadian behavior directly via actions on the SCN and that both androgens and estrogens modulate circadian rhythms through an indirect route, by affecting overall activity and arousal levels. Thus, this system has multiple levels of regulation; the SCN regulates circadian rhythms in gonadal hormone secretion, and hormones feed back to influence SCN functions.
Topics: Androgens; Animals; Circadian Rhythm; Estrogens; Gonadal Hormones; Mammals; Models, Biological; Neuroendocrinology; Suprachiasmatic Nucleus
PubMed: 17901227
DOI: 10.1210/en.2007-1083 -
The Journal of Neuroscience : the... Sep 2016The suprachiasmatic nucleus (SCN) is the master circadian oscillator encoding time-of-day information. SCN timekeeping is sustained by a cell-autonomous...
Combined Pharmacological and Genetic Manipulations Unlock Unprecedented Temporal Elasticity and Reveal Phase-Specific Modulation of the Molecular Circadian Clock of the Mouse Suprachiasmatic Nucleus.
UNLABELLED
The suprachiasmatic nucleus (SCN) is the master circadian oscillator encoding time-of-day information. SCN timekeeping is sustained by a cell-autonomous transcriptional-translational feedback loop, whereby expression of the Period and Cryptochrome genes is negatively regulated by their protein products. This loop in turn drives circadian oscillations in gene expression that direct SCN electrical activity and thence behavior. The robustness of SCN timekeeping is further enhanced by interneuronal, circuit-level coupling. The aim of this study was to combine pharmacological and genetic manipulations to push the SCN clockwork toward its limits and, by doing so, probe cell-autonomous and emergent, circuit-level properties. Circadian oscillation of mouse SCN organotypic slice cultures was monitored as PER2::LUC bioluminescence. SCN of three genetic backgrounds-wild-type, short-period CK1ε(Tau/Tau) mutant, and long-period Fbxl3(Afh/Afh) mutant-all responded reversibly to pharmacological manipulation with period-altering compounds: picrotoxin, PF-670462 (4-[1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinamine dihydrochloride), and KNK437 (N-Formyl-3,4-methylenedioxy-benzylidine-gamma-butyrolactam). This revealed a remarkably wide operating range of sustained periods extending across 25 h, from ≤17 h to >42 h. Moreover, this range was maintained at network and single-cell levels. Development of a new technique for formal analysis of circadian waveform, first derivative analysis (FDA), revealed internal phase patterning to the circadian oscillation at these extreme periods and differential phase sensitivity of the SCN to genetic and pharmacological manipulations. For example, FDA of the CK1ε(Tau/Tau) mutant SCN treated with the CK1ε-specific inhibitor PF-4800567 (3-[(3-Chlorophenoxy)methyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride) revealed that period acceleration in the mutant is due to inappropriately phased activity of the CK1ε isoform. In conclusion, extreme period manipulation reveals unprecedented elasticity and temporal structure of the SCN circadian oscillation.
SIGNIFICANCE STATEMENT
The master circadian clock of the suprachiasmatic nucleus (SCN) encodes time-of-day information that allows mammals to predict and thereby adapt to daily environmental cycles. Using combined genetic and pharmacological interventions, we assessed the temporal elasticity of the SCN network. Despite having evolved to generate a 24 h circadian period, we show that the molecular clock is surprisingly elastic, able to reversibly sustain coherent periods between ≤17 and >42 h at the levels of individual cells and the overall circuit. Using quantitative techniques to analyze these extreme periodicities, we reveal that the oscillator progresses as a sequence of distinct stages. These findings reveal new properties of how the SCN functions as a network and should inform biological and mathematical analyses of circadian timekeeping.
Topics: Animals; Animals, Newborn; Benzhydryl Compounds; Circadian Rhythm; Enzyme Inhibitors; Evoked Potentials; F-Box Proteins; GABA Antagonists; In Vitro Techniques; Mice; Mice, Transgenic; Organ Culture Techniques; Period Circadian Proteins; Pyrimidines; Pyrrolidinones; Sodium Channel Blockers; Suprachiasmatic Nucleus; Tetrodotoxin; Time Factors; tau Proteins
PubMed: 27605609
DOI: 10.1523/JNEUROSCI.0958-16.2016 -
Brain Research Feb 2008The suprachiasmatic nucleus (SCN) in mammals functions as the principal circadian pacemaker synchronizing diverse physiological and behavioral processes to environmental...
The suprachiasmatic nucleus (SCN) in mammals functions as the principal circadian pacemaker synchronizing diverse physiological and behavioral processes to environmental stimuli. It consists of heterogeneous populations of cells with unique spatial organization that can vary among species, but are commonly discussed within a framework of two principal regions, the ventrolateral or dorsomedial halves of the nucleus or in other instances the core and shell. In both hamsters and rats, cells of different SCN regions have been shown to have different developmental histories. Using bromodeoxyuridine as a marker of cell division, the present study investigated the time of SCN cell origin in mice (C57BL/6) and their settling patterns within the nucleus. Results show that SCN cytogenesis occurs between embryonic days 12 and 15 and is complete 5 days prior to birth. Cells born on embryonic day 12 are mainly confined to a ventrolateral region of the mid-SCN, whereas cells produced later on embryonic days 13.5 and 14.5 form a cap around the cells produced first and extend into the posterior and anterior ends of the nucleus. These results suggest an ordered spatiotemporal program of SCN cytogenesis whereby a mid-SCN core is born first followed by a surrounding shell of later-born cells. Variations in cytogenesis could affect the relative sizes of different SCN regions and, thereby, affect its function. The relative contributions of a highly ordered program of cytogenesis and intercellular interactions after postmitotic cells leave the germinal epithelium remain to be determined.
Topics: Animals; Cell Differentiation; Cell Movement; Embryonic Stem Cells; Female; Mice; Mice, Inbred C57BL; Organogenesis; Pregnancy; Suprachiasmatic Nucleus; Time Factors
PubMed: 18201688
DOI: 10.1016/j.brainres.2007.12.020 -
Reproductive Biology and Endocrinology... Jun 2016The suprachiasmatic nucleus (SCN) and the cholinergic system of various regions of the hypothalamus participate in the regulation of gonadotropin-releasing hormone...
BACKGROUND
The suprachiasmatic nucleus (SCN) and the cholinergic system of various regions of the hypothalamus participate in the regulation of gonadotropin-releasing hormone (GnRH) and gonadotropin secretion, which are necessary for the occurrence of ovulation. In the present study, our goal was to analyse the effects of unilaterally blocking the muscarinic receptors in the SCN on ovulation and steroid secretion.
METHODS
Cyclic rats were randomly allotted to one of the experimental groups. Groups of 8-14 rats were anaesthetized and microinjected with 0.3 μl of saline or a solution of atropine (62.5 ng in 0.3 μl of saline) into the left or right SCN at 09.00 or 19.00 h during diestrus-1 or on the proestrus day. The rats were euthanized on the predicted day of oestrus, and evaluated ovulation and levels of progesterone and oestradiol. Other groups of 10 rats were microinjected with atropine into the left or right SCNs at 09.00 h on the proestrus day, were euthanized eight h later, and luteinizing hormone (LH) was measured.
RESULTS
At 09.00 or 19.00 h during diestrus-1, atropine microinjections into the SCNs on either side did not modify ovulation. The atropine microinjections performed at 09.00 h of proestrus into either side of the SCN blocked ovulation (right SCN: 1/9 ovulated vs. 9/10 in the saline group; left SCN: 8/14 ovulated vs. 10/10 in the saline group). The LH levels at 17.00 h in the rats that were microinjected with atropine at 09.00 h of proestrus were lower than those of the controls. In the non-ovulating atropine-treated rats, the injection of synthetic LH-releasing hormone (LHRH) restored ovulation. Atropine treatment at 19.00 h of proestrus on either side of the SCN did not modify ovulation, while the progesterone and oestradiol levels were lower.
CONCLUSION
Based on the present results, we suggest that the cholinergic neural information arriving on either side of the SCN is necessary for the pre-ovulatory secretion of LH to induce ovulation. Additionally, the regulation of progesterone and oestradiol secretion by the cholinergic innervation of the SCN varies with the time of day, the day of the cycle, and the affected SCN.
Topics: Animals; Atropine; Female; Luteinizing Hormone; Muscarinic Antagonists; Ovary; Ovulation; Proestrus; Rats; Suprachiasmatic Nucleus
PubMed: 27306649
DOI: 10.1186/s12958-016-0168-7 -
Dialogues in Clinical Neuroscience 2007Mammalian behavior and physiology undergo daily rhythms that are coordinated by an endogenous circadian timing system. This system has a hierarchical structure, in that... (Review)
Review
Mammalian behavior and physiology undergo daily rhythms that are coordinated by an endogenous circadian timing system. This system has a hierarchical structure, in that a master pacemaker, residing in the suprachiasmatic nucleus of the ventral hypothalamus, synchronizes peripheral oscillators in virtually all body cells. While the basic molecular mechanisms generating the daily rhythms are similar in all cells, most clock outputs are cell-specific. This conclusion is based on genome-wide transcriptome profiling studies in several tissues that have revealed hundreds of rhythmically expressed genes. Cyclic gene expression in the various organs governs overt rhythms in behavior and physiology, encompassing sleep-wake cycles, metabolism, xenobiotic detoxification, and cellular proliferation. As a consequence, chronic perturbation of this temporal organization may lead to increased morbidity and reduced lifespan.
Topics: Animals; Cell Proliferation; Circadian Rhythm; Gene Expression Regulation; Humans; Mammals; Metabolic Networks and Pathways; Suprachiasmatic Nucleus
PubMed: 17969863
DOI: 10.31887/DCNS.2007.9.3/uschibler -
Journal of Biological Rhythms Feb 2018Modern imaging techniques allow the monitoring of circadian rhythms of single cells. Coupling between these single cellular circadian oscillators can generate coherent...
Modern imaging techniques allow the monitoring of circadian rhythms of single cells. Coupling between these single cellular circadian oscillators can generate coherent periodic signals on the tissue level that subsequently orchestrate physiological outputs. The strength of coupling in such systems of oscillators is often unclear. In particular, effects on coupling strength by varying cell densities, by knockouts, and by inhibitor applications are debated. In this study, we suggest to quantify the relative coupling strength via analyzing period, phase, and amplitude distributions in ensembles of individual circadian oscillators. Simulations of different oscillator networks show that period and phase distributions become narrower with increasing coupling strength. Moreover, amplitudes can increase due to resonance effects. Variances of periods and phases decay monotonically with coupling strength, and can serve therefore as measures of relative coupling strength. Our theoretical predictions are confirmed by studying recently published experimental data from PERIOD2 expression in slices of the suprachiasmatic nucleus during and after the application of tetrodotoxin (TTX). On analyzing the corresponding period, phase, and amplitude distributions, we can show that treatment with TTX can be associated with a reduced coupling strength in the system of coupled oscillators. Analysis of an oscillator network derived directly from the data confirms our conclusions. We suggest that our approach is also applicable to quantify coupling in fibroblast cultures and hepatocyte networks, and for social synchronization of circadian rhythmicity in rodents, flies, and bees.
Topics: Animals; Biological Clocks; Circadian Rhythm; Period Circadian Proteins; Suprachiasmatic Nucleus; Tetrodotoxin
PubMed: 29219034
DOI: 10.1177/0748730417740467